Pharmacology

A simple, fast screening questionnaire for substance use could have several benefits, say researchers from New York University and Boston Medical Center, such as streamlining workflow for primary care practitioners and staff and affording patients the privacy to report possibly stigmatizing behavior.

Related: Veterans' Use of Designer Cathinones and Cannabinoids

But there wasn’t such a tool, so the researchers developed the Substance Use Brief Screen (SUBS). They based it on the National Institute on Drug Abuse Quick Screen V1.0, which has not yet been validated. Then they tested their screen for reliability in 54 primary care patients and conducted another study to validate it in 586 more.

The questionnaire has 4 questions: In the past 12 months, how many days did you use tobacco; have 4 or more alcoholic drinks in a day; use illegal drug(s); or use prescription medication(s) “recreationally”?

Related: Tracking Tramadol-Related ED Visits

The SUBS had high sensitivity and moderate-to-high specificity for detecting unhealthy use of tobacco, alcohol, and other drugs. Sensitivity was lower for prescription drugs alone but increased when they were combined into a single “any drug” category. The researchers say this may reflect drug users’ lack of clarity about what constitutes illicit vs prescription drug misuse.

Related: Living Tobacco Free

The test was well accepted among a diverse patient population (although 11% in the reliability study needed some help with questions or technical assistance) and easily used on a tablet computer. It compared favorably with other widely recommended brief substance use screening tools—all of which are interviewer administered, the researchers point out. They add that a self-administered tool may put patients at greater ease about reporting substance use and thus be more consistently accurate in real-world practice.

Source
McNeely J, Strauss SM, Saitz R, et al. Am J Med. 2015;128(7):784.e9-784.e19.
doi: 10.1016/j.amjmed.2015.02.007.

A simple, fast screening questionnaire for substance use could have several benefits, say researchers from New York University and Boston Medical Center, such as streamlining workflow for primary care practitioners and staff and affording patients the privacy to report possibly stigmatizing behavior.

Related: Veterans' Use of Designer Cathinones and Cannabinoids

But there wasn’t such a tool, so the researchers developed the Substance Use Brief Screen (SUBS). They based it on the National Institute on Drug Abuse Quick Screen V1.0, which has not yet been validated. Then they tested their screen for reliability in 54 primary care patients and conducted another study to validate it in 586 more.

The questionnaire has 4 questions: In the past 12 months, how many days did you use tobacco; have 4 or more alcoholic drinks in a day; use illegal drug(s); or use prescription medication(s) “recreationally”?

Related: Tracking Tramadol-Related ED Visits

The SUBS had high sensitivity and moderate-to-high specificity for detecting unhealthy use of tobacco, alcohol, and other drugs. Sensitivity was lower for prescription drugs alone but increased when they were combined into a single “any drug” category. The researchers say this may reflect drug users’ lack of clarity about what constitutes illicit vs prescription drug misuse.

Related: Living Tobacco Free

The test was well accepted among a diverse patient population (although 11% in the reliability study needed some help with questions or technical assistance) and easily used on a tablet computer. It compared favorably with other widely recommended brief substance use screening tools—all of which are interviewer administered, the researchers point out. They add that a self-administered tool may put patients at greater ease about reporting substance use and thus be more consistently accurate in real-world practice.

Source
McNeely J, Strauss SM, Saitz R, et al. Am J Med. 2015;128(7):784.e9-784.e19.
doi: 10.1016/j.amjmed.2015.02.007.

A simple, fast screening questionnaire for substance use could have several benefits, say researchers from New York University and Boston Medical Center, such as streamlining workflow for primary care practitioners and staff and affording patients the privacy to report possibly stigmatizing behavior.

Related: Veterans' Use of Designer Cathinones and Cannabinoids

But there wasn’t such a tool, so the researchers developed the Substance Use Brief Screen (SUBS). They based it on the National Institute on Drug Abuse Quick Screen V1.0, which has not yet been validated. Then they tested their screen for reliability in 54 primary care patients and conducted another study to validate it in 586 more.

The questionnaire has 4 questions: In the past 12 months, how many days did you use tobacco; have 4 or more alcoholic drinks in a day; use illegal drug(s); or use prescription medication(s) “recreationally”?

Related: Tracking Tramadol-Related ED Visits

The SUBS had high sensitivity and moderate-to-high specificity for detecting unhealthy use of tobacco, alcohol, and other drugs. Sensitivity was lower for prescription drugs alone but increased when they were combined into a single “any drug” category. The researchers say this may reflect drug users’ lack of clarity about what constitutes illicit vs prescription drug misuse.

Related: Living Tobacco Free

The test was well accepted among a diverse patient population (although 11% in the reliability study needed some help with questions or technical assistance) and easily used on a tablet computer. It compared favorably with other widely recommended brief substance use screening tools—all of which are interviewer administered, the researchers point out. They add that a self-administered tool may put patients at greater ease about reporting substance use and thus be more consistently accurate in real-world practice.

Source
McNeely J, Strauss SM, Saitz R, et al. Am J Med. 2015;128(7):784.e9-784.e19.
doi: 10.1016/j.amjmed.2015.02.007.

The combination of prolonged-release oxycodone and naloxone (PR OXN) better relieves pain and opioid-induced constipation than does prolonged-release oxycodone (PR OXY) alone, according to a team of Belgian researchers.

In their study, 65 patients with laxative-refractory opioid-induced constipation (OIC) were given PR OXY or PR OXN at a median dose of 20 mg/d. They were assessed for pain and constipation relief during 3 visits conducted over 12 weeks.

Related: Reducing Opioid Use for Chronic Pain

Study results showed PR OXN was superior to PR OXY in pain relief, OIC, and quality of life. The Bowel Function Index (BFI) showed a statistically significant and clinically relevant improvement of 48.5 points from visit 1 to visit 3 (P < .001; 95% confidence interval [CI], 44.4-52.7).

The researchers note that a change in the BFI of ≥ 12 points is related to clinically meaningful changes in bowel habits in patients with OIC. The average BFI was < 28.8 after 6 weeks of PR OXN, indicating that most patients were no longer constipated despite opioid treatment.

Related: Overprescription of Opioids in Women of Childbearing Age

The mean pain score was significantly reduced, on average 2.1 units during treatment (P < .001; 95% CI, 1.66-2.54). At 18 weeks, the mean score was 3.8, on a scale of 0 to 10.

The researchers say the median PR OXN dose remained consistent throughout the study. Moreover, the number of patients who used analgesic rescue medication in the 7 days before each visit was reduced from 44 (64.7%) to 26 (41.9%). Therefore, the researchers say, the improved pain relief cannot be explained by an increased dose or increased use of rescue medication and is probably related to the improved constipation relief.

Related: E-Consults in Gastroenterology: A Quality Improvement Project

Quality of life scores increased significantly. Only 2 patients reported an adverse event, both of which were mild or unrelated to the study treatment.

When the study began, the patients were each using at least 2 laxatives with different mechanisms of action. During the study, the number of patients using laxatives in the 7 days before each visit dropped significantly, from 65 to 24 by visit 3. The researchers say, to the best of their knowledge, this is the only noninterventional study of opioid treatment in which laxative use was documented before and during treatment.

The improvement in OIC the researchers observed during PR OXN treatment was not due to laxatives, thus their findings support the rationale that PR OXN treatment counteracts OIC through mechanisms other than those of laxatives and addresses the underlying mechanism of OIC.

Source
Poelaert J, Koopmans-Klein G, Dioh A, et al. Clin Ther. 2015;37(4):784-792.
doi: 10.1016/j.clinthera.2015.02.010.

The combination of prolonged-release oxycodone and naloxone (PR OXN) better relieves pain and opioid-induced constipation than does prolonged-release oxycodone (PR OXY) alone, according to a team of Belgian researchers.

In their study, 65 patients with laxative-refractory opioid-induced constipation (OIC) were given PR OXY or PR OXN at a median dose of 20 mg/d. They were assessed for pain and constipation relief during 3 visits conducted over 12 weeks.

Related: Reducing Opioid Use for Chronic Pain

Study results showed PR OXN was superior to PR OXY in pain relief, OIC, and quality of life. The Bowel Function Index (BFI) showed a statistically significant and clinically relevant improvement of 48.5 points from visit 1 to visit 3 (P < .001; 95% confidence interval [CI], 44.4-52.7).

The researchers note that a change in the BFI of ≥ 12 points is related to clinically meaningful changes in bowel habits in patients with OIC. The average BFI was < 28.8 after 6 weeks of PR OXN, indicating that most patients were no longer constipated despite opioid treatment.

Related: Overprescription of Opioids in Women of Childbearing Age

The mean pain score was significantly reduced, on average 2.1 units during treatment (P < .001; 95% CI, 1.66-2.54). At 18 weeks, the mean score was 3.8, on a scale of 0 to 10.

The researchers say the median PR OXN dose remained consistent throughout the study. Moreover, the number of patients who used analgesic rescue medication in the 7 days before each visit was reduced from 44 (64.7%) to 26 (41.9%). Therefore, the researchers say, the improved pain relief cannot be explained by an increased dose or increased use of rescue medication and is probably related to the improved constipation relief.

Related: E-Consults in Gastroenterology: A Quality Improvement Project

Quality of life scores increased significantly. Only 2 patients reported an adverse event, both of which were mild or unrelated to the study treatment.

When the study began, the patients were each using at least 2 laxatives with different mechanisms of action. During the study, the number of patients using laxatives in the 7 days before each visit dropped significantly, from 65 to 24 by visit 3. The researchers say, to the best of their knowledge, this is the only noninterventional study of opioid treatment in which laxative use was documented before and during treatment.

The improvement in OIC the researchers observed during PR OXN treatment was not due to laxatives, thus their findings support the rationale that PR OXN treatment counteracts OIC through mechanisms other than those of laxatives and addresses the underlying mechanism of OIC.

Source
Poelaert J, Koopmans-Klein G, Dioh A, et al. Clin Ther. 2015;37(4):784-792.
doi: 10.1016/j.clinthera.2015.02.010.

The combination of prolonged-release oxycodone and naloxone (PR OXN) better relieves pain and opioid-induced constipation than does prolonged-release oxycodone (PR OXY) alone, according to a team of Belgian researchers.

In their study, 65 patients with laxative-refractory opioid-induced constipation (OIC) were given PR OXY or PR OXN at a median dose of 20 mg/d. They were assessed for pain and constipation relief during 3 visits conducted over 12 weeks.

Related: Reducing Opioid Use for Chronic Pain

Study results showed PR OXN was superior to PR OXY in pain relief, OIC, and quality of life. The Bowel Function Index (BFI) showed a statistically significant and clinically relevant improvement of 48.5 points from visit 1 to visit 3 (P < .001; 95% confidence interval [CI], 44.4-52.7).

