Panayotis T. Tassios

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.

Proteus mirabilis isolates obtained in 1999 to 2008 from three European countries were analyzed; all carried chromosomal AmpC-type cephalosporinase bla _CMY genes from a Citrobacter freundii origin ( bla _CMY-2 -like genes). Isolates from Poland harbored several bla _CMY genes ( bla _CMY-4 , bla _CMY-12 , bla _CMY-14 , bla _CMY-15 , and bla _CMY-38 and the new gene bla _CMY-45 ), while isolates from Italy and Greece harbored bla _CMY-16 only. Earlier isolates with bla _CMY-4 or bla _CMY-12 , recovered in France from Greek and Algerian patients, were also studied. All isolates showed striking similarities. Their bla _CMY genes resided within IS Ecp1 transposition modules, named Tn 6093 , characterized by a 110-bp distance between IS Ecp1 and bla _CMY , and identical fragments of both C. freundii DNA and a ColE1-type plasmid backbone. Moreover, these modules were inserted into the same chromosomal site, within the pepQ gene. Since ColE1 plasmids carrying IS Ecp1 with similar C. freundii DNA fragments (Tn 6114 ) had been identified earlier, it is likely that a similar molecule had mediated at some stage this DNA transfer between C. freundii and P. mirabilis . In addition, isolates with bla _CMY-12 , bla _CMY-15 , and bla _CMY-38 genes harbored a second bla _CMY copy within a shorter IS Ecp1 module (Tn 6113 ), always inserted downstream of the ppiD gene. Sequence analysis of all mobile bla _CMY-2 -like genes indicated that those integrated in the P. mirabilis chromosome form a distinct cluster that may have evolved by the stepwise accumulation of mutations. All of these observations, coupled to strain typing data, suggest that the bla _CMY genes studied here may have originated from a single IS Ecp1 -mediated mobilization-transfer-integration process, followed by the spread and evolution of a P. mirabilis clone over time and a large geographic area.

To identify risk factors for bloodstream infections (BSIs) caused by VIM-1-producing Klebsiella pneumoniae (VPKP). Consecutive patients with K. pneumoniae BSIs were identified in three tertiary care hospitals between February 2004 and March 2006. Patients infected with VPKP were designated as cases and those infected with non-VPKP as controls. Potential risk factors for VPKP BSIs were examined by univariate and multivariate analysis. A total of 178 patients with K. pneumoniae BSIs were identified; 67 (37.6%) were infected with VPKP (cases) and 111 with non-VPKP (controls). In multivariate analysis, cases were more likely to have been in an intensive care unit (ICU) [odds ratio (OR), 6.78; 95% confidence interval (CI), 2.69–17.06; P < 0.001], have had prior exposure to >3 different classes of antibiotics (OR, 12.6; 95% CI, 2.17–73.27; P = 0.01) and have had prior use of carbapenems (OR, 2.83; 95% CI, 1.07–7.49; P = 0.03). Stay in an ICU, prior use of carbapenems and prior exposure to >3 different classes of antibiotics were independent predictors for VPKP BSIs. These findings provide guidance for antibiotic policies and infection control strategies to contain the spread of VPKP.

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.

In an attempt to compare the epidemiology of severeStreptococcus pyogenesinfection within Europe, prospective data were collected through the Strep-EURO program. Surveillance for severe cases ofS. pyogenesinfection diagnosed during 2003 and 2004 was undertaken in 11 countries across Europe by using a standardized case definition and questionnaire. Patient data as well as bacterial isolates were collected and characterized by T and M/emmtyping, and selected strains were analyzed for the presence of superantigen genes. Data were analyzed to compare the clinical and microbiological patterns of the infections across the participating countries. A total of 4,353 isolates were collected from 5,521 cases with severeS. pyogenesinfections who were identified. A wide diversity of M/emmtypes (n= 104) was found among theS. pyogenesclinical isolates, but the M/emmtype distribution varied broadly between participating countries. The 10 most predominant M/emmtypes were M/emmtype 1 (M/emm1), M/emm28, M/emm3, M/emm89, M/emm87, M/emm12, M/emm4, M/emm83, M/emm81, and M/emm5, in descending order. A correlation was found between some specific disease manifestations, the age of the patients, and theemmtypes. Although streptococcal toxic shock syndrome and necrotizing fasciitis were caused by a large number of types, they were particularly associated with M/emm1 and M/emm3. Theemmtypes included in the 26-valent vaccine under development were generally well represented in the present material; 16 of the vaccine types accounted for 69% of isolates. The Strep-EURO collaborative program has contributed to enhancement of the knowledge of the spread of invasive disease caused byS. pyogeneswithin Europe and encourages future surveillance by the notification of cases and the characterization of strains, which are important for vaccination strategies and other health care issues.