The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

"We need to be responsible individuals with how we shepherd in this new technology." From the Endometriosis Foundation of America's 4th Annual Medical Symposium: The American Perspective, March 11, 2013

Related article: The robot is gaining ground in gynecologic surgery. Should you be using it?
A roundtable discussion with:
Arnold P. Advincula, MD
Cheryl B. Iglesia, MD
Rosanne M. Kho, MD
Jamal Mourad, DO
Marie Fidela R. Paraiso, MD
Jason D. Wright, MD

"We need to be responsible individuals with how we shepherd in this new technology." From the Endometriosis Foundation of America's 4th Annual Medical Symposium: The American Perspective, March 11, 2013

Related article: The robot is gaining ground in gynecologic surgery. Should you be using it?
A roundtable discussion with:
Arnold P. Advincula, MD
Cheryl B. Iglesia, MD
Rosanne M. Kho, MD
Jamal Mourad, DO
Marie Fidela R. Paraiso, MD
Jason D. Wright, MD

"We need to be responsible individuals with how we shepherd in this new technology." From the Endometriosis Foundation of America's 4th Annual Medical Symposium: The American Perspective, March 11, 2013

Related article: The robot is gaining ground in gynecologic surgery. Should you be using it?
A roundtable discussion with:
Arnold P. Advincula, MD
Cheryl B. Iglesia, MD
Rosanne M. Kho, MD
Jamal Mourad, DO
Marie Fidela R. Paraiso, MD
Jason D. Wright, MD

Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.

In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.

The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).

Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.

Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.

Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."

Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.

Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.

Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.

Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.

Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.

Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.

Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.

Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.

In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.

The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).

Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.

Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.

Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."

Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.

Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.

Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.

Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.

Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.

Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.

Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.

Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.

In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.

The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).

Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.

Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.

Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."

Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.

Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.

Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.

Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.

Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.

Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.

Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.

A 57-year-old man presented to the emergency department (ED) with a two-day history of worsening shortness of breath, light-headedness, and back pain. The patient, who had a history of ankylosing spondylitis, had been receiving weekly therapy from a chiropractor for about 10 years. One week before presenting to the ED, he had begun to undergo daily manipulations under anesthesia (MUA)—an aggressive chiropractic procedure that is administered while the patient is under monitored, procedural sedation. After the second day of treatment, the patient began to experience worsening back pain and progressive light-headedness and shortness of breath.

At a follow-up visit with his chiropractor, he was found to have decreased O2 saturation and was directed to go to the hospital for evaluation. On arrival at the ED, the patient was awake and alert. He had intact motor strength in all extremities, no sensory abnormalities, intact symmetric reflexes, and no bladder or bowel dysfunction, with a negative Babinski sign. His O2 saturation was 92% on 5 L of oxygen. An absence of breath sounds was noted on the left side.

Chest x-ray (see Figure 1) was performed, which demonstrated complete opacification of the left hemithorax, consistent with a large pleural effusion or hemothorax. CT scan of the thoracic spine showed diffuse ankylosis. A complex oblique coronal and transversely oriented fracture with 7 mm of displacement was identified, beginning at the right anterior inferior lateral margin of the T8 vertebral body and extending centrally and inferiorly to the left and right into the T9 vertebral body. The fracture continued through the right T9-10 neural foramen and what was probably the right fused T9-10 facet joint. The fracture exited through the left superior and lateral margin of the T10 vertebral body and the left T10-11 neural foramen (see Figures 2, 3, and 4).

A chest tube was inserted in the ED, and 1,600 mL of old blood was immediately drained. The patient was admitted to the ICU on the trauma service. He was taken to surgery for open reduction and internal fixation of his unstable thoracic spine fracture on day 3 of hospitalization, after his pulmonary condition stabilized. Pedicle screws were placed from T7 through T12 during the spinal fusion. Good reduction of the fracture was observed following the spine surgery (see Figures 5 and 6). At the conclusion of surgery, an epidural catheter was placed in the thoracic spine to administer pain control.

After the spine portion of the procedure, the patient was repositioned and underwent video-assisted thoracoscopic surgery of the left hemithorax for evacuation of retained hemothorax. The patient tolerated the procedure well and was taken to the ICU for recovery.

On postoperative day 2, the patient complained of chest pain and experienced hypoxemia with activity. CT angiography of the chest demonstrated bilateral segmental and subsegmental pulmonary emboli. The epidural catheter was discontinued. Six hours later, a heparin drip was started, and the patient was transitioned to therapeutic enoxaparin and warfarin. When methicillin-sensitive Staphylococcus aureus (MSSA) was detected in his hemothorax fluid, he was treated with a course of nafcillin.

The patient was discharged to home on postoperative day 12. He has remained neurologically intact and has returned to his former work activities. He is not taking narcotic pain medications.