The researchers note that a change in the BFI of ≥ 12 points is related to clinically meaningful changes in bowel habits in patients with OIC. The average BFI was < 28.8 after 6 weeks of PR OXN, indicating that most patients were no longer constipated despite opioid treatment.

Related: Overprescription of Opioids in Women of Childbearing Age

The mean pain score was significantly reduced, on average 2.1 units during treatment (P < .001; 95% CI, 1.66-2.54). At 18 weeks, the mean score was 3.8, on a scale of 0 to 10.

The researchers say the median PR OXN dose remained consistent throughout the study. Moreover, the number of patients who used analgesic rescue medication in the 7 days before each visit was reduced from 44 (64.7%) to 26 (41.9%). Therefore, the researchers say, the improved pain relief cannot be explained by an increased dose or increased use of rescue medication and is probably related to the improved constipation relief.

Related: E-Consults in Gastroenterology: A Quality Improvement Project

Quality of life scores increased significantly. Only 2 patients reported an adverse event, both of which were mild or unrelated to the study treatment.

When the study began, the patients were each using at least 2 laxatives with different mechanisms of action. During the study, the number of patients using laxatives in the 7 days before each visit dropped significantly, from 65 to 24 by visit 3. The researchers say, to the best of their knowledge, this is the only noninterventional study of opioid treatment in which laxative use was documented before and during treatment.

The improvement in OIC the researchers observed during PR OXN treatment was not due to laxatives, thus their findings support the rationale that PR OXN treatment counteracts OIC through mechanisms other than those of laxatives and addresses the underlying mechanism of OIC.

Source
Poelaert J, Koopmans-Klein G, Dioh A, et al. Clin Ther. 2015;37(4):784-792.
doi: 10.1016/j.clinthera.2015.02.010.

Pseudomonas is a genus of aerobic, Gram-negative bacilli consisting of about 200 species. Pseudomonas aeruginosa (P aeruginosa) is the species most commonly associated with serious hospital-acquired infections and is commonly found in moist environments in hospitals, such as sinks, showers, and machinery/equipment. The symptoms of an infection by this bacterium are variable based on the site of infection and can manifest in various sites, such as the respiratory tract, urinary tract, ears, eyes, heart, skin, and soft tissue.¹ General risk factors for infection with P aeruginosa include immunosuppression, history of lung disease, hospitalization lasting at least 5 days, history of repeated antibiotic use within 90 days, and a history of pseudomonal colonization/infection.

Related: Antibiotic Therapy and Bacterial Resistance in Patients With Spinal Cord Injury

Pseudomonas aeruginosa is a challenging organism to manage, as it is inherently resistant to many antibiotics. Furthermore, antibiotics effective against infections caused by P aeruginosa often require specific regimens as a result of the high minimum inhibitory concentration (MIC) of the organism. Two specific strategies that have been analyzed for proper coverage of P aeruginosa include the use of higher than usual doses and extended infusions. Due to significant challenges associated with obtaining patient outcomes data in human clinical trials, researchers often use Monte Carlo simulations, which are computational algorithms that simulate the variables of a study (ie, patient demographics) to be as real as possible to accurately predict therapeutic responses in patients.

Analyzing pharmacokinetic (PK) and pharmacodynamic (PD) indexes is valuable for determining therapeutic efficacy, as these indexes consider both the antibiotic dose/concentration and its effect over time in relation to response to therapy. The free-drug area under the concentration time curve (fAUC/MIC) ratio is a PK/PD value commonly used to describe the free-drug concentration over 24 hours that is above the MIC.² The fAUC is dependent on creatinine clearance (CrCl) and, therefore, is specific to each patient. A threshold value for the fAUC/MIC is determined for an antibiotic, and a therapeutic regimen is dosed accordingly to assure fAUC/MIC attainment above the minimum threshold. The probability of target attainment (PTA), which is the probability that the threshold value of a PD index is achieved at a certain MIC, and the probability of cure (POC) for a given antibiotic regimen are used to determine the efficacy of an antibiotic in Monte Carlo simulations.²

Related: Bacteremia From an Unlikely Source

A study by Zelenitsky and colleagues evaluated the efficacy of 3 ciprofloxacin dosing regimens using Monte Carlo simulations (400 mg IV every 12 hours [standard dose], 400 mg IV every 8 hours [high dose], and a PD-targeted regimen dosed to attain an fAUC/MIC value > 86).³ An fAUC/MIC value of 86 was previously determined to predict cure rates of at least 90%.⁴ The Clinical and Laboratory Standards Institute defines a P aeruginosa MIC of ≤ 1 μg/mL to be susceptible and an MIC of ≥ 4 μg/mL to be resistant to ciprofloxacin.⁵

The researchers determined PTA and POC values for each regimen based on various MICs. The in vitro laboratory simulations revealed the PTA and POC values approached 100% for all 3 regimens when the MIC was 0.125 μg/mL. However, when the MIC was 1 μg/mL, the PTA for the standard and high dose was 0%, and the PD-targeted regimen was 40%. The POC was 27%, 40%, and 72% for the standard dose, high dose, and the PD-targeted regimen, respectively. Although the PD-targeted regimen was the most efficacious, it took doses exceeding 1,300 mg and 1,800 mg daily to achieve similar results. In addition, PD-targeted regimens are not practical for dosing due to patient variability in CrCl. From these simulations, it was concluded that the high dose of ciprofloxacin 400 mg IV every 8 hours should be recommended for treating Pseudomonas infections in patients with normal renal function.

Related: Antimicrobial Stewardship in an Outpatient Parenteral Antibiotic Therapy Program

In another study by Lodise and colleagues, researchers examined the clinical implications of an extended-infusion dosing strategy for piperacillin-tazobactam in the critically ill.⁶ The 2 piperacillin- tazobactam regimens evaluated were 3.375 g IV over 30 minutes given every 4 or 6 hours and 3.375 g IV over 4 hours given every 8 hours. The 14-day mortality rate in critically ill patients who received the extended- and intermittent-infusion regimens was 12.2% and 31.6%, respectively (P = .04). Additionally, patients receiving the extended-infusion regimen had a decreased in-house length of stay compared with the intermittent-infusion group (21 vs 38 days, P = .02). Despite having a lower drug concentration peak, the extended-infusion regimen maintains steady drug concentrations above the MIC for a greater period, resulting in prolonged therapeutic efficacy. Other antibiotics (cefepime⁷ and ceftazidime⁸) have been studied by using the same methodology of comparing intermittent and extended infusions and have had similar results.

Given the management challenges associated with P aeruginosa infections, it is important for clinicians to recognize patients who may have or be at risk of infection with P aeruginosa and use appropriate dosing regimens to effectively manage infections and improve patient outcomes.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Pseudomonas is a genus of aerobic, Gram-negative bacilli consisting of about 200 species. Pseudomonas aeruginosa (P aeruginosa) is the species most commonly associated with serious hospital-acquired infections and is commonly found in moist environments in hospitals, such as sinks, showers, and machinery/equipment. The symptoms of an infection by this bacterium are variable based on the site of infection and can manifest in various sites, such as the respiratory tract, urinary tract, ears, eyes, heart, skin, and soft tissue.¹ General risk factors for infection with P aeruginosa include immunosuppression, history of lung disease, hospitalization lasting at least 5 days, history of repeated antibiotic use within 90 days, and a history of pseudomonal colonization/infection.

Related: Antibiotic Therapy and Bacterial Resistance in Patients With Spinal Cord Injury

Pseudomonas aeruginosa is a challenging organism to manage, as it is inherently resistant to many antibiotics. Furthermore, antibiotics effective against infections caused by P aeruginosa often require specific regimens as a result of the high minimum inhibitory concentration (MIC) of the organism. Two specific strategies that have been analyzed for proper coverage of P aeruginosa include the use of higher than usual doses and extended infusions. Due to significant challenges associated with obtaining patient outcomes data in human clinical trials, researchers often use Monte Carlo simulations, which are computational algorithms that simulate the variables of a study (ie, patient demographics) to be as real as possible to accurately predict therapeutic responses in patients.

Analyzing pharmacokinetic (PK) and pharmacodynamic (PD) indexes is valuable for determining therapeutic efficacy, as these indexes consider both the antibiotic dose/concentration and its effect over time in relation to response to therapy. The free-drug area under the concentration time curve (fAUC/MIC) ratio is a PK/PD value commonly used to describe the free-drug concentration over 24 hours that is above the MIC.² The fAUC is dependent on creatinine clearance (CrCl) and, therefore, is specific to each patient. A threshold value for the fAUC/MIC is determined for an antibiotic, and a therapeutic regimen is dosed accordingly to assure fAUC/MIC attainment above the minimum threshold. The probability of target attainment (PTA), which is the probability that the threshold value of a PD index is achieved at a certain MIC, and the probability of cure (POC) for a given antibiotic regimen are used to determine the efficacy of an antibiotic in Monte Carlo simulations.²

Related: Bacteremia From an Unlikely Source

A study by Zelenitsky and colleagues evaluated the efficacy of 3 ciprofloxacin dosing regimens using Monte Carlo simulations (400 mg IV every 12 hours [standard dose], 400 mg IV every 8 hours [high dose], and a PD-targeted regimen dosed to attain an fAUC/MIC value > 86).³ An fAUC/MIC value of 86 was previously determined to predict cure rates of at least 90%.⁴ The Clinical and Laboratory Standards Institute defines a P aeruginosa MIC of ≤ 1 μg/mL to be susceptible and an MIC of ≥ 4 μg/mL to be resistant to ciprofloxacin.⁵

The researchers determined PTA and POC values for each regimen based on various MICs. The in vitro laboratory simulations revealed the PTA and POC values approached 100% for all 3 regimens when the MIC was 0.125 μg/mL. However, when the MIC was 1 μg/mL, the PTA for the standard and high dose was 0%, and the PD-targeted regimen was 40%. The POC was 27%, 40%, and 72% for the standard dose, high dose, and the PD-targeted regimen, respectively. Although the PD-targeted regimen was the most efficacious, it took doses exceeding 1,300 mg and 1,800 mg daily to achieve similar results. In addition, PD-targeted regimens are not practical for dosing due to patient variability in CrCl. From these simulations, it was concluded that the high dose of ciprofloxacin 400 mg IV every 8 hours should be recommended for treating Pseudomonas infections in patients with normal renal function.

