Mitchell J. Schwaber

Comparison of Mortality Associated with Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Meta-analysis

A meta-analysis was performed to summarize the impact of methicillin-resistance on mortality in Staphylococcus aureus bacteremia. A search of the MEDLINE database for studies published during the period of 1 January 1980 through 31 December 2000 and a bibliographic review identified English-language studies of S. aureus bacteremia. Studies were included if they contained the numbers of and mortality rates for patients with methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) bacteremia. Data were extracted on demographic characteristics of the patients, adjustment for severity and comorbid illness, source of bacteremia, and crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for in-hospital mortality. When the results were pooled with a random-effects model, a significant increase in mortality associated with MRSA bacteremia was evident (OR, 1.93; 95% CI, 1.54-2.42; P<.001); significant heterogeneity was present. We explored the reasons for heterogeneity by means of subgroup analyses. MRSA bacteremia is associated with significantly higher mortality rate than is MSSA bacteremia.

Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.

Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.

Predictors of Carbapenem-Resistant Klebsiella pneumoniae Acquisition among Hospitalized Adults and Effect of Acquisition on Mortality

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging nosocomial pathogen. Little is known about its risk factors or mortality. We performed a case-case-control study to assess the risks for CRKP isolation and a retrospective cohort study to assess mortality in three groups of hospitalized adults: (i) patients from whom CRKP was isolated, (ii) patients from whom carbapenem-susceptible Klebsiella spp. (CSKS) were isolated, and (iii) controls from whom no Klebsiella spp. were isolated. After adjustment for length of stay (LOS), the demographics, comorbidities, and exposures of each case group were compared with those of the controls. Significant covariates were incorporated into LOS-adjusted multivariable models. In the mortality study, we evaluated the effect of CRKP on in-hospital death. There were 48 patients with CRKP isolation (21 died [44%]), 56 patients with CSKS isolation (7 died [12.5%]), and 59 controls (1 died [2%]). Independent risk factors for CRKP isolation were poor functional status (odds ratio [OR], 15.4; 95% confidence interval [CI], 4.0 to 58.6; P < 0.001); intensive care unit (ICU) stay (OR, 17.4; 95% CI, 1.5 to 201.9; P = 0.02); and receipt of antibiotics (OR, 4.4; 95% CI, 1.0 to 19.2; P = 0.05), particularly fluoroquinolones (OR, 7.2; 95% CI, 1.1 to 49.4; P = 0.04). CRKP was independently associated with death when patients with CRKP were compared with patients with CSKS (OR, 5.4; 95% CI, 1.7 to 17.1; P = 0.005) and with controls (OR, 6.7; 95% CI, 2.4 to 18.8; P < 0.001). After adjustment for the severity of illness, CRKP isolation remained predictive of death, albeit with a lower OR (for the CRKP group versus the CSKS group, OR, 3.9; 95% CI, 1.1 to 13.6; and P = 0.03; for the CRKP group versus the controls, OR, 5.0; 95% CI, 1.7 to 14.8; and P = 0.004). CRKP affects patients with poor functional status, an ICU stay, and antibiotic exposure and is an independent predictor of death.

Clinical and Economic Impact of Bacteremia with Extended- Spectrum-β-Lactamase-Producing Enterobacteriaceae

ABSTRACT We studied outcomes of extended-spectrum β-lactamase (ESBL) production in Enterobacteriaceae bacteremia. Inpatients with bacteremia caused by ESBL-producing Escherichia coli, Klebsiella spp., or Proteus spp. (cases) were compared with patients with bacteremia caused by non-ESBL producers (controls). Outcomes included mortality, mortality due to infection, length of stay (LOS), delay in appropriate therapy (DAT), discharge to a chronic care facility, and hospital cost. Ninety-nine cases and 99 controls were enrolled. Thirty-five percent of cases died, versus 18% of controls (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.3 to 4.7; P = 0.01). Thirty percent of cases died due to infection, versus 16% of controls (OR, 2.3; 95% CI, 1.1 to 4.5; P = 0.03). The median LOS after bacteremia for cases was 11 days (interquartile range, 5 to 21), versus 5 days for controls (interquartile range, 3 to 9) (P < 0.001). DAT occurred in 66% of cases, versus 7% of controls (OR, 25.1; 95% CI, 10.5 to 60.2; P < 0.001). Cases were more likely than controls to be discharged to chronic care (52% versus 21%; OR, 4.0; 95% CI, 1.9 to 8.3; P < 0.001). The average hospital cost for cases was 65,509 Israeli shekels, versus 23,538 shekels for controls (P < 0.001). After adjusting for differences between groups by using multivariable analysis, ESBL production remained a significant predictor of mortality (OR, 3.6; 95% CI, 1.4 to 9.5; P = 0.008), increased LOS (1.56-fold; P = 0.001), DAT (OR, 25.1; 95% CI, 10.5 to 60.2; P < 0.001), and increased cost (1.57-fold; P = 0.003). The mean increase in equivalent cost attributable to ESBL production was

Influx of Extended-Spectrum β-Lactamase—Producing Enterobacteriaceae into the Hospital

9,620. ESBL production was associated with severe adverse outcomes, including higher overall and infection-related mortality, increased LOS, DAT, discharge to chronic care, and higher costs.