Discussion
Chiropractic care is a popular alternative health care modality in the United States. Researchers for the 2007 National Health Interview Study¹ reported an annual use of chiropractic manipulation of 8.6%, while the Medical Expenditure Panel Survey² data yielded an estimate of 12.6 million adults using chiropractic manipulation in 2006—translating to a prevalence of 5.6%. Despite the popularity of chiropractic medicine, few well-designed studies have been conducted to support its use.^3,4 Because of its designation as an alternative therapy, however, chiropractic manipulation has not been subjected to rigorous efficacy and safety evaluations.⁵

Given the inconsistency of the evidence to support chiropractic manipulation, the practice's safety profile is a concern. The risks associated with spinal manipulation are generally described in case reports and small series. Most serious adverse events described in the literature are cerebrovascular in nature and tend to occur after cervical manipulation.^6,7 Fractures after spine manipulation are exceedingly rare, and published literature on this topic consists of a few isolated case reports, with all fractures occurring in the cervical spine in patients with an underlying pathologic condition.^8-10

In 2009, Gouveia et al⁵ reviewed the published literature regarding all adverse events resulting from chiropractic manipulation. The authors found one randomized controlled trial, two case-control studies, six prospective studies, 12 surveys, three retrospective studies, and 100 case reports. The spectrum of complications identified ranged from benign and transient, such as local discomfort, to far more serious: stroke, myelopathy, radiculopathy, subdural hematoma, spinal fluid leakage, cauda equina syndrome, herniated disc, diaphragmatic palsy, and vertebral fractures. The authors were unable to perform a true meta-analysis because of the heterogeneity of the data, but they concluded that complications associated with chiropractic procedures are "frequent."⁵

Manipulations Under Anesthesia
MUA is a procedure that combines chiropractic adjustments and manipulations with general anesthesia or procedural sedation.¹¹ The theory behind this strategy is that the anesthesia or sedation reduces pain and muscle spasm that may hinder the manipulation, allowing the practitioner to more effectively break up joint adhesions and reduce segmental dysfunction than if the patient had not undergone anesthesia.¹¹

MUA is generally indicated in patients who have not responded to a 4- to 8-week trial of traditional manipulation therapy.¹² It is also considered in patients who have "painful and restricting muscular guarding [that] interferes with the performance of spinal adjustments, mobilizations, and soft tissue release techniques."¹³

In the chiropractic literature, between 3% and 10% of patients are estimated to be candidates for MUA.^12,14 It is not completely clear, however, what diagnoses are most likely to be treated successfully with this technique. Contraindications to MUA are generally the same as those for manipulation in conscious patients. A published list of contraindications from the Committee for Manipulation under Anesthesia (2003)¹⁵ included malignancy with bony metastasis, tuberculosis of the bone, recent fracture, acute arthritis, acute gout, diabetic neuropathy, syphilitic articular lesions, excessive spinal osteoporosis, disk fragmentation, direct nerve root impingement, and evidence of cord or caudal compression by tumor, ankylosis, or other space-occupying lesions.

MUA generally begins with deep procedural sedation, managed by an anesthesiologist. Once an adequate level of sedation is achieved, the manipulations are performed. Both high- and low-velocity thrusts are used, but it is recommended that the force exerted should be much less, and the manipulations performed with more caution, than in patients who are not anesthetized.¹²

For the thoracic spine, the patient is manipulated in the supine position with the arms crossed over the chest. The practitioner places one hand in a fist under the spine with the other hand on the patient's crossed arms, then delivers an anterior-to-posterior thrust. This is repeated until all affected segments have been treated.^11,12

Literature to support the use of MUA for various indications is largely anecdotal. The largest published series¹³ is of 177 patients with chronic spinal pain who each underwent three MUA sessions followed by four to six weeks of traditional manipulations. The authors found that pain, as measured by visual analog scale, was reduced by 62% in patients with cervical spine pain, and by 60% in patients with lumbar pain. No adverse events were reported in the study.

Kohlbeck and Haldeman¹² reviewed the reported complications of MUA across all published literature. They found that in 17 published papers, the overall complication rate was 0.7%, mainly represented by transitory increased pain. No spinal fractures were reported.

This case demonstrates a rare but serious complication of chiropractic MUA. It is unclear exactly what mechanism of injury led to an unstable thoracic spine fracture with massive hemothorax, and the precise cause will probably never be known. The clinicians who treated the case patient find it curious that the reported rate of adverse events following this procedure is so low, but they suspect an element of reporting bias in the chiropractic literature.

Conclusion
Iatrogenic injury after chiropractic manipulation is uncommon, but it can be devastating. Few serious complications of chiropractic MUA have been reported, but the literature is lacking in well-designed research studies. Despite the dearth of clinical trials to support its safety and efficacy, use of MUA has continued in the chiropractic community. This case demonstrates that serious adverse outcomes can occur, and more rigorous studies are needed to delineate the true benefits and risks of this set of chiropractic procedures.

References
1. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;12:1-9.

2. Davis MA, Sirovich BE, Weeks WB. Utilization and expenditures on chiropractic care in the United States from 1997 to 2006. Health Serv Res. 2009;45:748-761.