Related: Antimicrobial Stewardship in an Outpatient Parenteral Antibiotic Therapy Program

In another study by Lodise and colleagues, researchers examined the clinical implications of an extended-infusion dosing strategy for piperacillin-tazobactam in the critically ill.⁶ The 2 piperacillin- tazobactam regimens evaluated were 3.375 g IV over 30 minutes given every 4 or 6 hours and 3.375 g IV over 4 hours given every 8 hours. The 14-day mortality rate in critically ill patients who received the extended- and intermittent-infusion regimens was 12.2% and 31.6%, respectively (P = .04). Additionally, patients receiving the extended-infusion regimen had a decreased in-house length of stay compared with the intermittent-infusion group (21 vs 38 days, P = .02). Despite having a lower drug concentration peak, the extended-infusion regimen maintains steady drug concentrations above the MIC for a greater period, resulting in prolonged therapeutic efficacy. Other antibiotics (cefepime⁷ and ceftazidime⁸) have been studied by using the same methodology of comparing intermittent and extended infusions and have had similar results.

Given the management challenges associated with P aeruginosa infections, it is important for clinicians to recognize patients who may have or be at risk of infection with P aeruginosa and use appropriate dosing regimens to effectively manage infections and improve patient outcomes.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Pseudomonas is a genus of aerobic, Gram-negative bacilli consisting of about 200 species. Pseudomonas aeruginosa (P aeruginosa) is the species most commonly associated with serious hospital-acquired infections and is commonly found in moist environments in hospitals, such as sinks, showers, and machinery/equipment. The symptoms of an infection by this bacterium are variable based on the site of infection and can manifest in various sites, such as the respiratory tract, urinary tract, ears, eyes, heart, skin, and soft tissue.¹ General risk factors for infection with P aeruginosa include immunosuppression, history of lung disease, hospitalization lasting at least 5 days, history of repeated antibiotic use within 90 days, and a history of pseudomonal colonization/infection.

Related: Antibiotic Therapy and Bacterial Resistance in Patients With Spinal Cord Injury

Pseudomonas aeruginosa is a challenging organism to manage, as it is inherently resistant to many antibiotics. Furthermore, antibiotics effective against infections caused by P aeruginosa often require specific regimens as a result of the high minimum inhibitory concentration (MIC) of the organism. Two specific strategies that have been analyzed for proper coverage of P aeruginosa include the use of higher than usual doses and extended infusions. Due to significant challenges associated with obtaining patient outcomes data in human clinical trials, researchers often use Monte Carlo simulations, which are computational algorithms that simulate the variables of a study (ie, patient demographics) to be as real as possible to accurately predict therapeutic responses in patients.

Analyzing pharmacokinetic (PK) and pharmacodynamic (PD) indexes is valuable for determining therapeutic efficacy, as these indexes consider both the antibiotic dose/concentration and its effect over time in relation to response to therapy. The free-drug area under the concentration time curve (fAUC/MIC) ratio is a PK/PD value commonly used to describe the free-drug concentration over 24 hours that is above the MIC.² The fAUC is dependent on creatinine clearance (CrCl) and, therefore, is specific to each patient. A threshold value for the fAUC/MIC is determined for an antibiotic, and a therapeutic regimen is dosed accordingly to assure fAUC/MIC attainment above the minimum threshold. The probability of target attainment (PTA), which is the probability that the threshold value of a PD index is achieved at a certain MIC, and the probability of cure (POC) for a given antibiotic regimen are used to determine the efficacy of an antibiotic in Monte Carlo simulations.²

Related: Bacteremia From an Unlikely Source

A study by Zelenitsky and colleagues evaluated the efficacy of 3 ciprofloxacin dosing regimens using Monte Carlo simulations (400 mg IV every 12 hours [standard dose], 400 mg IV every 8 hours [high dose], and a PD-targeted regimen dosed to attain an fAUC/MIC value > 86).³ An fAUC/MIC value of 86 was previously determined to predict cure rates of at least 90%.⁴ The Clinical and Laboratory Standards Institute defines a P aeruginosa MIC of ≤ 1 μg/mL to be susceptible and an MIC of ≥ 4 μg/mL to be resistant to ciprofloxacin.⁵

The researchers determined PTA and POC values for each regimen based on various MICs. The in vitro laboratory simulations revealed the PTA and POC values approached 100% for all 3 regimens when the MIC was 0.125 μg/mL. However, when the MIC was 1 μg/mL, the PTA for the standard and high dose was 0%, and the PD-targeted regimen was 40%. The POC was 27%, 40%, and 72% for the standard dose, high dose, and the PD-targeted regimen, respectively. Although the PD-targeted regimen was the most efficacious, it took doses exceeding 1,300 mg and 1,800 mg daily to achieve similar results. In addition, PD-targeted regimens are not practical for dosing due to patient variability in CrCl. From these simulations, it was concluded that the high dose of ciprofloxacin 400 mg IV every 8 hours should be recommended for treating Pseudomonas infections in patients with normal renal function.

Related: Antimicrobial Stewardship in an Outpatient Parenteral Antibiotic Therapy Program

In another study by Lodise and colleagues, researchers examined the clinical implications of an extended-infusion dosing strategy for piperacillin-tazobactam in the critically ill.⁶ The 2 piperacillin- tazobactam regimens evaluated were 3.375 g IV over 30 minutes given every 4 or 6 hours and 3.375 g IV over 4 hours given every 8 hours. The 14-day mortality rate in critically ill patients who received the extended- and intermittent-infusion regimens was 12.2% and 31.6%, respectively (P = .04). Additionally, patients receiving the extended-infusion regimen had a decreased in-house length of stay compared with the intermittent-infusion group (21 vs 38 days, P = .02). Despite having a lower drug concentration peak, the extended-infusion regimen maintains steady drug concentrations above the MIC for a greater period, resulting in prolonged therapeutic efficacy. Other antibiotics (cefepime⁷ and ceftazidime⁸) have been studied by using the same methodology of comparing intermittent and extended infusions and have had similar results.

Given the management challenges associated with P aeruginosa infections, it is important for clinicians to recognize patients who may have or be at risk of infection with P aeruginosa and use appropriate dosing regimens to effectively manage infections and improve patient outcomes.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

When vancomycin doesn’t work, ceftaroline may be a viable alternative for patients with nosocomial pneumonia (NP) due to methicillin-resistant Staphylococcus aureus (MRSA), say researchers from Summa Akron City Hospital in Ohio. They point out that ceftaroline is already approved for treatment of community-acquired bacterial pneumonia (CABP) due to Streptococcus pneumonia and MRSA (methicillin-susceptible isolates only), among other pathogens. Two large prospective, randomized clinical trials found ceftaroline effective and well tolerated in patients with CABP. However, its use in MRSA NP is unknown, the researchers say, which is why they retrospectively reviewed the cases of 10 patients admitted to their hospital who received ceftaroline for MRSA NP from September 2011 to September 2012.

Related: VA Drastically Cuts Rates of MRSA Infection

Of the 10 patients, 6 had health care-associated pneumonia, 3 had hospital-acquired pneumonia, and 1 had ventilator-associated pneumonia. All 10 had respiratory cultures positive for MRSA. Eight patients had MRSA isolates with resistance patterns consistent with traditional health care-associated MRSA strains, and 2 were consistent with community-acquired MRSA.

Related: Risk of Readmission After Pneumonia

In all, 9 patients received prior anti-MRSA therapy before the initiation of ceftaroline. Eight patients received ceftaroline 600 mg infused over 1 hour every 12 hours; 2 patients received renally adjusted lower doses. Therapy lasted from 4 to 28 days.

Related: HIV-Negative Patients at Risk for Pneumocystosis

Three patients died due to advanced age and multiple medical conditions after stopping antibiotic treatment and moving to palliative care. The remaining 7 patients responded well to the ceftaroline treatment, although 1 had microbiological and clinical relapse. The drug was well tolerated.

Although their case series is small and uncontrolled, the researchers say it suggests the potential of ceftaroline as an alternative agent for MRSA NP.

Source
Pasquale TR, Tan MJ, Trienski TL, File TM Jr. J Chemother. 2015;27(1):29-34.
doi: 10.1179/1973947813Y.0000000156.

When vancomycin doesn’t work, ceftaroline may be a viable alternative for patients with nosocomial pneumonia (NP) due to methicillin-resistant Staphylococcus aureus (MRSA), say researchers from Summa Akron City Hospital in Ohio. They point out that ceftaroline is already approved for treatment of community-acquired bacterial pneumonia (CABP) due to Streptococcus pneumonia and MRSA (methicillin-susceptible isolates only), among other pathogens. Two large prospective, randomized clinical trials found ceftaroline effective and well tolerated in patients with CABP. However, its use in MRSA NP is unknown, the researchers say, which is why they retrospectively reviewed the cases of 10 patients admitted to their hospital who received ceftaroline for MRSA NP from September 2011 to September 2012.

Related: VA Drastically Cuts Rates of MRSA Infection

Of the 10 patients, 6 had health care-associated pneumonia, 3 had hospital-acquired pneumonia, and 1 had ventilator-associated pneumonia. All 10 had respiratory cultures positive for MRSA. Eight patients had MRSA isolates with resistance patterns consistent with traditional health care-associated MRSA strains, and 2 were consistent with community-acquired MRSA.

Related: Risk of Readmission After Pneumonia

In all, 9 patients received prior anti-MRSA therapy before the initiation of ceftaroline. Eight patients received ceftaroline 600 mg infused over 1 hour every 12 hours; 2 patients received renally adjusted lower doses. Therapy lasted from 4 to 28 days.

Related: HIV-Negative Patients at Risk for Pneumocystosis

Three patients died due to advanced age and multiple medical conditions after stopping antibiotic treatment and moving to palliative care. The remaining 7 patients responded well to the ceftaroline treatment, although 1 had microbiological and clinical relapse. The drug was well tolerated.

Although their case series is small and uncontrolled, the researchers say it suggests the potential of ceftaroline as an alternative agent for MRSA NP.

Source
Pasquale TR, Tan MJ, Trienski TL, File TM Jr. J Chemother. 2015;27(1):29-34.
doi: 10.1179/1973947813Y.0000000156.

When vancomycin doesn’t work, ceftaroline may be a viable alternative for patients with nosocomial pneumonia (NP) due to methicillin-resistant Staphylococcus aureus (MRSA), say researchers from Summa Akron City Hospital in Ohio. They point out that ceftaroline is already approved for treatment of community-acquired bacterial pneumonia (CABP) due to Streptococcus pneumonia and MRSA (methicillin-susceptible isolates only), among other pathogens. Two large prospective, randomized clinical trials found ceftaroline effective and well tolerated in patients with CABP. However, its use in MRSA NP is unknown, the researchers say, which is why they retrospectively reviewed the cases of 10 patients admitted to their hospital who received ceftaroline for MRSA NP from September 2011 to September 2012.

