Susan J. Rehm, MD, FACP, FIDSA

Streptococcus pneumoniae (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1)^2,3; about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^{3, 14}

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak. (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

Information from reference 16.

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

Streptococcus pneumoniae (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1)^2,3; about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^{3, 14}

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak. (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

Information from reference 16.

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

Streptococcus pneumoniae (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1)^2,3; about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^{3, 14}

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak. (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

Information from reference 16.

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

Physicians who have been involved in malpractice actions are all too familiar with the range of emotions they experience during the process. Anxiety, fear, frustration, remorse, self-doubt, shame, betrayal, anger…no pleasant feelings here. Add malpractice stress to the high level of pressure experienced at home and at work, and crisis looms.

In his commentary in this issue, Kevin Giordano states, “it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team toward disconnection.”¹

See related commentary

Because of the nature of our work as physicians, we are isolated, and malpractice isolates us further. Because of embarrassment, we avoid talking with our colleagues and managers. Legal counsel reminds us to correspond with no one about the details of the case. Spouses and friends may offer support, but it is difficult— perhaps impossible—to be reassured.

Isolation fuels our self-doubt and erodes our confidence, leading us to focus on what may go wrong, rather than on healing. Every decision is fraught with anxiety, and efficiency evaporates. Paralysis may set in, leading to disengagement from patient care and increasing the chance of further problems. 

IT TAKES RESILIENCE TO THRIVE

It takes resilience to thrive in today’s pressure-cooker healthcare environment, let alone in the setting of malpractice stress. Resilient people are able to face reality and see a better future, put things into perspective, and bounce back from adversity.² Resilience, a trait that protects against stress and burnout, is relevant at the personal, managerial, and system levels. Though this definition is not specific to caregiver or malpractice stress, it is applicable. It is an essential component of wellness and requires perpetual attention to self-care for successful maintenance.

Resilient people can face reality, see a better future, put things into perspective, and bounce back from adversity

Studies of physicians who have avoided burnout reveal remarkably consistent qualities, including finding gratification related to work, maintaining useful habits and practices, and developing attitudes that keep them resilient.³ Rather than adding activities to their full schedules, these physicians stayed resilient through mindfulness of various aspects of their daily lives. Interactions with colleagues—discussing cases, treatments, and outcomes (including errors)—proved vital. Professional development, encompassing activities such as continuing education, coaching, mentoring, and counseling, was recognized as an important self-directed resilience measure. Maintenance of relationships with family and friends, cultivation of leisure-time activities, and appreciation of the need for personal reflection time were traits often found in resilient physicians.

FOSTERING RESILIENCE

As part of the Mayo Clinic’s biannual survey of its physicians, Shanafelt et al⁴ studied relationships between qualities of physician leaders and burnout and satisfaction among the physicians they supervised. Many of the desirable leadership traits were related to building relationships through respectful communication, along with provision of opportunities for personal and professional development. The acknowledgment that resilient, healthy physicians are satisfied, productive, and able to provide safer and higher-quality patient care should lead to the establishment of physician wellness as a “dashboard metric.” This makes priorities clear by rewarding managers who foster self-care and resilience among their staff.

Likewise, at the healthcare system level, Beckman⁵ recognized that organizations can provide opportunities to promote resilience among caregivers. Organizational initiatives that set the stage for resilience include:

• Curricula to enhance communication with patients, coworkers, and family
• “Best practices” for efficient and effective patient care
• Self-care through health insurance incentives and educational sessions
• Accessible, affordable, and confidential behavioral health support
• Time for self-care activities during the workday
• Coaching and mentoring programs
• Narrative-and-reflection groups and mindfulness training.⁵

Through an atmosphere of support for resilience, organizations provide a place for physicians to maintain a sense of meaning and purpose in their work. For individuals facing malpractice action, this infrastructure can be used to weather the storm. As Mr. Giordano writes, staying engaged “may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.”¹ We must pay attention to developing individual physicians, educating managers, and building systems so that caregivers can remain engaged and resilient. It may help those affected by malpractice stress, and perhaps as importantly, it may reduce the chance of future “disconnection” leading to recourse in the legal system.

Physicians who have been involved in malpractice actions are all too familiar with the range of emotions they experience during the process. Anxiety, fear, frustration, remorse, self-doubt, shame, betrayal, anger…no pleasant feelings here. Add malpractice stress to the high level of pressure experienced at home and at work, and crisis looms.

In his commentary in this issue, Kevin Giordano states, “it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team toward disconnection.”¹

See related commentary

Because of the nature of our work as physicians, we are isolated, and malpractice isolates us further. Because of embarrassment, we avoid talking with our colleagues and managers. Legal counsel reminds us to correspond with no one about the details of the case. Spouses and friends may offer support, but it is difficult— perhaps impossible—to be reassured.

Isolation fuels our self-doubt and erodes our confidence, leading us to focus on what may go wrong, rather than on healing. Every decision is fraught with anxiety, and efficiency evaporates. Paralysis may set in, leading to disengagement from patient care and increasing the chance of further problems. 

IT TAKES RESILIENCE TO THRIVE

It takes resilience to thrive in today’s pressure-cooker healthcare environment, let alone in the setting of malpractice stress. Resilient people are able to face reality and see a better future, put things into perspective, and bounce back from adversity.² Resilience, a trait that protects against stress and burnout, is relevant at the personal, managerial, and system levels. Though this definition is not specific to caregiver or malpractice stress, it is applicable. It is an essential component of wellness and requires perpetual attention to self-care for successful maintenance.