3. Canadian Chiropractic Association; Canadian Federation of Chiropractic Regulatory Boards; Clinical Practice Guidelines Development Initiative; Guidelines Development Committee. Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash. J Can Chiropr Assoc. 2005;49:417-421.

4.

Hurwitz EL, Aker PD, Adams AH, et al. Manipulation and mobilization of the cervical spine: a systematic review of the literature. Spine (Phila Pa 1976). 1996;21:1746-1760.

5.Gouveia LO, Castanho P, Ferreira JJ. Safety of chiropractic interventions: a systematic review. Spine (Phila Pa 1976). 2009;34:E405-E413. 

6. Di Fabio RP. Manipulation of the cervical spine: risks and benefits. Phys Ther. 1999;79:50-65.

7. Nadareishvili Z, Norris JW. Stroke from traumatic arterial dissection. Lancet. 1999;354:159-160.

8. Austin RT. Pathological vertebral fractures after spinal manipulation. Br Med J (Clin Res Ed). 1985;291:1114-1115.

9. Ea HK, Weber AJ, Yon F, Lioté F. Osteoporotic fracture of the dens revealed by cervical manipulation. Joint Bone Spine. 2004;71:246-250.

10. Schmitz A, Lutterbey G, von Engelhardt L, et al. Pathological cervical fracture after spinal manipulation in a pregnant patient. J Manipulative Physiol Ther. 2005;28:633-636.

11. Cremata E, Collins S, Clauson W, et al. Manipulation under anesthesia: a report of four cases. J Manipulative Physiol Ther. 2005;28:526-533.

12. Kohlbeck FJ, Haldeman S. Medication-assisted spinal manipulation. Spine J. 2002;2:288-302.

13. West DT, Mathews RS, Miller MR, Kent GM. Effective management of spinal pain in one hundred seventy-seven patients evaluated for manipulation under anesthesia. J Manipulative Physiol Ther. 1999;22:299-308.

14. Morey LW Jr. Osteopathic manipulation under general anesthesia. J Am Osteopath Assoc. 1973;73:116-127.

15. Tain L, Gunderson C, Cremata E, et al; Committee for Manipulation Under Anesthesia. Recommendations to the Industrial Medical Council Work Group of California for manipulation under anesthesia use for injured workers. Sacramento, CA: Industrial Medical Council; 2003.

A 57-year-old man presented to the emergency department (ED) with a two-day history of worsening shortness of breath, light-headedness, and back pain. The patient, who had a history of ankylosing spondylitis, had been receiving weekly therapy from a chiropractor for about 10 years. One week before presenting to the ED, he had begun to undergo daily manipulations under anesthesia (MUA)—an aggressive chiropractic procedure that is administered while the patient is under monitored, procedural sedation. After the second day of treatment, the patient began to experience worsening back pain and progressive light-headedness and shortness of breath.

At a follow-up visit with his chiropractor, he was found to have decreased O2 saturation and was directed to go to the hospital for evaluation. On arrival at the ED, the patient was awake and alert. He had intact motor strength in all extremities, no sensory abnormalities, intact symmetric reflexes, and no bladder or bowel dysfunction, with a negative Babinski sign. His O2 saturation was 92% on 5 L of oxygen. An absence of breath sounds was noted on the left side.

Chest x-ray (see Figure 1) was performed, which demonstrated complete opacification of the left hemithorax, consistent with a large pleural effusion or hemothorax. CT scan of the thoracic spine showed diffuse ankylosis. A complex oblique coronal and transversely oriented fracture with 7 mm of displacement was identified, beginning at the right anterior inferior lateral margin of the T8 vertebral body and extending centrally and inferiorly to the left and right into the T9 vertebral body. The fracture continued through the right T9-10 neural foramen and what was probably the right fused T9-10 facet joint. The fracture exited through the left superior and lateral margin of the T10 vertebral body and the left T10-11 neural foramen (see Figures 2, 3, and 4).

A chest tube was inserted in the ED, and 1,600 mL of old blood was immediately drained. The patient was admitted to the ICU on the trauma service. He was taken to surgery for open reduction and internal fixation of his unstable thoracic spine fracture on day 3 of hospitalization, after his pulmonary condition stabilized. Pedicle screws were placed from T7 through T12 during the spinal fusion. Good reduction of the fracture was observed following the spine surgery (see Figures 5 and 6). At the conclusion of surgery, an epidural catheter was placed in the thoracic spine to administer pain control.

After the spine portion of the procedure, the patient was repositioned and underwent video-assisted thoracoscopic surgery of the left hemithorax for evacuation of retained hemothorax. The patient tolerated the procedure well and was taken to the ICU for recovery.

On postoperative day 2, the patient complained of chest pain and experienced hypoxemia with activity. CT angiography of the chest demonstrated bilateral segmental and subsegmental pulmonary emboli. The epidural catheter was discontinued. Six hours later, a heparin drip was started, and the patient was transitioned to therapeutic enoxaparin and warfarin. When methicillin-sensitive Staphylococcus aureus (MSSA) was detected in his hemothorax fluid, he was treated with a course of nafcillin.