Related: VA Drastically Cuts Rates of MRSA Infection

Of the 10 patients, 6 had health care-associated pneumonia, 3 had hospital-acquired pneumonia, and 1 had ventilator-associated pneumonia. All 10 had respiratory cultures positive for MRSA. Eight patients had MRSA isolates with resistance patterns consistent with traditional health care-associated MRSA strains, and 2 were consistent with community-acquired MRSA.

Related: Risk of Readmission After Pneumonia

In all, 9 patients received prior anti-MRSA therapy before the initiation of ceftaroline. Eight patients received ceftaroline 600 mg infused over 1 hour every 12 hours; 2 patients received renally adjusted lower doses. Therapy lasted from 4 to 28 days.

Related: HIV-Negative Patients at Risk for Pneumocystosis

Three patients died due to advanced age and multiple medical conditions after stopping antibiotic treatment and moving to palliative care. The remaining 7 patients responded well to the ceftaroline treatment, although 1 had microbiological and clinical relapse. The drug was well tolerated.

Although their case series is small and uncontrolled, the researchers say it suggests the potential of ceftaroline as an alternative agent for MRSA NP.

Source
Pasquale TR, Tan MJ, Trienski TL, File TM Jr. J Chemother. 2015;27(1):29-34.
doi: 10.1179/1973947813Y.0000000156.

The FDA has expanded the approved use of nivolumab to include patients with metastatic squamous non-small cell lung cancer (NSCLC). As the most common type of lung cancer, NSCLC affects nearly 90% of patients with lung cancer.

Used to treat tumor progression on or after platinum-based chemotherapy, nivolumab blocks the signals by which lung cancer inactivates T cells, thereby helping to restore the immune response.

Related: Timely Assessment of Cancer Symptoms

In a randomized trial comparing nivolumab with docetaxel in 272 patients, those who received nivolumab lived, on average, 3.2 months longer than did those on docetaxel (9.2 months vs 6 months). Another study followed 117 patients with metastatic squamous NSCLC who previously had platinum-based therapy and one or more additional systemic therapies. Of those, 17 patients (15%) experienced partial shrinkage or complete disappearance of the tumor; in 10 patients, the response lasted ≥ 6 months. In that trial, the median time to onset of response was 3.3 months after the start of treatment. The duration of response ranged from 1.9 to 11.5 months.

Related: Pulmonary Vein Thrombosis Associated With Metastatic Carcinoma

The most frequent adverse effects (AEs) are fatigue, shortness of breath, musculoskeletal pain, reduced appetite, cough, nausea, and constipation. Because of the mode of action, nivolumab can cause the immune system to attack normal organs and tissues, which means some of the most serious AEs are severe immune-mediated diseases, such as pneumonitis, colitis, and hepatitis.

Related: On the Scent of Cancer

Nivolumab was approved in 2014 for IV use, based on tumor response rate and durability of response. According to the manufacturer, Bristol-Myers Squibb Company, which conducted a study of patients with advanced melanoma, the single-arm, noncomparative interim analysis of the first 120 patients who received the drug showed a 32% response rate: 4 patients achieved a complete response and 34 had a partial response. The response lasted from 2 to 10-plus months; 13 patients had ongoing responses of ≥ 6 months.

Sources
U.S. Food and Drug Administration. FDA expands approved use of Opdivo to treat lung cancer [press release]. Silver Spring, MD: U.S. Food and Drug Administration; March 4, 2015.

OPDIVO [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2015.

Food and Drug Administration. FDA approves Opdivo for advanced melanoma [press release]. Silver Spring, MD: U.S. Food and Drug Administration; December 22, 2014.

The FDA has expanded the approved use of nivolumab to include patients with metastatic squamous non-small cell lung cancer (NSCLC). As the most common type of lung cancer, NSCLC affects nearly 90% of patients with lung cancer.

Used to treat tumor progression on or after platinum-based chemotherapy, nivolumab blocks the signals by which lung cancer inactivates T cells, thereby helping to restore the immune response.

Related: Timely Assessment of Cancer Symptoms

In a randomized trial comparing nivolumab with docetaxel in 272 patients, those who received nivolumab lived, on average, 3.2 months longer than did those on docetaxel (9.2 months vs 6 months). Another study followed 117 patients with metastatic squamous NSCLC who previously had platinum-based therapy and one or more additional systemic therapies. Of those, 17 patients (15%) experienced partial shrinkage or complete disappearance of the tumor; in 10 patients, the response lasted ≥ 6 months. In that trial, the median time to onset of response was 3.3 months after the start of treatment. The duration of response ranged from 1.9 to 11.5 months.

Related: Pulmonary Vein Thrombosis Associated With Metastatic Carcinoma

The most frequent adverse effects (AEs) are fatigue, shortness of breath, musculoskeletal pain, reduced appetite, cough, nausea, and constipation. Because of the mode of action, nivolumab can cause the immune system to attack normal organs and tissues, which means some of the most serious AEs are severe immune-mediated diseases, such as pneumonitis, colitis, and hepatitis.

Related: On the Scent of Cancer

Nivolumab was approved in 2014 for IV use, based on tumor response rate and durability of response. According to the manufacturer, Bristol-Myers Squibb Company, which conducted a study of patients with advanced melanoma, the single-arm, noncomparative interim analysis of the first 120 patients who received the drug showed a 32% response rate: 4 patients achieved a complete response and 34 had a partial response. The response lasted from 2 to 10-plus months; 13 patients had ongoing responses of ≥ 6 months.

Sources
U.S. Food and Drug Administration. FDA expands approved use of Opdivo to treat lung cancer [press release]. Silver Spring, MD: U.S. Food and Drug Administration; March 4, 2015.

OPDIVO [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2015.

Food and Drug Administration. FDA approves Opdivo for advanced melanoma [press release]. Silver Spring, MD: U.S. Food and Drug Administration; December 22, 2014.

The FDA has expanded the approved use of nivolumab to include patients with metastatic squamous non-small cell lung cancer (NSCLC). As the most common type of lung cancer, NSCLC affects nearly 90% of patients with lung cancer.

Used to treat tumor progression on or after platinum-based chemotherapy, nivolumab blocks the signals by which lung cancer inactivates T cells, thereby helping to restore the immune response.

Related: Timely Assessment of Cancer Symptoms

In a randomized trial comparing nivolumab with docetaxel in 272 patients, those who received nivolumab lived, on average, 3.2 months longer than did those on docetaxel (9.2 months vs 6 months). Another study followed 117 patients with metastatic squamous NSCLC who previously had platinum-based therapy and one or more additional systemic therapies. Of those, 17 patients (15%) experienced partial shrinkage or complete disappearance of the tumor; in 10 patients, the response lasted ≥ 6 months. In that trial, the median time to onset of response was 3.3 months after the start of treatment. The duration of response ranged from 1.9 to 11.5 months.

Related: Pulmonary Vein Thrombosis Associated With Metastatic Carcinoma

The most frequent adverse effects (AEs) are fatigue, shortness of breath, musculoskeletal pain, reduced appetite, cough, nausea, and constipation. Because of the mode of action, nivolumab can cause the immune system to attack normal organs and tissues, which means some of the most serious AEs are severe immune-mediated diseases, such as pneumonitis, colitis, and hepatitis.

Related: On the Scent of Cancer

Nivolumab was approved in 2014 for IV use, based on tumor response rate and durability of response. According to the manufacturer, Bristol-Myers Squibb Company, which conducted a study of patients with advanced melanoma, the single-arm, noncomparative interim analysis of the first 120 patients who received the drug showed a 32% response rate: 4 patients achieved a complete response and 34 had a partial response. The response lasted from 2 to 10-plus months; 13 patients had ongoing responses of ≥ 6 months.

Sources
U.S. Food and Drug Administration. FDA expands approved use of Opdivo to treat lung cancer [press release]. Silver Spring, MD: U.S. Food and Drug Administration; March 4, 2015.

OPDIVO [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2015.

Food and Drug Administration. FDA approves Opdivo for advanced melanoma [press release]. Silver Spring, MD: U.S. Food and Drug Administration; December 22, 2014.

Hyponatremia is an uncommon adverse effect of psychotropic drugs, thought to be caused by the release of an antidiuretic hormone. And serotonergic drugs are known to cause syndrome of inappropriate antidiuretic hormone secretion (SIADH). But the relationship between SIADH and antipsychotics is not well understood, say clinicians from University College of Medical Science and Guru Teg Bahadur Hospital and Institute of Human Behaviour and Allied Sciences, both in Delhi, India. Their own case report should add to the body of knowledge, they say.

They reported the case of a patient who developed SIADH after starting risperidone. The patient, a woman aged 22 years, had been experiencing psychotic symptoms for a year, including persecutory beliefs and hallucinations. She was treatment naïve, having visited only faith healers, with no contact with medical or psychiatric services. The mental status examination result was consistent with the diagnosis of paranoid schizophrenia. A physical examination did not reveal any sign of physical illness, nor did routine blood tests reveal any abnormalities; she did not have polydipsia.

Related: Lurasidone Approved for Bipolar Disorder

She was started on risperidone tablet 2 mg/d, which she tolerated well. After 3 days, the dosage was increased to 4 mg/d. She was not prescribed any other medications.

After 5 days on risperidone, she had an episode of generalized tonic-clonic seizures and was hospitalized. She was drowsy, but her vital signs and physical examination results were normal. Laboratory results revealed her blood sugar was 90 mg/dL; sodium, 118 mEq/dL; potassium, 4.1 mEq/dL; uric acid, 2.0 mg/dL; calcium, 8.4 mg/dL; osmolarity, and 258 mOsm/kg of water. Her blood urea nitrogen was 10 mEq/dL, urinary sodium was 34 mEq/L; urine routine and microscopic examination were normal. The serum cortisol level and thyroid profile were also normal.

After all the tests were done, the patient was diagnosed with SIADH. The risperidone was stopped. She was treated for the hyponatremia, and by the third day, her serum sodium had increased to 134 mEq/dL. Her mental status had returned to normal.

Related: Fiduciary Services for Veterans With Psychiatric Disabilities

The authors note that SIADH is the cause of hyponatremia in about one-third of cases. Various psychotropic and antipsychotic drugs, both typical and atypical, have been reported to cause SIADH, but the mechanism is not clear. However, because their patient’s blood pressure was normal and she was on risperidone for only 5 days (making the possibility of D2 receptor supersensitivity unlikely), the authors hypothesize that the SIADH was mediated by the action of risperidone on 5-HT receptors.

