Antimicrobial Resistance Update: Klebsiella pneumoniae Carbapenemases

September 20, 2009

The rapid spread of Klebsiella pneumoniae carbapenemases (KPCs) is limiting the effectiveness of carbapenems in the treatment of multidrug-resistant infections. The resistance genes found in KPCs have been identified in other organisms as well and have properties that have raised concerns regarding their transmissibility and epidemic potential.

Evolving antimicrobial resistance continues to limit the current antimicrobial armamentarium. The care of hospitalized patients is becoming more complex because of the difficulty in choosing appropriate treatment for infections caused by multidrug-resistant organisms, such as Pseudomonas aeruginosa and Acinetobacter baumannii, and extended-spectrum -lactamase (ESBL)-producing organisms. Fortunately, the carbapenems have been reasonably effective last-line agents for the treatment of infections caused by these pathogens. Unfortunately, the rapid spread of Klebsiella pneumoniae carbapenemases (KPCs), which hydrolyze carbapenems as part of a novel resistance mechanism, is limiting the value of these venerable agents.

Originally isolated in North Carolina in 1996, KPCs are becoming more prevalent globally, with outbreaks in Israel, South America, the Caribbean, Scotland, and China, as well as scattered cases elsewhere.1,2 Although 24 states have reported KPCs, the New York/New Jersey area remains “ground zero” of the KPC pandemic, with 24% to 37% of K pneumoniae isolates in select New York City hospitals being identified as KPCs.2

The patient groups most likely to acquire KPC-producing bacteria include the usual patients at risk for infections caused by multidrugresistant organisms: patients with invasive devices, prolonged hospital stays (especially in an ICU), and heavy antibiotic exposure and those who are immunocompromised.3,4

Mechanism and Detection
KPCs are classified as molecular class A, functional group 2f serine b-lactamases.5 They were first identified in K pneumoniae isolates; hence the term “KPC.”6 However, these resistance genes have subsequently been observed in other organisms, including Serratia species, Enterobacter species, Escherichia coli, Citrobacter species, Salmonella enterica, and P aeruginosa.5 These isolates differ from other functional group 2f enzymes (NMC, IMI, SME, GES) in that they have the ability to hydrolyze cefotaxime and are found on plasmids, which are pieces of genetic material that are easily transferable to other similar bacteria and different organisms.5

KPCs also differ from molecular class B metallo--lactamases, which have a zinc atom at the active site, are inhibited by metal ion chelators such as EDTA (ethylenediaminetetraacetic acid), and lack the ability to hydrolyze aztreonam.5 The gene en-coding KPC, blaKPC, is carried on a plasmid, and this factor has raised serious concern regarding the transmissibility and epidemic potential of KPCs.7

Detection of carbapenemase-producing isolates in the microbiology laboratory is difficult.8 Acquisition of a blaKPC gene alone does not always confer resistance to carbapenems, as defined by current breakpoints of the Clinical and Laboratory Standards Institute (CLSI). Some KPC isolates show low-level resistance to carbapenems; the minimal inhibitory concentrations (MICs) are 2 to 4 µg/mL for imipenem and meropenem.9

KPC isolates are generally not susceptible to ertapenem; a study of automated and nonautomated methods to detect KPC production in clinical isolates demonstrated ertapenem susceptibility testing to be the most sensitive method of detecting KPC activity.10 However, as the authors of this study noted, nonsusceptibility to ertapenem is not specific to carbapenemase production and can result from other mechanisms, such as ESBL or AmpC -lactamase production with porin loss.10,11

An effective phenotypic method for confirmation of suspected KPC is the modified Hodge test.12 Anderson and associates10 reported 100% sensitivity and specificity for detection of carbapenemase activity using this test. Polymerase chain reaction (PCR)-based methods will most likely increase the specificity of detection; however, their cost is prohibitive at most centers.2

Clinical Evaluation
As with the isolation of any multi- drug-resistant organism, care must be taken to establish whether the KPC isolate is a colonizer or an invasive pathogen. Isolates from intact skin or stool usually represent colonization, while blood isolates are of obvious clinical importance. Isolates from wounds, urine, and sputum are the most difficult to interpret, and clinical judgment is necessary to avoid either overtreatment of colonization or undertreatment of potentially life-threatening disease. Given the approximate 35% attributable mortality of invasive disease caused by KPCs, this is a critical distinction.7

Treating infections caused by KPCs is difficult because of the limited options. The production of carbapen- emase results in resistance to all penicillins (ampicillin/sulbactam, piperacillin/tazobactam), cephalosporins (cefepime, ceftriaxone), carbapenems (meropenem, imipenem, doripenem, ertapenem), and aztreonam. Resistance to fluoroquinolones, trimethoprim/sulfamethoxazole, and aminoglycosides is commonly observed as well.

