Carbapenem-resistant Enterobacteriaceae: A menace to our most vulnerable patients
ABSTRACTThe emergence of carbapenem-resistant Enterobacteriaceae (CRE) highlights the importance of effective antibiotics to maintain the safety of our health care system. Clinicians will encounter CRE as a cause of difficult-to-treat and often fatal infections in hospitalized patients. We review the mechanisms of carbapenem resistance, the dissemination and clinical impact of these resistant organisms, and challenges to their detection, treatment, and control.
KEY POINTS
- The utility of carbapenems is being undermined by the emergence of resistance in Enterobacteriaceae and other bacteria.
- The clinical impact of CRE falls on elderly patients exposed to these organisms in hospitals and long-term care facilities. In this vulnerable group, invasive infections with CRE exact a high death rate.
- Long-term care facilities play an important role in the transmission dynamics of CRE.
- Tigecycline and colistin are treatments of last resort against infections caused by CRE. Their use in combination with other agents, especially carbapenems, may improve outcomes and needs to be explored further.
- Early detection of CRE in the microbiology laboratory is key to guiding infection control and treatment decisions and supporting surveillance efforts.
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.