During clinical trials of oral risperidone, the authors say, a small percentage of adults and children reported thirst, and risperidone was suspected of causing polydipsia. That mechanism may be relevant to the development of hyponatremia, they suggest. In premarketing trials, some patients also had seizures thought to be due to oral risperidone. Two cases of seizures were associated with hyponatremia. For that reason, risperidone should be used cautiously in patients with a history of seizure, the authors advise.

Related: Veterans' Use of Designer Cathinones and Cannabinoids

In the case of their patient, clinical history and investigations supported the diagnosis of SIADH. The lack of a history of polydipsia, combined with the onset of hyponatremia with seizures shortly after starting risperidone and the rapid correction of serum sodium after stopping the drug make a relationship with the drug likely. The authors recommend measuring serum sodium at baseline and after starting antipsychotics as part of a routine clinical practice.

Source
Singh Ranga G, Ramkumarsingh Tomar L, Narang S, Tripathi P, Prakash Jirwal O. J Acute Med. 2014;4(3):133-134.
doi: 10.1016/j.jacme.2014.03.004.

Hyponatremia is an uncommon adverse effect of psychotropic drugs, thought to be caused by the release of an antidiuretic hormone. And serotonergic drugs are known to cause syndrome of inappropriate antidiuretic hormone secretion (SIADH). But the relationship between SIADH and antipsychotics is not well understood, say clinicians from University College of Medical Science and Guru Teg Bahadur Hospital and Institute of Human Behaviour and Allied Sciences, both in Delhi, India. Their own case report should add to the body of knowledge, they say.

They reported the case of a patient who developed SIADH after starting risperidone. The patient, a woman aged 22 years, had been experiencing psychotic symptoms for a year, including persecutory beliefs and hallucinations. She was treatment naïve, having visited only faith healers, with no contact with medical or psychiatric services. The mental status examination result was consistent with the diagnosis of paranoid schizophrenia. A physical examination did not reveal any sign of physical illness, nor did routine blood tests reveal any abnormalities; she did not have polydipsia.

Related: Lurasidone Approved for Bipolar Disorder

She was started on risperidone tablet 2 mg/d, which she tolerated well. After 3 days, the dosage was increased to 4 mg/d. She was not prescribed any other medications.

After 5 days on risperidone, she had an episode of generalized tonic-clonic seizures and was hospitalized. She was drowsy, but her vital signs and physical examination results were normal. Laboratory results revealed her blood sugar was 90 mg/dL; sodium, 118 mEq/dL; potassium, 4.1 mEq/dL; uric acid, 2.0 mg/dL; calcium, 8.4 mg/dL; osmolarity, and 258 mOsm/kg of water. Her blood urea nitrogen was 10 mEq/dL, urinary sodium was 34 mEq/L; urine routine and microscopic examination were normal. The serum cortisol level and thyroid profile were also normal.

After all the tests were done, the patient was diagnosed with SIADH. The risperidone was stopped. She was treated for the hyponatremia, and by the third day, her serum sodium had increased to 134 mEq/dL. Her mental status had returned to normal.

Related: Fiduciary Services for Veterans With Psychiatric Disabilities

The authors note that SIADH is the cause of hyponatremia in about one-third of cases. Various psychotropic and antipsychotic drugs, both typical and atypical, have been reported to cause SIADH, but the mechanism is not clear. However, because their patient’s blood pressure was normal and she was on risperidone for only 5 days (making the possibility of D2 receptor supersensitivity unlikely), the authors hypothesize that the SIADH was mediated by the action of risperidone on 5-HT receptors.

During clinical trials of oral risperidone, the authors say, a small percentage of adults and children reported thirst, and risperidone was suspected of causing polydipsia. That mechanism may be relevant to the development of hyponatremia, they suggest. In premarketing trials, some patients also had seizures thought to be due to oral risperidone. Two cases of seizures were associated with hyponatremia. For that reason, risperidone should be used cautiously in patients with a history of seizure, the authors advise.

Related: Veterans' Use of Designer Cathinones and Cannabinoids

In the case of their patient, clinical history and investigations supported the diagnosis of SIADH. The lack of a history of polydipsia, combined with the onset of hyponatremia with seizures shortly after starting risperidone and the rapid correction of serum sodium after stopping the drug make a relationship with the drug likely. The authors recommend measuring serum sodium at baseline and after starting antipsychotics as part of a routine clinical practice.

Source
Singh Ranga G, Ramkumarsingh Tomar L, Narang S, Tripathi P, Prakash Jirwal O. J Acute Med. 2014;4(3):133-134.
doi: 10.1016/j.jacme.2014.03.004.

Hyponatremia is an uncommon adverse effect of psychotropic drugs, thought to be caused by the release of an antidiuretic hormone. And serotonergic drugs are known to cause syndrome of inappropriate antidiuretic hormone secretion (SIADH). But the relationship between SIADH and antipsychotics is not well understood, say clinicians from University College of Medical Science and Guru Teg Bahadur Hospital and Institute of Human Behaviour and Allied Sciences, both in Delhi, India. Their own case report should add to the body of knowledge, they say.

They reported the case of a patient who developed SIADH after starting risperidone. The patient, a woman aged 22 years, had been experiencing psychotic symptoms for a year, including persecutory beliefs and hallucinations. She was treatment naïve, having visited only faith healers, with no contact with medical or psychiatric services. The mental status examination result was consistent with the diagnosis of paranoid schizophrenia. A physical examination did not reveal any sign of physical illness, nor did routine blood tests reveal any abnormalities; she did not have polydipsia.

Related: Lurasidone Approved for Bipolar Disorder

She was started on risperidone tablet 2 mg/d, which she tolerated well. After 3 days, the dosage was increased to 4 mg/d. She was not prescribed any other medications.

After 5 days on risperidone, she had an episode of generalized tonic-clonic seizures and was hospitalized. She was drowsy, but her vital signs and physical examination results were normal. Laboratory results revealed her blood sugar was 90 mg/dL; sodium, 118 mEq/dL; potassium, 4.1 mEq/dL; uric acid, 2.0 mg/dL; calcium, 8.4 mg/dL; osmolarity, and 258 mOsm/kg of water. Her blood urea nitrogen was 10 mEq/dL, urinary sodium was 34 mEq/L; urine routine and microscopic examination were normal. The serum cortisol level and thyroid profile were also normal.

After all the tests were done, the patient was diagnosed with SIADH. The risperidone was stopped. She was treated for the hyponatremia, and by the third day, her serum sodium had increased to 134 mEq/dL. Her mental status had returned to normal.

Related: Fiduciary Services for Veterans With Psychiatric Disabilities

The authors note that SIADH is the cause of hyponatremia in about one-third of cases. Various psychotropic and antipsychotic drugs, both typical and atypical, have been reported to cause SIADH, but the mechanism is not clear. However, because their patient’s blood pressure was normal and she was on risperidone for only 5 days (making the possibility of D2 receptor supersensitivity unlikely), the authors hypothesize that the SIADH was mediated by the action of risperidone on 5-HT receptors.

During clinical trials of oral risperidone, the authors say, a small percentage of adults and children reported thirst, and risperidone was suspected of causing polydipsia. That mechanism may be relevant to the development of hyponatremia, they suggest. In premarketing trials, some patients also had seizures thought to be due to oral risperidone. Two cases of seizures were associated with hyponatremia. For that reason, risperidone should be used cautiously in patients with a history of seizure, the authors advise.

Related: Veterans' Use of Designer Cathinones and Cannabinoids

In the case of their patient, clinical history and investigations supported the diagnosis of SIADH. The lack of a history of polydipsia, combined with the onset of hyponatremia with seizures shortly after starting risperidone and the rapid correction of serum sodium after stopping the drug make a relationship with the drug likely. The authors recommend measuring serum sodium at baseline and after starting antipsychotics as part of a routine clinical practice.

Source
Singh Ranga G, Ramkumarsingh Tomar L, Narang S, Tripathi P, Prakash Jirwal O. J Acute Med. 2014;4(3):133-134.
doi: 10.1016/j.jacme.2014.03.004.

Pneumocystis jiroveci pneumonia is associated with high mortality rates in immunocompromised patients who are HIV-negative. In-hospital mortality rates range from 50% to 86%. Although trimethoprim-sulfamethoxazole (TMP-SMX) is an effective prophylaxis, the wide spectrum of immunosuppressive conditions predisposing to pneumocystosis and the limited data available on its incidence in non–HIV-infected patients has made it hard to establish an evidence-based guideline, say researchers from Hôpital Pontchaillou, Hôpital Sud, and Université Rennes 1, all in Rennes, France. The study is the first to offer comparative estimates of pneumocystosis incidence rates across this patient population and helps narrow down the patients at greatest risk.

The researchers retrospectively analyzed all cases of documented pneumocystosis in HIV-negative patients admitted to Rennes University Hospital between 1990 and 2010. Of 293 cases of pneumocystosis, 154 (52.6%) tested negative for HIV.

Related: NSAIDs Linked to Poor Pneumonia Outcomes

One of the study’s main findings was that pneumocystosis remains a significant problem in both HIV-positive and HIV-negative immunocompromised patients. Second, the researchers found pneumocystosis is more severe in HIV-negative patients compared with HIV-positive patients, with much higher rates of intensive care unit (ICU) admission and in-ICU mortality.

The risk of pneumocystosis was particularly high (> 45 cases per 100,000 patient-years) in 2 groups: patients with inflammatory diseases/vasculitis (polyarteritis nodosa, granulomatosis with polyangiitis, polymyositis/dermatopolymyositis) and 3 hematologic malignancies (acute leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma).

Related: Linezolid Contributes to "Clinical Success" in MRSA Pneumonia

They found intermediate risk (25-45 cases per 100,000 patient-years) for Waldenström macroglobulinemia, multiple myeloma, and central nervous system cancer. For those patients, the researchers recommend a low threshold for prophylaxis; that is, any additional risk factor, such as prolonged use of corticosteroids, should prompt initiation of TMP-SMX. Most patients with solid tumors and inflammatory diseases were at low risk (< 25 cases per 100,000 patient-years).

Their study findings can help guide more systematic use of TMP-SMX prophylaxis, the researchers say. For high-risk patients, they suggest TMP-SMX prophylaxis may be beneficial, especially given the high morbidity and mortality rates. For intermediate-risk patients, the researchers recommend a low threshold for prophylaxis; that is, any additional risk factor, such as prolonged use of corticosteroids, should prompt initiation of TMP-SMX. But for low-risk patients, they advise avoiding routine pneumocystosis prophylaxis.

Source
Fillatre P, Decaux O, Jouneau S, et al. Am J Med. 2014;127(12):1242.e11-1242.e17.
doi: 10.1016/j.amjmed.2014.07.010.