The patient was discharged to home on postoperative day 12. He has remained neurologically intact and has returned to his former work activities. He is not taking narcotic pain medications.

Discussion
Chiropractic care is a popular alternative health care modality in the United States. Researchers for the 2007 National Health Interview Study¹ reported an annual use of chiropractic manipulation of 8.6%, while the Medical Expenditure Panel Survey² data yielded an estimate of 12.6 million adults using chiropractic manipulation in 2006—translating to a prevalence of 5.6%. Despite the popularity of chiropractic medicine, few well-designed studies have been conducted to support its use.^3,4 Because of its designation as an alternative therapy, however, chiropractic manipulation has not been subjected to rigorous efficacy and safety evaluations.⁵

Given the inconsistency of the evidence to support chiropractic manipulation, the practice's safety profile is a concern. The risks associated with spinal manipulation are generally described in case reports and small series. Most serious adverse events described in the literature are cerebrovascular in nature and tend to occur after cervical manipulation.^6,7 Fractures after spine manipulation are exceedingly rare, and published literature on this topic consists of a few isolated case reports, with all fractures occurring in the cervical spine in patients with an underlying pathologic condition.^8-10

In 2009, Gouveia et al⁵ reviewed the published literature regarding all adverse events resulting from chiropractic manipulation. The authors found one randomized controlled trial, two case-control studies, six prospective studies, 12 surveys, three retrospective studies, and 100 case reports. The spectrum of complications identified ranged from benign and transient, such as local discomfort, to far more serious: stroke, myelopathy, radiculopathy, subdural hematoma, spinal fluid leakage, cauda equina syndrome, herniated disc, diaphragmatic palsy, and vertebral fractures. The authors were unable to perform a true meta-analysis because of the heterogeneity of the data, but they concluded that complications associated with chiropractic procedures are "frequent."⁵

Manipulations Under Anesthesia
MUA is a procedure that combines chiropractic adjustments and manipulations with general anesthesia or procedural sedation.¹¹ The theory behind this strategy is that the anesthesia or sedation reduces pain and muscle spasm that may hinder the manipulation, allowing the practitioner to more effectively break up joint adhesions and reduce segmental dysfunction than if the patient had not undergone anesthesia.¹¹

MUA is generally indicated in patients who have not responded to a 4- to 8-week trial of traditional manipulation therapy.¹² It is also considered in patients who have "painful and restricting muscular guarding [that] interferes with the performance of spinal adjustments, mobilizations, and soft tissue release techniques."¹³

In the chiropractic literature, between 3% and 10% of patients are estimated to be candidates for MUA.^12,14 It is not completely clear, however, what diagnoses are most likely to be treated successfully with this technique. Contraindications to MUA are generally the same as those for manipulation in conscious patients. A published list of contraindications from the Committee for Manipulation under Anesthesia (2003)¹⁵ included malignancy with bony metastasis, tuberculosis of the bone, recent fracture, acute arthritis, acute gout, diabetic neuropathy, syphilitic articular lesions, excessive spinal osteoporosis, disk fragmentation, direct nerve root impingement, and evidence of cord or caudal compression by tumor, ankylosis, or other space-occupying lesions.

MUA generally begins with deep procedural sedation, managed by an anesthesiologist. Once an adequate level of sedation is achieved, the manipulations are performed. Both high- and low-velocity thrusts are used, but it is recommended that the force exerted should be much less, and the manipulations performed with more caution, than in patients who are not anesthetized.¹²

For the thoracic spine, the patient is manipulated in the supine position with the arms crossed over the chest. The practitioner places one hand in a fist under the spine with the other hand on the patient's crossed arms, then delivers an anterior-to-posterior thrust. This is repeated until all affected segments have been treated.^11,12

Literature to support the use of MUA for various indications is largely anecdotal. The largest published series¹³ is of 177 patients with chronic spinal pain who each underwent three MUA sessions followed by four to six weeks of traditional manipulations. The authors found that pain, as measured by visual analog scale, was reduced by 62% in patients with cervical spine pain, and by 60% in patients with lumbar pain. No adverse events were reported in the study.

Kohlbeck and Haldeman¹² reviewed the reported complications of MUA across all published literature. They found that in 17 published papers, the overall complication rate was 0.7%, mainly represented by transitory increased pain. No spinal fractures were reported.

This case demonstrates a rare but serious complication of chiropractic MUA. It is unclear exactly what mechanism of injury led to an unstable thoracic spine fracture with massive hemothorax, and the precise cause will probably never be known. The clinicians who treated the case patient find it curious that the reported rate of adverse events following this procedure is so low, but they suspect an element of reporting bias in the chiropractic literature.