Results from in vitro studies consistently show the polymyxins and tigecycline as highly active; however, these agents are less than ideal because of their narrow therapeutic indices and pharmacokinetic profiles.9,13 The polymyxins were abandoned long ago because of the their high rate of nephrotoxicity.14

Despite the availability of these agents for approximately 50 years, little is known regarding their pharmacokinetic and pharmacodynamic profiles to suggest optimal dosing schemes.14 For instance, a pharmacokinetic study by Zavascki and associates15 found that the concentration-time profile of polymyxin B was much lower than what the historical data in the package insert indicated. These data show that the maximal concentration in plasma approaches the MIC of gram-negative pathogens (0.5 to 2 µg/mL), but it does not exceed the MIC to an appreciable degree. Also, less than 1% was found to be excreted in the urine, which brings into question the commonly held belief that the dose must be reduced in patients with preexisting renal impairment.15 Additional work is needed to better define the optimal dosing of polymyxins.

The use of tigecycline is hampered by its high rate of clinically significant nausea (approximately 40%) and low blood levels.16 The maximal concentration after maintenance dosing is less than 1 µg/mL, which is at or below the MIC of gram-negative pathogens for which this agent is considered useful (FDA breakpoint, 2 µg/mL).16 For polymyxins and tigecycline, very little information is available regarding dosing modifications in special populations, such as patients in the ICU, burn victims, or morbidly obese patients.

Clinical outcomes data for patients treated with these agents are sparse. Kelesidis and colleagues17 reviewed the published evidence about the use of tigecycline for multidrug-resistant Enterobacteriaceae. These investigators noted clinical success in 23 of 33 (69.7%); however, only 3 patients had a KPC-producing isolate, and clinical success was observed in only 1 patient.18,19 Despite being classified as a clinical success, this patient had a recurrence of empyema with an increase in the tigecycline MIC from 0.75 to 2 µg/mL.19 This experience is similar to that in other reports of the development of tigecycline resistance during therapy for A baumannii infection.20

Nadkarni and associates21 described 7 patients with PCR-confirmed KPC bacteremia. Only 1 of 3 patients treated with polymyxin B had a successful outcome. Weisenberg and colleagues22 demonstrated a high rate (55.6%) of treatment failure when using imipenem or meropenem alone despite the fact that these drugs had an MIC that was considered susceptible at the start of treatment.

Because of the poor outcomes in the limited published data, it will be imperative to determine the utility of combination therapy with agents not typically active against gram-negative organisms. For example, the novel combination of polymyxin with rifampin has been effective, at least in vitro, against multidrug- resistant P aeruginosa and A baumannii, and carbapenem-resistant K pneumoniae.13,23 It is uncertain what clinical impact the addition of imipenem or meropenem will have for isolates still considered susceptible to tigecycline or colistin by CLSI breakpoints (MICs of 2 or 4 µg/mL, respectively).

Because no alternative antibiotics are available, it is likely that clinicians will turn to unconventional combinations to treat KPC infections. Published results of patient outcomes after treatment with these unconventional regimens are sorely needed. Because of the uncertain results with available antibiotic therapy, interventions to remove the source of infection by mechanical means are of paramount importance. Patel and associates4 identified debridement of infected tissue, drainage of a focus of infection, and removal of infected intravenous catheters as independent predictors of reduced mortality in patients with invasive KPC infections (odds ratio, 0.14; 95% confidence interval, 0.04 to 0.49; P = .002). These adjunctive interventions should be performed in all patients infected with this multidrug-resis- tant organism.

Prevention and Control
The CDC has recently provided guidance on infection control for KPC organisms.3 Detection is obviously paramount, and a review of microbiology records over the preceding 6 to 12 months to determine whether KPCs are present is recommended for facilities that have not previously isolated these organisms. Once KPCs are identified, active surveillance is indicated, which may involve point prevalence surveys in high-risk areas. Patients who are either infected or colonized with KPCs should be placed on contact precautions, and hand hygiene should be emphasized.3

In areas where KPC organisms are already widespread, eradication of organisms may prove difficult, but scrupulous infection control, coupled with a rectal screening surveillance program, has been shown to reduce the incidence of KPC-producing strains.24


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