Pneumocystis jiroveci pneumonia is associated with high mortality rates in immunocompromised patients who are HIV-negative. In-hospital mortality rates range from 50% to 86%. Although trimethoprim-sulfamethoxazole (TMP-SMX) is an effective prophylaxis, the wide spectrum of immunosuppressive conditions predisposing to pneumocystosis and the limited data available on its incidence in non–HIV-infected patients has made it hard to establish an evidence-based guideline, say researchers from Hôpital Pontchaillou, Hôpital Sud, and Université Rennes 1, all in Rennes, France. The study is the first to offer comparative estimates of pneumocystosis incidence rates across this patient population and helps narrow down the patients at greatest risk.

The researchers retrospectively analyzed all cases of documented pneumocystosis in HIV-negative patients admitted to Rennes University Hospital between 1990 and 2010. Of 293 cases of pneumocystosis, 154 (52.6%) tested negative for HIV.

Related: NSAIDs Linked to Poor Pneumonia Outcomes

One of the study’s main findings was that pneumocystosis remains a significant problem in both HIV-positive and HIV-negative immunocompromised patients. Second, the researchers found pneumocystosis is more severe in HIV-negative patients compared with HIV-positive patients, with much higher rates of intensive care unit (ICU) admission and in-ICU mortality.

The risk of pneumocystosis was particularly high (> 45 cases per 100,000 patient-years) in 2 groups: patients with inflammatory diseases/vasculitis (polyarteritis nodosa, granulomatosis with polyangiitis, polymyositis/dermatopolymyositis) and 3 hematologic malignancies (acute leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma).

Related: Linezolid Contributes to "Clinical Success" in MRSA Pneumonia

They found intermediate risk (25-45 cases per 100,000 patient-years) for Waldenström macroglobulinemia, multiple myeloma, and central nervous system cancer. For those patients, the researchers recommend a low threshold for prophylaxis; that is, any additional risk factor, such as prolonged use of corticosteroids, should prompt initiation of TMP-SMX. Most patients with solid tumors and inflammatory diseases were at low risk (< 25 cases per 100,000 patient-years).

Their study findings can help guide more systematic use of TMP-SMX prophylaxis, the researchers say. For high-risk patients, they suggest TMP-SMX prophylaxis may be beneficial, especially given the high morbidity and mortality rates. For intermediate-risk patients, the researchers recommend a low threshold for prophylaxis; that is, any additional risk factor, such as prolonged use of corticosteroids, should prompt initiation of TMP-SMX. But for low-risk patients, they advise avoiding routine pneumocystosis prophylaxis.

Source
Fillatre P, Decaux O, Jouneau S, et al. Am J Med. 2014;127(12):1242.e11-1242.e17.
doi: 10.1016/j.amjmed.2014.07.010.

Pneumocystis jiroveci pneumonia is associated with high mortality rates in immunocompromised patients who are HIV-negative. In-hospital mortality rates range from 50% to 86%. Although trimethoprim-sulfamethoxazole (TMP-SMX) is an effective prophylaxis, the wide spectrum of immunosuppressive conditions predisposing to pneumocystosis and the limited data available on its incidence in non–HIV-infected patients has made it hard to establish an evidence-based guideline, say researchers from Hôpital Pontchaillou, Hôpital Sud, and Université Rennes 1, all in Rennes, France. The study is the first to offer comparative estimates of pneumocystosis incidence rates across this patient population and helps narrow down the patients at greatest risk.

The researchers retrospectively analyzed all cases of documented pneumocystosis in HIV-negative patients admitted to Rennes University Hospital between 1990 and 2010. Of 293 cases of pneumocystosis, 154 (52.6%) tested negative for HIV.

Related: NSAIDs Linked to Poor Pneumonia Outcomes

One of the study’s main findings was that pneumocystosis remains a significant problem in both HIV-positive and HIV-negative immunocompromised patients. Second, the researchers found pneumocystosis is more severe in HIV-negative patients compared with HIV-positive patients, with much higher rates of intensive care unit (ICU) admission and in-ICU mortality.

The risk of pneumocystosis was particularly high (> 45 cases per 100,000 patient-years) in 2 groups: patients with inflammatory diseases/vasculitis (polyarteritis nodosa, granulomatosis with polyangiitis, polymyositis/dermatopolymyositis) and 3 hematologic malignancies (acute leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma).

Related: Linezolid Contributes to "Clinical Success" in MRSA Pneumonia

They found intermediate risk (25-45 cases per 100,000 patient-years) for Waldenström macroglobulinemia, multiple myeloma, and central nervous system cancer. For those patients, the researchers recommend a low threshold for prophylaxis; that is, any additional risk factor, such as prolonged use of corticosteroids, should prompt initiation of TMP-SMX. Most patients with solid tumors and inflammatory diseases were at low risk (< 25 cases per 100,000 patient-years).

Their study findings can help guide more systematic use of TMP-SMX prophylaxis, the researchers say. For high-risk patients, they suggest TMP-SMX prophylaxis may be beneficial, especially given the high morbidity and mortality rates. For intermediate-risk patients, the researchers recommend a low threshold for prophylaxis; that is, any additional risk factor, such as prolonged use of corticosteroids, should prompt initiation of TMP-SMX. But for low-risk patients, they advise avoiding routine pneumocystosis prophylaxis.

Source
Fillatre P, Decaux O, Jouneau S, et al. Am J Med. 2014;127(12):1242.e11-1242.e17.
doi: 10.1016/j.amjmed.2014.07.010.

Endocrine therapy reduces the risk of recurrent breast cancer, but nonadherence is high. Researchers from Utrecht University, Leiden University Medical University, Diaconessenhuis Hospital, and the Netherlands Institute for Health Services Research, all in the Netherlands, felt there was more to nonadherence than most surveys were reporting. So they developed the Tailored Medicine Inventory, which allowed respondents to skip irrelevant items and expand on areas that are usually more limited, such as practical problems they encounter with the treatment.

The 241 survey respondents answered questions about their perceptions of the efficacy of endocrine therapy, worries about adverse effects (AEs), and practical problems that impact adherence, such as packaging, refills, and understanding information. The researchers also assessed perceived self-efficacy, using the Medication Use and Understanding Self-Efficacy scale. They used 2 scales to assess nonadherence: the Medication Adherence Rating Scale-5 and because that scale seemed to underrepresent unintentional nonadherence, they included the Morisky Medication Adherence Scale, with additional questions about forgetting to take the endocrine tablets and persistence.

Related: New Protocol Aims to Evaluate Medication Nonadherence

A substantial number of women were not convinced of the efficacy of endocrine therapy (30%). Some did not believe it was necessary (14%) or doubted its capacity to prevent cancer recurrence (32%). Nineteen percent of the women said they didn’t know how endocrine therapy works, and 20% said that they lacked information about it and didn’t know to what extent it reduced the chance of recurrence.

One hundred sixteen of the women surveyed (48%) experienced ≥ 1 practical problems, most often in the categories of information, intake of tablets, and packaging. All categories except “limitations in daily life” posed “substantial bother” to the women, the researchers say. Practical problems more than doubled the chance of unintentional nonadherence.

Related: Gene Expression Signatures in Breast Cancer: A Surgical Oncologist's Perspective

Self-reported unintentional nonadherence was high (85%), and intentional nonadherence or premature discontinuation was even higher (90%-92%). However, the researchers found no association between perceptions of the efficacy of endocrine therapy and nonadherence. Older women and those who were being treated for recurrent breast cancer were less likely to be unintentionally nonadherent. Perceived self-efficacy was associated with lower levels of both unintentional and intentional nonadherence.

The likelihood of intentional nonadherence rose by 20% for every additional AE experienced. Common AEs were a source of worry; particularly the best-known ones, such as hot flushes, reduced libido, cramps, joint ache, and joint stiffness. But the respondents often mentioned other AEs than those most often described in the literature. Memory and concentration problems, the researchers say, are consistent with AEs documented in the neuropsychologic side study of the Tamoxifen Exemestane Adjuvant Multinational trial. This finding, the researchers say, underscores the importance of not restricting assessment in clinical practice to only familiar AEs.

Related: Early Cancer Detection Helps Underserved Women

The researchers concluded with the acknowledgment that endocrine nonadherence is a complex and multifaceted issue in which women’s varied experiences are all factors. In short, one size does not fit all. Thus, they suggest—absent a unifying causal model—that a “promising approach” is to investigate a wide array of women’s experiences and perceptions. Targeting specific concerns and helping women boost self-efficacy could help drive up adherence.

Source
Wouters H, Stiggelbout AM, Bouvy ML, et al. Clin Breast Cancer. 2014;14(6):460-467e2.
doi: 10.1016/j.clbc.2014.04.005.

Endocrine therapy reduces the risk of recurrent breast cancer, but nonadherence is high. Researchers from Utrecht University, Leiden University Medical University, Diaconessenhuis Hospital, and the Netherlands Institute for Health Services Research, all in the Netherlands, felt there was more to nonadherence than most surveys were reporting. So they developed the Tailored Medicine Inventory, which allowed respondents to skip irrelevant items and expand on areas that are usually more limited, such as practical problems they encounter with the treatment.

The 241 survey respondents answered questions about their perceptions of the efficacy of endocrine therapy, worries about adverse effects (AEs), and practical problems that impact adherence, such as packaging, refills, and understanding information. The researchers also assessed perceived self-efficacy, using the Medication Use and Understanding Self-Efficacy scale. They used 2 scales to assess nonadherence: the Medication Adherence Rating Scale-5 and because that scale seemed to underrepresent unintentional nonadherence, they included the Morisky Medication Adherence Scale, with additional questions about forgetting to take the endocrine tablets and persistence.

Related: New Protocol Aims to Evaluate Medication Nonadherence

A substantial number of women were not convinced of the efficacy of endocrine therapy (30%). Some did not believe it was necessary (14%) or doubted its capacity to prevent cancer recurrence (32%). Nineteen percent of the women said they didn’t know how endocrine therapy works, and 20% said that they lacked information about it and didn’t know to what extent it reduced the chance of recurrence.

One hundred sixteen of the women surveyed (48%) experienced ≥ 1 practical problems, most often in the categories of information, intake of tablets, and packaging. All categories except “limitations in daily life” posed “substantial bother” to the women, the researchers say. Practical problems more than doubled the chance of unintentional nonadherence.

Related: Gene Expression Signatures in Breast Cancer: A Surgical Oncologist's Perspective

Self-reported unintentional nonadherence was high (85%), and intentional nonadherence or premature discontinuation was even higher (90%-92%). However, the researchers found no association between perceptions of the efficacy of endocrine therapy and nonadherence. Older women and those who were being treated for recurrent breast cancer were less likely to be unintentionally nonadherent. Perceived self-efficacy was associated with lower levels of both unintentional and intentional nonadherence.

