SUMMARY: The spread of Enterobacteriaceae , primarily Klebsiella pneumoniae , producing KPC, VIM, IMP, and NDM carbapenemases, is causing an unprecedented public health crisis. Carbapenemase-producing enterobacteria (CPE) infect mainly hospitalized patients but also have been spreading in long-term care facilities. Given their multidrug resistance, therapeutic options are limited and, as discussed here, should be reevaluated and optimized. Based on susceptibility data, colistin and tigecycline are commonly used to treat CPE infections. Nevertheless, a review of the literature revealed high failure rates in cases of monotherapy with these drugs, whilst monotherapy with either a carbapenem or an aminoglycoside appeared to be more effective. Combination therapies not including carbapenems were comparable to aminoglycoside and carbapenem monotherapies. Higher success rates have been achieved with carbapenem-containing combinations. Pharmacodynamic simulations and experimental infections indicate that modification of the current patterns of carbapenem use against CPE warrants further attention. Epidemiological data, though fragmentary in many countries, indicate CPE foci and transmission routes, to some extent, whilst also underlining the lack of international collaborative systems that could react promptly and effectively. Fortunately, there are sound studies showing successful containment of CPE by bundles of measures, among which the most important are active surveillance cultures, separation of carriers, and assignment of dedicated nursing staff.

Carbapenemase-producing Klebsiella pneumoniae strains (CP-Kps) are currently among the most important nosocomial pathogens. An observational study was conducted during 2009 to 2010 in two hospitals located in a high-prevalence area (Athens, Greece). The aims were (i) to evaluate the clinical outcome of patients with CP-Kp bloodstream infections (BSIs), (ii) to identify predictors of mortality, and (iii) to evaluate the various antibiotic schemes employed. A total of 205 patients with CP-Kp BSIs were identified: 163 (79.5%) were infected with KPC or KPC and VIM, and 42 were infected with VIM producers. For definitive treatment, 103 patients received combination therapy (two or more active drugs), 72 received monotherapy (one active drug), and 12 received therapy with no active drug. The remaining 18 patients died within 48 h after the onset of bacteremia. The all-cause 28-day mortality was 40%. A significantly higher mortality rate was observed in patients treated with monotherapy than in those treated with combination therapy (44.4% versus 27.2%; P = 0.018). The lowest mortality rate (19.3%) was observed in patients treated with carbapenem-containing combinations. In the Cox proportion hazards model, ultimately fatal disease (hazards ratio [HR], 3.25; 95% confidence interval [CI], 1.51 to 7.03; P = 0.003), the presence of rapidly fatal underlying diseases (HR, 4.20; 95% CI, 2.19 to 8.08; P < 0.001), and septic shock (HR, 2.15; 95% CI, 1.16 to 3.96; P = 0.015) were independent predictors of death. Combination therapy was strongly associated with survival (HR of death for monotherapy versus combination, 2.08; 95% CI, 1.23 to 3.51; P = 0.006), mostly due to the effectiveness of the carbapenem-containing regimens.

Carbapenemase-producing Enterobacteriaceae (CPE) have spread worldwide, causing serious infections with increasing frequency. CPE are resistant to almost all available antibiotics, complicating therapy and limiting treatment options. Mortality rates associated with CPE infections are unacceptably high, indicating that the current therapeutic approaches are inadequate and must be revised. Here, we review 20 clinical studies (including those describing the largest cohorts of CPE-infected patients) that provided the necessary information regarding isolate and patient characteristics and treatment schemes, as well as a clear assessment of outcome. The data summarized here indicate that treatment with a single in vitro active agent resulted in mortality rates not significantly different from that observed in patients treated with no active therapy, whereas combination therapy with two or more in vitro active agents was superior to monotherapy, providing a clear survival benefit (mortality rate, 27.4% vs. 38.7%; p <0.001). The lowest mortality rate (18.8%) was observed in patients treated with carbapenem-containing combinations.

Infections caused by carbapenemase-producing Klebsiella pneumoniae (CPKP) are increasing in frequency worldwide. CPKP isolates exhibit extensive drug resistance phenotypes, complicate therapy, and limit treatment options. Although CPKP isolates are often highly resistant to carbapenems, a proportion of these have relatively low MICs for carbapenems, raising the question of whether this class of agents has any therapeutic potential against CPKP infections. Results from animal studies and patient outcome data indicate that carbapenems retain meaningful in vitro activity against CPKP isolates with carbapenem MICs of ≤ 4 mg/L. Accumulating clinical experience also suggests that the therapeutic efficacy of carbapenems against CPKP isolates with MICs of ≤ 4 mg/L is enhanced when these agents are administered in combination with another active antibiotic. The results of human pharmacokinetic/pharmacodynamic studies are in line with the above observations; it is highly probable that a high-dose/prolonged-infusion regimen of a carbapenem would attain a time above the MIC value of 50% for CPKP isolates with MICs up to 4 mg/L, ensuring acceptable drug exposure and favourable treatment outcome. The analyses summarized in this review support the notion that carbapenems have their place in the treatment of CPKP infections and that the currently proposed EUCAST clinical breakpoints could direct physicians in making treatment decisions.

VIM-1-producing Klebsiella pneumoniae (VPKP) is an emerging pathogen. A prospective observational study was conducted to evaluate the importance of VIM production on outcome of patients with K. pneumoniae bloodstream infections (BSIs). Consecutive patients with K. pneumoniae BSIs were identified and followed up until patient discharge or death. A total of 162 patients were included in the analysis; 67 (41.4%) were infected with VPKP, and 95 were infected with non-VPKP. Fourteen of the patients infected with VPKP were carbapenem resistant (Carb ^r ) (MIC > 4 μg/ml), whereas none of the non-VPKP exhibited carbapenem resistance. The patients infected with a Carb ^r organism were more likely (odds ratio, 4.08; 95% confidence interval [CI], 1.29 to 12.85; P = 0.02) to receive inappropriate empirical therapy. The all-cause 14-day mortality rates were 15.8% (15 of 95) for patients infected with VIM-negative organisms, 18.9% (10 of 53) for those infected with VIM-positive carbapenem-susceptible organisms, and 42.9% (6 of 14) for those infected with VIM-positive Carb ^r organisms ( P = 0.044). In Cox regression analysis, age (hazard ratio [HR], 1.03; 95% CI, 1.01 to 1.06; P = 0.021), rapidly fatal underlying disease (HR, 2.84; 95% CI, 1.26 to 6.39; P = 0.012), and carbapenem resistance (HR, 2.83; 95% CI, 1.08 to 7.41; P = 0.035) were independent predictors of death. After adjustment for inappropriate empirical or definitive therapy, the effect of carbapenem resistance on outcome was reduced to a level of nonsignificance. In patients with K. pneumoniae BSIs, carbapenem resistance, advanced, age, and severity of underlying disease were independent predictors of outcome, whereas VIM production had no effect on mortality. The higher mortality associated with carbapenem resistance was probably mediated by the failure to provide effective therapy.