Conclusion
Iatrogenic injury after chiropractic manipulation is uncommon, but it can be devastating. Few serious complications of chiropractic MUA have been reported, but the literature is lacking in well-designed research studies. Despite the dearth of clinical trials to support its safety and efficacy, use of MUA has continued in the chiropractic community. This case demonstrates that serious adverse outcomes can occur, and more rigorous studies are needed to delineate the true benefits and risks of this set of chiropractic procedures.

References
1. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;12:1-9.

2. Davis MA, Sirovich BE, Weeks WB. Utilization and expenditures on chiropractic care in the United States from 1997 to 2006. Health Serv Res. 2009;45:748-761.

3. Canadian Chiropractic Association; Canadian Federation of Chiropractic Regulatory Boards; Clinical Practice Guidelines Development Initiative; Guidelines Development Committee. Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash. J Can Chiropr Assoc. 2005;49:417-421.

4.

Hurwitz EL, Aker PD, Adams AH, et al. Manipulation and mobilization of the cervical spine: a systematic review of the literature. Spine (Phila Pa 1976). 1996;21:1746-1760.

5.Gouveia LO, Castanho P, Ferreira JJ. Safety of chiropractic interventions: a systematic review. Spine (Phila Pa 1976). 2009;34:E405-E413. 

6. Di Fabio RP. Manipulation of the cervical spine: risks and benefits. Phys Ther. 1999;79:50-65.

7. Nadareishvili Z, Norris JW. Stroke from traumatic arterial dissection. Lancet. 1999;354:159-160.

8. Austin RT. Pathological vertebral fractures after spinal manipulation. Br Med J (Clin Res Ed). 1985;291:1114-1115.

9. Ea HK, Weber AJ, Yon F, Lioté F. Osteoporotic fracture of the dens revealed by cervical manipulation. Joint Bone Spine. 2004;71:246-250.

10. Schmitz A, Lutterbey G, von Engelhardt L, et al. Pathological cervical fracture after spinal manipulation in a pregnant patient. J Manipulative Physiol Ther. 2005;28:633-636.

11. Cremata E, Collins S, Clauson W, et al. Manipulation under anesthesia: a report of four cases. J Manipulative Physiol Ther. 2005;28:526-533.

12. Kohlbeck FJ, Haldeman S. Medication-assisted spinal manipulation. Spine J. 2002;2:288-302.

13. West DT, Mathews RS, Miller MR, Kent GM. Effective management of spinal pain in one hundred seventy-seven patients evaluated for manipulation under anesthesia. J Manipulative Physiol Ther. 1999;22:299-308.

14. Morey LW Jr. Osteopathic manipulation under general anesthesia. J Am Osteopath Assoc. 1973;73:116-127.

15. Tain L, Gunderson C, Cremata E, et al; Committee for Manipulation Under Anesthesia. Recommendations to the Industrial Medical Council Work Group of California for manipulation under anesthesia use for injured workers. Sacramento, CA: Industrial Medical Council; 2003.

A 57-year-old man presented to the emergency department (ED) with a two-day history of worsening shortness of breath, light-headedness, and back pain. The patient, who had a history of ankylosing spondylitis, had been receiving weekly therapy from a chiropractor for about 10 years. One week before presenting to the ED, he had begun to undergo daily manipulations under anesthesia (MUA)—an aggressive chiropractic procedure that is administered while the patient is under monitored, procedural sedation. After the second day of treatment, the patient began to experience worsening back pain and progressive light-headedness and shortness of breath.

At a follow-up visit with his chiropractor, he was found to have decreased O2 saturation and was directed to go to the hospital for evaluation. On arrival at the ED, the patient was awake and alert. He had intact motor strength in all extremities, no sensory abnormalities, intact symmetric reflexes, and no bladder or bowel dysfunction, with a negative Babinski sign. His O2 saturation was 92% on 5 L of oxygen. An absence of breath sounds was noted on the left side.

Chest x-ray (see Figure 1) was performed, which demonstrated complete opacification of the left hemithorax, consistent with a large pleural effusion or hemothorax. CT scan of the thoracic spine showed diffuse ankylosis. A complex oblique coronal and transversely oriented fracture with 7 mm of displacement was identified, beginning at the right anterior inferior lateral margin of the T8 vertebral body and extending centrally and inferiorly to the left and right into the T9 vertebral body. The fracture continued through the right T9-10 neural foramen and what was probably the right fused T9-10 facet joint. The fracture exited through the left superior and lateral margin of the T10 vertebral body and the left T10-11 neural foramen (see Figures 2, 3, and 4).

A chest tube was inserted in the ED, and 1,600 mL of old blood was immediately drained. The patient was admitted to the ICU on the trauma service. He was taken to surgery for open reduction and internal fixation of his unstable thoracic spine fracture on day 3 of hospitalization, after his pulmonary condition stabilized. Pedicle screws were placed from T7 through T12 during the spinal fusion. Good reduction of the fracture was observed following the spine surgery (see Figures 5 and 6). At the conclusion of surgery, an epidural catheter was placed in the thoracic spine to administer pain control.