The likelihood of intentional nonadherence rose by 20% for every additional AE experienced. Common AEs were a source of worry; particularly the best-known ones, such as hot flushes, reduced libido, cramps, joint ache, and joint stiffness. But the respondents often mentioned other AEs than those most often described in the literature. Memory and concentration problems, the researchers say, are consistent with AEs documented in the neuropsychologic side study of the Tamoxifen Exemestane Adjuvant Multinational trial. This finding, the researchers say, underscores the importance of not restricting assessment in clinical practice to only familiar AEs.

Related: Early Cancer Detection Helps Underserved Women

The researchers concluded with the acknowledgment that endocrine nonadherence is a complex and multifaceted issue in which women’s varied experiences are all factors. In short, one size does not fit all. Thus, they suggest—absent a unifying causal model—that a “promising approach” is to investigate a wide array of women’s experiences and perceptions. Targeting specific concerns and helping women boost self-efficacy could help drive up adherence.

Source
Wouters H, Stiggelbout AM, Bouvy ML, et al. Clin Breast Cancer. 2014;14(6):460-467e2.
doi: 10.1016/j.clbc.2014.04.005.

Endocrine therapy reduces the risk of recurrent breast cancer, but nonadherence is high. Researchers from Utrecht University, Leiden University Medical University, Diaconessenhuis Hospital, and the Netherlands Institute for Health Services Research, all in the Netherlands, felt there was more to nonadherence than most surveys were reporting. So they developed the Tailored Medicine Inventory, which allowed respondents to skip irrelevant items and expand on areas that are usually more limited, such as practical problems they encounter with the treatment.

The 241 survey respondents answered questions about their perceptions of the efficacy of endocrine therapy, worries about adverse effects (AEs), and practical problems that impact adherence, such as packaging, refills, and understanding information. The researchers also assessed perceived self-efficacy, using the Medication Use and Understanding Self-Efficacy scale. They used 2 scales to assess nonadherence: the Medication Adherence Rating Scale-5 and because that scale seemed to underrepresent unintentional nonadherence, they included the Morisky Medication Adherence Scale, with additional questions about forgetting to take the endocrine tablets and persistence.

Related: New Protocol Aims to Evaluate Medication Nonadherence

A substantial number of women were not convinced of the efficacy of endocrine therapy (30%). Some did not believe it was necessary (14%) or doubted its capacity to prevent cancer recurrence (32%). Nineteen percent of the women said they didn’t know how endocrine therapy works, and 20% said that they lacked information about it and didn’t know to what extent it reduced the chance of recurrence.

One hundred sixteen of the women surveyed (48%) experienced ≥ 1 practical problems, most often in the categories of information, intake of tablets, and packaging. All categories except “limitations in daily life” posed “substantial bother” to the women, the researchers say. Practical problems more than doubled the chance of unintentional nonadherence.

Related: Gene Expression Signatures in Breast Cancer: A Surgical Oncologist's Perspective

Self-reported unintentional nonadherence was high (85%), and intentional nonadherence or premature discontinuation was even higher (90%-92%). However, the researchers found no association between perceptions of the efficacy of endocrine therapy and nonadherence. Older women and those who were being treated for recurrent breast cancer were less likely to be unintentionally nonadherent. Perceived self-efficacy was associated with lower levels of both unintentional and intentional nonadherence.

The likelihood of intentional nonadherence rose by 20% for every additional AE experienced. Common AEs were a source of worry; particularly the best-known ones, such as hot flushes, reduced libido, cramps, joint ache, and joint stiffness. But the respondents often mentioned other AEs than those most often described in the literature. Memory and concentration problems, the researchers say, are consistent with AEs documented in the neuropsychologic side study of the Tamoxifen Exemestane Adjuvant Multinational trial. This finding, the researchers say, underscores the importance of not restricting assessment in clinical practice to only familiar AEs.

Related: Early Cancer Detection Helps Underserved Women

The researchers concluded with the acknowledgment that endocrine nonadherence is a complex and multifaceted issue in which women’s varied experiences are all factors. In short, one size does not fit all. Thus, they suggest—absent a unifying causal model—that a “promising approach” is to investigate a wide array of women’s experiences and perceptions. Targeting specific concerns and helping women boost self-efficacy could help drive up adherence.

Source
Wouters H, Stiggelbout AM, Bouvy ML, et al. Clin Breast Cancer. 2014;14(6):460-467e2.
doi: 10.1016/j.clbc.2014.04.005.

The FDA has approved the first combination pill to treat chronic hepatitis C virus (HCV) infection. This drug is also the first approved regimen that does not require administration with interferon or ribavirin.

The pill combines ledipasvir and sofosbuvir, 2 drugs that interfere with the enzymes HCV needs to multiply. Ledipasvir, a new drug, is an HCV NS5A inhibitor; sofosbuvir is an HCV nucleotide analog NS5B polymerase inhibitor.

Related: Viral Hepatitis Awareness

The recommended dose is 1 tablet taken once daily with or without food. The recommended treatment is 12 weeks for treatment-naïve patients with or without cirrhosis; 12 weeks for treatment-experienced patients (ie, those who have not responded to peginterferon alfa in combination with ribavirin or an HCV protease inhibitor combined with peginterferon alfa and ribavirin) without cirrhosis; and 24 weeks for treatment-experienced patients with cirrhosis. An 8-week treatment can be considered for treatment-naïve patients without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL.

Related: Is Age-Based HCV Screening a Benefit?

The fixed-dose combination (ledipasvir 90 mg, sofosbuvir 400 mg) was evaluated in 3 clinical trials involving 1,518 patients who had not previously received treatment for their infection or who had not responded to previous treatment. Participants were randomly assigned to receive the combination pill with or without ribavirin. In the first trial of treatment-naïve patients, 202 of 215 patients (94%) who received ledipasvir-sofosbuvir for 8 weeks and 208 of 216 patients (96%) who received it for 12 weeks achieved sustained virologic response (SVR). In the second trial, 99% of patients with and without cirrhosis achieved SVR after 12 weeks.

The third trial evaluated efficacy in treatment-experienced participants with and without cirrhosis. In the 12-week arm, 102 of 109 patients (94%) achieved SVR, as did 108 of 109 patients (99%) in the 24-week arm. In all the trials, ribavirin did not increase response rates.

Related: Hepatitis C (Patient Information)

This is the seventh new drug designated as breakthrough therapy to receive FDA approval. It was reviewed under the priority review program, which expedites review of drugs that treat serious conditions and could significantly improve safety or effectiveness. 

Sources
FDA Hepatitis Update—Approval of Harvoni fixed-dose combination tablet (ledipasvir and sofosbuvir) for treatment of Hepatitis C. Silver Spring; MD: U.S. Food and Drug Administration; 2014.

FDA approves first combination pill to treat hepatitis C [news release]. Silver Spring, MD: U.S. Food and Drug Administration; October 10, 2014.

The FDA has approved the first combination pill to treat chronic hepatitis C virus (HCV) infection. This drug is also the first approved regimen that does not require administration with interferon or ribavirin.

The pill combines ledipasvir and sofosbuvir, 2 drugs that interfere with the enzymes HCV needs to multiply. Ledipasvir, a new drug, is an HCV NS5A inhibitor; sofosbuvir is an HCV nucleotide analog NS5B polymerase inhibitor.

Related: Viral Hepatitis Awareness

The recommended dose is 1 tablet taken once daily with or without food. The recommended treatment is 12 weeks for treatment-naïve patients with or without cirrhosis; 12 weeks for treatment-experienced patients (ie, those who have not responded to peginterferon alfa in combination with ribavirin or an HCV protease inhibitor combined with peginterferon alfa and ribavirin) without cirrhosis; and 24 weeks for treatment-experienced patients with cirrhosis. An 8-week treatment can be considered for treatment-naïve patients without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL.

Related: Is Age-Based HCV Screening a Benefit?

The fixed-dose combination (ledipasvir 90 mg, sofosbuvir 400 mg) was evaluated in 3 clinical trials involving 1,518 patients who had not previously received treatment for their infection or who had not responded to previous treatment. Participants were randomly assigned to receive the combination pill with or without ribavirin. In the first trial of treatment-naïve patients, 202 of 215 patients (94%) who received ledipasvir-sofosbuvir for 8 weeks and 208 of 216 patients (96%) who received it for 12 weeks achieved sustained virologic response (SVR). In the second trial, 99% of patients with and without cirrhosis achieved SVR after 12 weeks.

The third trial evaluated efficacy in treatment-experienced participants with and without cirrhosis. In the 12-week arm, 102 of 109 patients (94%) achieved SVR, as did 108 of 109 patients (99%) in the 24-week arm. In all the trials, ribavirin did not increase response rates.

Related: Hepatitis C (Patient Information)

This is the seventh new drug designated as breakthrough therapy to receive FDA approval. It was reviewed under the priority review program, which expedites review of drugs that treat serious conditions and could significantly improve safety or effectiveness. 

Sources
FDA Hepatitis Update—Approval of Harvoni fixed-dose combination tablet (ledipasvir and sofosbuvir) for treatment of Hepatitis C. Silver Spring; MD: U.S. Food and Drug Administration; 2014.

FDA approves first combination pill to treat hepatitis C [news release]. Silver Spring, MD: U.S. Food and Drug Administration; October 10, 2014.

The FDA has approved the first combination pill to treat chronic hepatitis C virus (HCV) infection. This drug is also the first approved regimen that does not require administration with interferon or ribavirin.

The pill combines ledipasvir and sofosbuvir, 2 drugs that interfere with the enzymes HCV needs to multiply. Ledipasvir, a new drug, is an HCV NS5A inhibitor; sofosbuvir is an HCV nucleotide analog NS5B polymerase inhibitor.

Related: Viral Hepatitis Awareness

The recommended dose is 1 tablet taken once daily with or without food. The recommended treatment is 12 weeks for treatment-naïve patients with or without cirrhosis; 12 weeks for treatment-experienced patients (ie, those who have not responded to peginterferon alfa in combination with ribavirin or an HCV protease inhibitor combined with peginterferon alfa and ribavirin) without cirrhosis; and 24 weeks for treatment-experienced patients with cirrhosis. An 8-week treatment can be considered for treatment-naïve patients without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL.

Related: Is Age-Based HCV Screening a Benefit?

The fixed-dose combination (ledipasvir 90 mg, sofosbuvir 400 mg) was evaluated in 3 clinical trials involving 1,518 patients who had not previously received treatment for their infection or who had not responded to previous treatment. Participants were randomly assigned to receive the combination pill with or without ribavirin. In the first trial of treatment-naïve patients, 202 of 215 patients (94%) who received ledipasvir-sofosbuvir for 8 weeks and 208 of 216 patients (96%) who received it for 12 weeks achieved sustained virologic response (SVR). In the second trial, 99% of patients with and without cirrhosis achieved SVR after 12 weeks.

