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.

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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.

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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 g/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.Over the last few years, the reliance on carbapenems has been challenged owing to the wide spread of acquired metallo-␤-lactamases [MBLs] (2,11,20,25,31). Two dominant groups of acquired MBLs have been recognized: the IMP and VIM types. This class of enzymes is characterized by the ability to hydrolyze carbapenems and all available ␤-lactams with the exception of aztreonam. Moreover, since the MBL genes are linked to other resistance determinants within the same integron or plasmid, MBL-producing organisms are commonly multidrug resistant, further compromising our therapeutic options (8,26,28).MBLs have spread throughout the world with an overall trend moving from Pseudomonas aeruginosa into Enterobacteriaceae (9,10,14,16,18,22,23,28). Recently, there have been several reports on the emergence of VIM-producing Klebsiella pneumoniae (VPKP), mainly in Southern Europe (16,20). In Greece, VPKP isolates are endemic in various hospitals and cause life-threatening infections (5,8,29). Based on previous reports (30) and on the National Surveillance System for Antibiotic Resistance Database (www.mednet.gr/whonet/top .htm), the dissemination of such isolates appears to have occurred in a r...

The wide dissemination of carbapenemase-producing Gram-negatives (CPGNs), including enterobacterial species and non-fermenters, has caused a public health crisis of global dimensions. These organisms cause serious infections in hospitalized patients, and are associated with increased mortality. Cross-transmission is common, and outbreaks may occur in healthcare facilities where the infection control practices are inadequate. CPGNs exhibit extensive drug-resistant phenotypes, complicate therapy, and limit treatment options. Systematic data on therapy are limited. However, regimens combining two or more active agents seem to be more efficacious than monotherapy in carbapenemase-producing Klebsiella pneumoniae infections. Strict infection control measures, including active surveillance for timely detection of colonized patients, separation of carriers from non-carriers, and contact precautions, are of utmost importance, and may be the only effective way of preventing the introduction and transmission of these bacteria in healthcare settings.

Seventeen Klebsiella pneumoniae clinical isolates carrying the bla VIM-1 metallo-␤-lactamase gene were collected in the intensive care units of three hospitals in Athens, Greece, in 2002. They exhibited various carbapenem resistance levels (Etest MICs of imipenem ranged from 4 to 32 g/ml). All isolates gave positive results by the imipenem-EDTA synergy Etest. The isolates were classified into four main types by pulsed-field gel electrophoresis; the majority of the isolates (5 and 10 isolates) belonged to two types. The bla VIM-1 gene cassette was part of the variable region of a class 1 integron that also included aac6, dhfrI, and aadA. This structure was carried by transferable plasmids.

Apart from the epidemic of KPC-2-producing K. pneumoniae belonging to ST258 in Greece, diffusion of bla(KPC-2) to at least 10 additional STs has taken place. Notably, strains from three of the latter STs (147, 323 and 383) were found to carry both bla(KPC-2) and bla(VIM).