Resilient people can face reality, see a better future, put things into perspective, and bounce back from adversity

Studies of physicians who have avoided burnout reveal remarkably consistent qualities, including finding gratification related to work, maintaining useful habits and practices, and developing attitudes that keep them resilient.³ Rather than adding activities to their full schedules, these physicians stayed resilient through mindfulness of various aspects of their daily lives. Interactions with colleagues—discussing cases, treatments, and outcomes (including errors)—proved vital. Professional development, encompassing activities such as continuing education, coaching, mentoring, and counseling, was recognized as an important self-directed resilience measure. Maintenance of relationships with family and friends, cultivation of leisure-time activities, and appreciation of the need for personal reflection time were traits often found in resilient physicians.

FOSTERING RESILIENCE

As part of the Mayo Clinic’s biannual survey of its physicians, Shanafelt et al⁴ studied relationships between qualities of physician leaders and burnout and satisfaction among the physicians they supervised. Many of the desirable leadership traits were related to building relationships through respectful communication, along with provision of opportunities for personal and professional development. The acknowledgment that resilient, healthy physicians are satisfied, productive, and able to provide safer and higher-quality patient care should lead to the establishment of physician wellness as a “dashboard metric.” This makes priorities clear by rewarding managers who foster self-care and resilience among their staff.

Likewise, at the healthcare system level, Beckman⁵ recognized that organizations can provide opportunities to promote resilience among caregivers. Organizational initiatives that set the stage for resilience include:

• Curricula to enhance communication with patients, coworkers, and family
• “Best practices” for efficient and effective patient care
• Self-care through health insurance incentives and educational sessions
• Accessible, affordable, and confidential behavioral health support
• Time for self-care activities during the workday
• Coaching and mentoring programs
• Narrative-and-reflection groups and mindfulness training.⁵

Through an atmosphere of support for resilience, organizations provide a place for physicians to maintain a sense of meaning and purpose in their work. For individuals facing malpractice action, this infrastructure can be used to weather the storm. As Mr. Giordano writes, staying engaged “may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.”¹ We must pay attention to developing individual physicians, educating managers, and building systems so that caregivers can remain engaged and resilient. It may help those affected by malpractice stress, and perhaps as importantly, it may reduce the chance of future “disconnection” leading to recourse in the legal system.

Physicians who have been involved in malpractice actions are all too familiar with the range of emotions they experience during the process. Anxiety, fear, frustration, remorse, self-doubt, shame, betrayal, anger…no pleasant feelings here. Add malpractice stress to the high level of pressure experienced at home and at work, and crisis looms.

In his commentary in this issue, Kevin Giordano states, “it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team toward disconnection.”¹

See related commentary

Because of the nature of our work as physicians, we are isolated, and malpractice isolates us further. Because of embarrassment, we avoid talking with our colleagues and managers. Legal counsel reminds us to correspond with no one about the details of the case. Spouses and friends may offer support, but it is difficult— perhaps impossible—to be reassured.

Isolation fuels our self-doubt and erodes our confidence, leading us to focus on what may go wrong, rather than on healing. Every decision is fraught with anxiety, and efficiency evaporates. Paralysis may set in, leading to disengagement from patient care and increasing the chance of further problems. 

IT TAKES RESILIENCE TO THRIVE

It takes resilience to thrive in today’s pressure-cooker healthcare environment, let alone in the setting of malpractice stress. Resilient people are able to face reality and see a better future, put things into perspective, and bounce back from adversity.² Resilience, a trait that protects against stress and burnout, is relevant at the personal, managerial, and system levels. Though this definition is not specific to caregiver or malpractice stress, it is applicable. It is an essential component of wellness and requires perpetual attention to self-care for successful maintenance.

Resilient people can face reality, see a better future, put things into perspective, and bounce back from adversity

Studies of physicians who have avoided burnout reveal remarkably consistent qualities, including finding gratification related to work, maintaining useful habits and practices, and developing attitudes that keep them resilient.³ Rather than adding activities to their full schedules, these physicians stayed resilient through mindfulness of various aspects of their daily lives. Interactions with colleagues—discussing cases, treatments, and outcomes (including errors)—proved vital. Professional development, encompassing activities such as continuing education, coaching, mentoring, and counseling, was recognized as an important self-directed resilience measure. Maintenance of relationships with family and friends, cultivation of leisure-time activities, and appreciation of the need for personal reflection time were traits often found in resilient physicians.

FOSTERING RESILIENCE

As part of the Mayo Clinic’s biannual survey of its physicians, Shanafelt et al⁴ studied relationships between qualities of physician leaders and burnout and satisfaction among the physicians they supervised. Many of the desirable leadership traits were related to building relationships through respectful communication, along with provision of opportunities for personal and professional development. The acknowledgment that resilient, healthy physicians are satisfied, productive, and able to provide safer and higher-quality patient care should lead to the establishment of physician wellness as a “dashboard metric.” This makes priorities clear by rewarding managers who foster self-care and resilience among their staff.

Likewise, at the healthcare system level, Beckman⁵ recognized that organizations can provide opportunities to promote resilience among caregivers. Organizational initiatives that set the stage for resilience include:

• Curricula to enhance communication with patients, coworkers, and family
• “Best practices” for efficient and effective patient care
• Self-care through health insurance incentives and educational sessions
• Accessible, affordable, and confidential behavioral health support
• Time for self-care activities during the workday
• Coaching and mentoring programs
• Narrative-and-reflection groups and mindfulness training.⁵

Through an atmosphere of support for resilience, organizations provide a place for physicians to maintain a sense of meaning and purpose in their work. For individuals facing malpractice action, this infrastructure can be used to weather the storm. As Mr. Giordano writes, staying engaged “may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.”¹ We must pay attention to developing individual physicians, educating managers, and building systems so that caregivers can remain engaged and resilient. It may help those affected by malpractice stress, and perhaps as importantly, it may reduce the chance of future “disconnection” leading to recourse in the legal system.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