After the spine portion of the procedure, the patient was repositioned and underwent video-assisted thoracoscopic surgery of the left hemithorax for evacuation of retained hemothorax. The patient tolerated the procedure well and was taken to the ICU for recovery.

On postoperative day 2, the patient complained of chest pain and experienced hypoxemia with activity. CT angiography of the chest demonstrated bilateral segmental and subsegmental pulmonary emboli. The epidural catheter was discontinued. Six hours later, a heparin drip was started, and the patient was transitioned to therapeutic enoxaparin and warfarin. When methicillin-sensitive Staphylococcus aureus (MSSA) was detected in his hemothorax fluid, he was treated with a course of nafcillin.

The patient was discharged to home on postoperative day 12. He has remained neurologically intact and has returned to his former work activities. He is not taking narcotic pain medications.

Discussion
Chiropractic care is a popular alternative health care modality in the United States. Researchers for the 2007 National Health Interview Study¹ reported an annual use of chiropractic manipulation of 8.6%, while the Medical Expenditure Panel Survey² data yielded an estimate of 12.6 million adults using chiropractic manipulation in 2006—translating to a prevalence of 5.6%. Despite the popularity of chiropractic medicine, few well-designed studies have been conducted to support its use.^3,4 Because of its designation as an alternative therapy, however, chiropractic manipulation has not been subjected to rigorous efficacy and safety evaluations.⁵

Given the inconsistency of the evidence to support chiropractic manipulation, the practice's safety profile is a concern. The risks associated with spinal manipulation are generally described in case reports and small series. Most serious adverse events described in the literature are cerebrovascular in nature and tend to occur after cervical manipulation.^6,7 Fractures after spine manipulation are exceedingly rare, and published literature on this topic consists of a few isolated case reports, with all fractures occurring in the cervical spine in patients with an underlying pathologic condition.^8-10

In 2009, Gouveia et al⁵ reviewed the published literature regarding all adverse events resulting from chiropractic manipulation. The authors found one randomized controlled trial, two case-control studies, six prospective studies, 12 surveys, three retrospective studies, and 100 case reports. The spectrum of complications identified ranged from benign and transient, such as local discomfort, to far more serious: stroke, myelopathy, radiculopathy, subdural hematoma, spinal fluid leakage, cauda equina syndrome, herniated disc, diaphragmatic palsy, and vertebral fractures. The authors were unable to perform a true meta-analysis because of the heterogeneity of the data, but they concluded that complications associated with chiropractic procedures are "frequent."⁵

Manipulations Under Anesthesia
MUA is a procedure that combines chiropractic adjustments and manipulations with general anesthesia or procedural sedation.¹¹ The theory behind this strategy is that the anesthesia or sedation reduces pain and muscle spasm that may hinder the manipulation, allowing the practitioner to more effectively break up joint adhesions and reduce segmental dysfunction than if the patient had not undergone anesthesia.¹¹

MUA is generally indicated in patients who have not responded to a 4- to 8-week trial of traditional manipulation therapy.¹² It is also considered in patients who have "painful and restricting muscular guarding [that] interferes with the performance of spinal adjustments, mobilizations, and soft tissue release techniques."¹³

In the chiropractic literature, between 3% and 10% of patients are estimated to be candidates for MUA.^12,14 It is not completely clear, however, what diagnoses are most likely to be treated successfully with this technique. Contraindications to MUA are generally the same as those for manipulation in conscious patients. A published list of contraindications from the Committee for Manipulation under Anesthesia (2003)¹⁵ included malignancy with bony metastasis, tuberculosis of the bone, recent fracture, acute arthritis, acute gout, diabetic neuropathy, syphilitic articular lesions, excessive spinal osteoporosis, disk fragmentation, direct nerve root impingement, and evidence of cord or caudal compression by tumor, ankylosis, or other space-occupying lesions.

MUA generally begins with deep procedural sedation, managed by an anesthesiologist. Once an adequate level of sedation is achieved, the manipulations are performed. Both high- and low-velocity thrusts are used, but it is recommended that the force exerted should be much less, and the manipulations performed with more caution, than in patients who are not anesthetized.¹²

For the thoracic spine, the patient is manipulated in the supine position with the arms crossed over the chest. The practitioner places one hand in a fist under the spine with the other hand on the patient's crossed arms, then delivers an anterior-to-posterior thrust. This is repeated until all affected segments have been treated.^11,12

Literature to support the use of MUA for various indications is largely anecdotal. The largest published series¹³ is of 177 patients with chronic spinal pain who each underwent three MUA sessions followed by four to six weeks of traditional manipulations. The authors found that pain, as measured by visual analog scale, was reduced by 62% in patients with cervical spine pain, and by 60% in patients with lumbar pain. No adverse events were reported in the study.

Kohlbeck and Haldeman¹² reviewed the reported complications of MUA across all published literature. They found that in 17 published papers, the overall complication rate was 0.7%, mainly represented by transitory increased pain. No spinal fractures were reported.