The third trial evaluated efficacy in treatment-experienced participants with and without cirrhosis. In the 12-week arm, 102 of 109 patients (94%) achieved SVR, as did 108 of 109 patients (99%) in the 24-week arm. In all the trials, ribavirin did not increase response rates.

Related: Hepatitis C (Patient Information)

This is the seventh new drug designated as breakthrough therapy to receive FDA approval. It was reviewed under the priority review program, which expedites review of drugs that treat serious conditions and could significantly improve safety or effectiveness. 

Sources
FDA Hepatitis Update—Approval of Harvoni fixed-dose combination tablet (ledipasvir and sofosbuvir) for treatment of Hepatitis C. Silver Spring; MD: U.S. Food and Drug Administration; 2014.

FDA approves first combination pill to treat hepatitis C [news release]. Silver Spring, MD: U.S. Food and Drug Administration; October 10, 2014.

Lhermitte sign, a neuropathic symptom commonly associated with multiple sclerosis, may also be an adverse effect (AE) of oxaliplatin therapy, according to a case report by clinicians from Western Michigan University School of Medicine, Bronson Methodist Hospital, and West Michigan Cancer Center, all in Kalamazoo, Michigan.

Their patient, a Hispanic man aged 50 years with locally advanced colorectal cancer, underwent a laparoscopic low anterior resection, with end-to-end anastomosis. His tumor was stage 3. Because he had a busy work schedule, his physicians decided to treat him with capecitabine and oxaliplatin (CAPEOX), rather than the treatment recommended by the National Comprehensive Cancer Network guidelines of 6 months of adjuvant chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). The FOLFOX regimen uses 85 mg/m² of oxaliplatin every 2 weeks. The CAPEOX regimen uses 130 mg/m² of oxaliplatin every 3 weeks.

Related: The Best Times to Try Abiraterone

After 7 cycles of chemotherapy, the patient developed severe electric shocklike pain that shot down his back and extremities when he bent his neck. He also had a slight tingling and numbness in his upper arms and fingertips. A thorough history and physical examination revealed a classic Lhermitte sign on neck flexion with no other significant findings. The oxaliplatin was discontinued, and he was switched to capecitabine to complete 6 months of adjuvant chemotherapy.

Six months after the oxaliplatin was stopped, his symptoms resolved. A repeat computed tomography scan and 1-year follow-up colonoscopy did not reveal any evidence for recurrent colorectal cancer.

Related: Efficacy of the Colonoscopy Outsourcing Systems Used at a Large VA Medical Center

Lhermitte phenomenon due to chemotherapy is rare, the authors say, although polyneuropathy is a common AE of oxaliplatin at higher doses. The onset of Lhermitte sign can be delayed by weeks to months. The usual cause is cisplatin or oxaliplatin, but it has also been implicated in regimens that include docetaxel, cyclophosphamide, and fludarabine. The cumulative dose in affected patients has ranged from 574 mg to 2,040 mg (this patient had a cumulative dose of 830 mg/m²).

The fact that their patient received a lower cumulative dose than in the other reported cases led his clinicians to believe that there might be an additional mechanism at work in his case, such as greater interval dosing (130 mg/m²) and/or coadministration with capecitabine. A literature review revealed that the case is the first report of Lhermitte sign induced by oxaliplatin in combination with capecitabine in a Hispanic patient with colorectal cancer, concurrently being treated with capecitabine.

They say it isn’t clear, though, whether capecitabine could have a role in causing or potentiating Lhermitte sign. But because capecitabine is being used more often instead of 5-fluorouracil with oxaliplatin in colorectal cancer, the researchers caution that neurologic AEs could happen more frequently. Interestingly, although the authors found reported cases of Lhermitte sign with oxaliplatin, they note that no clinical trials have reported it as an AE of oxaliplatin.

Lhermitte sign, though it can be debilitating, seems to be almost fully reversible, the authors say, with few, if any, residual paresthesias.

Source
Amaraneni A, Seth A, Itawi EA, Chandana SR. Clin Colorectal Cancer. 2014:13(4):257-259.
doi: 10.1016/j.clcc.2014.09.006.

Lhermitte sign, a neuropathic symptom commonly associated with multiple sclerosis, may also be an adverse effect (AE) of oxaliplatin therapy, according to a case report by clinicians from Western Michigan University School of Medicine, Bronson Methodist Hospital, and West Michigan Cancer Center, all in Kalamazoo, Michigan.

Their patient, a Hispanic man aged 50 years with locally advanced colorectal cancer, underwent a laparoscopic low anterior resection, with end-to-end anastomosis. His tumor was stage 3. Because he had a busy work schedule, his physicians decided to treat him with capecitabine and oxaliplatin (CAPEOX), rather than the treatment recommended by the National Comprehensive Cancer Network guidelines of 6 months of adjuvant chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). The FOLFOX regimen uses 85 mg/m² of oxaliplatin every 2 weeks. The CAPEOX regimen uses 130 mg/m² of oxaliplatin every 3 weeks.

Related: The Best Times to Try Abiraterone

After 7 cycles of chemotherapy, the patient developed severe electric shocklike pain that shot down his back and extremities when he bent his neck. He also had a slight tingling and numbness in his upper arms and fingertips. A thorough history and physical examination revealed a classic Lhermitte sign on neck flexion with no other significant findings. The oxaliplatin was discontinued, and he was switched to capecitabine to complete 6 months of adjuvant chemotherapy.

Six months after the oxaliplatin was stopped, his symptoms resolved. A repeat computed tomography scan and 1-year follow-up colonoscopy did not reveal any evidence for recurrent colorectal cancer.

Related: Efficacy of the Colonoscopy Outsourcing Systems Used at a Large VA Medical Center

Lhermitte phenomenon due to chemotherapy is rare, the authors say, although polyneuropathy is a common AE of oxaliplatin at higher doses. The onset of Lhermitte sign can be delayed by weeks to months. The usual cause is cisplatin or oxaliplatin, but it has also been implicated in regimens that include docetaxel, cyclophosphamide, and fludarabine. The cumulative dose in affected patients has ranged from 574 mg to 2,040 mg (this patient had a cumulative dose of 830 mg/m²).

The fact that their patient received a lower cumulative dose than in the other reported cases led his clinicians to believe that there might be an additional mechanism at work in his case, such as greater interval dosing (130 mg/m²) and/or coadministration with capecitabine. A literature review revealed that the case is the first report of Lhermitte sign induced by oxaliplatin in combination with capecitabine in a Hispanic patient with colorectal cancer, concurrently being treated with capecitabine.

They say it isn’t clear, though, whether capecitabine could have a role in causing or potentiating Lhermitte sign. But because capecitabine is being used more often instead of 5-fluorouracil with oxaliplatin in colorectal cancer, the researchers caution that neurologic AEs could happen more frequently. Interestingly, although the authors found reported cases of Lhermitte sign with oxaliplatin, they note that no clinical trials have reported it as an AE of oxaliplatin.

Lhermitte sign, though it can be debilitating, seems to be almost fully reversible, the authors say, with few, if any, residual paresthesias.

Source
Amaraneni A, Seth A, Itawi EA, Chandana SR. Clin Colorectal Cancer. 2014:13(4):257-259.
doi: 10.1016/j.clcc.2014.09.006.

Lhermitte sign, a neuropathic symptom commonly associated with multiple sclerosis, may also be an adverse effect (AE) of oxaliplatin therapy, according to a case report by clinicians from Western Michigan University School of Medicine, Bronson Methodist Hospital, and West Michigan Cancer Center, all in Kalamazoo, Michigan.

Their patient, a Hispanic man aged 50 years with locally advanced colorectal cancer, underwent a laparoscopic low anterior resection, with end-to-end anastomosis. His tumor was stage 3. Because he had a busy work schedule, his physicians decided to treat him with capecitabine and oxaliplatin (CAPEOX), rather than the treatment recommended by the National Comprehensive Cancer Network guidelines of 6 months of adjuvant chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). The FOLFOX regimen uses 85 mg/m² of oxaliplatin every 2 weeks. The CAPEOX regimen uses 130 mg/m² of oxaliplatin every 3 weeks.

Related: The Best Times to Try Abiraterone

After 7 cycles of chemotherapy, the patient developed severe electric shocklike pain that shot down his back and extremities when he bent his neck. He also had a slight tingling and numbness in his upper arms and fingertips. A thorough history and physical examination revealed a classic Lhermitte sign on neck flexion with no other significant findings. The oxaliplatin was discontinued, and he was switched to capecitabine to complete 6 months of adjuvant chemotherapy.

Six months after the oxaliplatin was stopped, his symptoms resolved. A repeat computed tomography scan and 1-year follow-up colonoscopy did not reveal any evidence for recurrent colorectal cancer.

Related: Efficacy of the Colonoscopy Outsourcing Systems Used at a Large VA Medical Center

Lhermitte phenomenon due to chemotherapy is rare, the authors say, although polyneuropathy is a common AE of oxaliplatin at higher doses. The onset of Lhermitte sign can be delayed by weeks to months. The usual cause is cisplatin or oxaliplatin, but it has also been implicated in regimens that include docetaxel, cyclophosphamide, and fludarabine. The cumulative dose in affected patients has ranged from 574 mg to 2,040 mg (this patient had a cumulative dose of 830 mg/m²).

The fact that their patient received a lower cumulative dose than in the other reported cases led his clinicians to believe that there might be an additional mechanism at work in his case, such as greater interval dosing (130 mg/m²) and/or coadministration with capecitabine. A literature review revealed that the case is the first report of Lhermitte sign induced by oxaliplatin in combination with capecitabine in a Hispanic patient with colorectal cancer, concurrently being treated with capecitabine.

They say it isn’t clear, though, whether capecitabine could have a role in causing or potentiating Lhermitte sign. But because capecitabine is being used more often instead of 5-fluorouracil with oxaliplatin in colorectal cancer, the researchers caution that neurologic AEs could happen more frequently. Interestingly, although the authors found reported cases of Lhermitte sign with oxaliplatin, they note that no clinical trials have reported it as an AE of oxaliplatin.

Lhermitte sign, though it can be debilitating, seems to be almost fully reversible, the authors say, with few, if any, residual paresthesias.

Source
Amaraneni A, Seth A, Itawi EA, Chandana SR. Clin Colorectal Cancer. 2014:13(4):257-259.
doi: 10.1016/j.clcc.2014.09.006.