This case demonstrates a rare but serious complication of chiropractic MUA. It is unclear exactly what mechanism of injury led to an unstable thoracic spine fracture with massive hemothorax, and the precise cause will probably never be known. The clinicians who treated the case patient find it curious that the reported rate of adverse events following this procedure is so low, but they suspect an element of reporting bias in the chiropractic literature.

Conclusion
Iatrogenic injury after chiropractic manipulation is uncommon, but it can be devastating. Few serious complications of chiropractic MUA have been reported, but the literature is lacking in well-designed research studies. Despite the dearth of clinical trials to support its safety and efficacy, use of MUA has continued in the chiropractic community. This case demonstrates that serious adverse outcomes can occur, and more rigorous studies are needed to delineate the true benefits and risks of this set of chiropractic procedures.

References
1. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;12:1-9.

2. Davis MA, Sirovich BE, Weeks WB. Utilization and expenditures on chiropractic care in the United States from 1997 to 2006. Health Serv Res. 2009;45:748-761.

3. Canadian Chiropractic Association; Canadian Federation of Chiropractic Regulatory Boards; Clinical Practice Guidelines Development Initiative; Guidelines Development Committee. Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash. J Can Chiropr Assoc. 2005;49:417-421.

4.

Hurwitz EL, Aker PD, Adams AH, et al. Manipulation and mobilization of the cervical spine: a systematic review of the literature. Spine (Phila Pa 1976). 1996;21:1746-1760.

5.Gouveia LO, Castanho P, Ferreira JJ. Safety of chiropractic interventions: a systematic review. Spine (Phila Pa 1976). 2009;34:E405-E413. 

6. Di Fabio RP. Manipulation of the cervical spine: risks and benefits. Phys Ther. 1999;79:50-65.

7. Nadareishvili Z, Norris JW. Stroke from traumatic arterial dissection. Lancet. 1999;354:159-160.

8. Austin RT. Pathological vertebral fractures after spinal manipulation. Br Med J (Clin Res Ed). 1985;291:1114-1115.

9. Ea HK, Weber AJ, Yon F, Lioté F. Osteoporotic fracture of the dens revealed by cervical manipulation. Joint Bone Spine. 2004;71:246-250.

10. Schmitz A, Lutterbey G, von Engelhardt L, et al. Pathological cervical fracture after spinal manipulation in a pregnant patient. J Manipulative Physiol Ther. 2005;28:633-636.

11. Cremata E, Collins S, Clauson W, et al. Manipulation under anesthesia: a report of four cases. J Manipulative Physiol Ther. 2005;28:526-533.

12. Kohlbeck FJ, Haldeman S. Medication-assisted spinal manipulation. Spine J. 2002;2:288-302.

13. West DT, Mathews RS, Miller MR, Kent GM. Effective management of spinal pain in one hundred seventy-seven patients evaluated for manipulation under anesthesia. J Manipulative Physiol Ther. 1999;22:299-308.

14. Morey LW Jr. Osteopathic manipulation under general anesthesia. J Am Osteopath Assoc. 1973;73:116-127.

15. Tain L, Gunderson C, Cremata E, et al; Committee for Manipulation Under Anesthesia. Recommendations to the Industrial Medical Council Work Group of California for manipulation under anesthesia use for injured workers. Sacramento, CA: Industrial Medical Council; 2003.

To read the full study, click here.

To read the full study, click here.

To read the full study, click here.

“Counseling is a must with this smoking cessation aid,” stated a PURL published in March 2012 (J Fam Pract. 2012;61:156, 176). “Varenicline [Chantix] is associated with a small but significant harmful effect on CV outcomes.” That statement, and the PURL itself, was based on a meta-analysis published in 2011 by Singh et al.1 The meta-analysis included 14 randomized controlled trials (RCTs) that compared varenicline with placebo for the occurrence of serious cardiovascular disease (CVD) events, including myocardial infarction, coronary artery disease, arrhythmias, stroke, sudden death, and any related coronary death. RCTs that reported no CVD events were excluded.

Using a Peto odds ratio [OR] for analysis, Singh et al reported that varenicline use increased the risk of CVD events compared with placebo (OR=1.72; 95% CI, 1.09-2.71). A more recent meta-analysis by Prochaska et al,² however, challenges the validity of the Singh meta-analysis. As members of the Family Physicians Inquiries Network, which produces the PURLs, we would like to address the questions this newer study raises about varenicline’s actual risk.

The Prochaska meta-analysis included all 14 RCTs analyzed by Singh, and used the same CVD event outcome measures. In addition, Prochaska included 8 trials in which no CVD events were reported, some of which were published after the Singh meta-analysis. And rather than use the Peto OR to estimate the risk, Prochaska calculated the absolute risk (AR). The result? The researchers found no difference in CVD events in the varenicline group compared with placebo (AR=0.27; 95% CI, -0.10 to 0.63; P=.15).

This is a good example of how inclusion criteria, subsequently published clinical trials, and the choice of statistical methods can lead to conflicting conclusions from meta-analyses on the same topic. Including studies that showed no adverse CVD events is more likely to capture the true risk than excluding them, and reporting AR is more meaningful than estimating relative risk based on the Peto OR.

Therefore, the Prochaska findings are more convincing. Given the effectiveness of varenicline and the known benefits of successful smoking cessation, it is important for clinicians to understand that the true risk of CVD adverse events attributable to varenicline is extremely low or even nonexistent.

Dionna Brown, MD
Bernard Ewigman, MD, MSPH
Chicago

“Counseling is a must with this smoking cessation aid,” stated a PURL published in March 2012 (J Fam Pract. 2012;61:156, 176). “Varenicline [Chantix] is associated with a small but significant harmful effect on CV outcomes.” That statement, and the PURL itself, was based on a meta-analysis published in 2011 by Singh et al.1 The meta-analysis included 14 randomized controlled trials (RCTs) that compared varenicline with placebo for the occurrence of serious cardiovascular disease (CVD) events, including myocardial infarction, coronary artery disease, arrhythmias, stroke, sudden death, and any related coronary death. RCTs that reported no CVD events were excluded.

Using a Peto odds ratio [OR] for analysis, Singh et al reported that varenicline use increased the risk of CVD events compared with placebo (OR=1.72; 95% CI, 1.09-2.71). A more recent meta-analysis by Prochaska et al,² however, challenges the validity of the Singh meta-analysis. As members of the Family Physicians Inquiries Network, which produces the PURLs, we would like to address the questions this newer study raises about varenicline’s actual risk.

The Prochaska meta-analysis included all 14 RCTs analyzed by Singh, and used the same CVD event outcome measures. In addition, Prochaska included 8 trials in which no CVD events were reported, some of which were published after the Singh meta-analysis. And rather than use the Peto OR to estimate the risk, Prochaska calculated the absolute risk (AR). The result? The researchers found no difference in CVD events in the varenicline group compared with placebo (AR=0.27; 95% CI, -0.10 to 0.63; P=.15).

This is a good example of how inclusion criteria, subsequently published clinical trials, and the choice of statistical methods can lead to conflicting conclusions from meta-analyses on the same topic. Including studies that showed no adverse CVD events is more likely to capture the true risk than excluding them, and reporting AR is more meaningful than estimating relative risk based on the Peto OR.

Therefore, the Prochaska findings are more convincing. Given the effectiveness of varenicline and the known benefits of successful smoking cessation, it is important for clinicians to understand that the true risk of CVD adverse events attributable to varenicline is extremely low or even nonexistent.

Dionna Brown, MD
Bernard Ewigman, MD, MSPH
Chicago

“Counseling is a must with this smoking cessation aid,” stated a PURL published in March 2012 (J Fam Pract. 2012;61:156, 176). “Varenicline [Chantix] is associated with a small but significant harmful effect on CV outcomes.” That statement, and the PURL itself, was based on a meta-analysis published in 2011 by Singh et al.1 The meta-analysis included 14 randomized controlled trials (RCTs) that compared varenicline with placebo for the occurrence of serious cardiovascular disease (CVD) events, including myocardial infarction, coronary artery disease, arrhythmias, stroke, sudden death, and any related coronary death. RCTs that reported no CVD events were excluded.

Using a Peto odds ratio [OR] for analysis, Singh et al reported that varenicline use increased the risk of CVD events compared with placebo (OR=1.72; 95% CI, 1.09-2.71). A more recent meta-analysis by Prochaska et al,² however, challenges the validity of the Singh meta-analysis. As members of the Family Physicians Inquiries Network, which produces the PURLs, we would like to address the questions this newer study raises about varenicline’s actual risk.

The Prochaska meta-analysis included all 14 RCTs analyzed by Singh, and used the same CVD event outcome measures. In addition, Prochaska included 8 trials in which no CVD events were reported, some of which were published after the Singh meta-analysis. And rather than use the Peto OR to estimate the risk, Prochaska calculated the absolute risk (AR). The result? The researchers found no difference in CVD events in the varenicline group compared with placebo (AR=0.27; 95% CI, -0.10 to 0.63; P=.15).

This is a good example of how inclusion criteria, subsequently published clinical trials, and the choice of statistical methods can lead to conflicting conclusions from meta-analyses on the same topic. Including studies that showed no adverse CVD events is more likely to capture the true risk than excluding them, and reporting AR is more meaningful than estimating relative risk based on the Peto OR.

Therefore, the Prochaska findings are more convincing. Given the effectiveness of varenicline and the known benefits of successful smoking cessation, it is important for clinicians to understand that the true risk of CVD adverse events attributable to varenicline is extremely low or even nonexistent.

Dionna Brown, MD
Bernard Ewigman, MD, MSPH
Chicago