Containment of a Country-wide Outbreak of Carbapenem-Resistant Klebsiella pneumoniae in Israeli Hospitals via a Nationally Implemented Intervention

BACKGROUND The prevalence of infections caused by extended-spectrum beta -lactamase (ESBL)-producing Enterobacteriaceae is increasing worldwide. The influx of these bacteria into hospitals has major implications for infection-control and empirical treatment strategies. METHODS Isolates from 2 patient cohorts--patients with gram-negative bacteremia within 2 days after admission and patients screened for fecal colonization at admission--were assessed for ESBL production. ESBL phenotype was confirmed according to Clinical and Laboratory Standards Institute guidelines. Predictors of ESBL phenotype were examined by univariate and multivariate analyses. RESULTS Of 80 Enterobacteriaceae isolates from blood samples obtained at admission to the hospital, 13.7% produced ESBL. Thirty-eight patients with ESBL-positive isolates and 72 with ESBL-negative isolates were included in a case-control study. Predictors of ESBL production were male sex and nursing home residence (area under receiver operator characteristic curve, 0.7). Of 241 persons screened at admission, 26 (10.8%) had fecal carriage of ESBL-producing Enterobacteriaceae. Predictors of fecal carriage were poor functional status, antibiotic use, chronic renal insufficiency, liver disease, and use of histamine2 blockers (area under receiver operator characteristic curve, 0.8). Four (15.4%) of the 26 individuals with fecal carriage had subsequent bacteremia with ceftazidime-resistant Enterobacteriaceae, compared with 1 (0.5%) noncarrier (odds ratio, 38.9; P<.001). Of 80 ESBL-producing Enterobacteriaceae isolates obtained at admission, 65 were health care associated, and 15 were community acquired. The 15 community-acquired ESBL-producing Enterobacteriaceae belonged to diverse clones. The most prevalent ESBL gene among these isolates was CTX-M-2 (found in 53.3% of the isolates). CONCLUSIONS We report high rates of bacteremia and colonization with ESBL-producing Enterobacteriaceae at admission to our institution, which may undermine infection-control measures and complicate the selection of empirical treatment.

Emergence of KPC-2 and KPC-3 in Carbapenem-Resistant Klebsiella pneumoniae Strains in an Israeli Hospital

BACKGROUND During 2006, Israeli hospitals faced a clonal outbreak of carbapenem-resistant Klebsiella pneumoniae that was not controlled by local measures. A nationwide intervention was launched to contain the outbreak and to introduce a strategy to control future dissemination of antibiotic-resistant bacteria in hospitals. METHODS In March 2007, the Ministry of Health issued guidelines mandating physical separation of hospitalized carriers of carbapenem-resistant Enterobacteriaceae (CRE) and dedicated staffing and appointed a professional task force charged with containment. The task force paid site visits at acute-care hospitals, evaluated infection-control policies and laboratory methods, supervised adherence to the guidelines via daily census reports on carriers and their conditions of isolation, provided daily feedback on performance to hospital directors, and intervened additionally when necessary. The initial intervention period was 1 April 2007-31 May 2008. The primary outcome measure was incidence of clinically diagnosed nosocomial CRE cases. RESULTS By 31 March 2007, 1275 patients were affected in 27 hospitals (175 cases per 1 million population). Prior to the intervention, the monthly incidence of nosocomial CRE was 55.5 cases per 100,000 patient-days. With the intervention, the continuous increase in the incidence of CRE acquisition was halted, and by May 2008, the number of new monthly cases was reduced to 11.7 cases per 100,000 patient-days (P<.001). There was a direct correlation between compliance with isolation guidelines and success in containment of transmission (P=.02). Compliance neutralized the effect of carrier prevalence on new incidence (P=.03). CONCLUSIONS A centrally coordinated intervention succeeded in containing a nationwide CRE outbreak after local measures failed. The intervention demonstrates the importance of strategic planning and national oversight in combating antimicrobial resistance.

Carbapenem-Resistant Enterobacteriaceae: A Potential Threat

ABSTRACT Carbapenem resistance due to KPC has rarely been observed outside the United States. We noticed a sharp increase in carbapenem-resistant Klebsiella pneumoniae strains possessing KPC in Tel Aviv Medical Center from 2004 to 2006. Sixty percent of the isolates belonged to a single clone susceptible only to gentamicin and colistin and carried the blaKPC-3 gene, while almost all other clones carried the blaKPC-2 gene. This rapid dissemination of KPC outside the United States is worrisome.

Staphylococcus aureus Accessory Gene Regulator (agr) Group II: Is There a Relationship to the Development of Intermediate-Level Glycopeptide Resistance?

AFTER MORE THAN 7 DECADES OF ANTIBIOTIC USE, A REcurrent pattern of antimicrobial resistance spread is evident among certain bacterial pathogens. In this pattern, resistance occurs first among the most severely ill hospitalized patients, then spreads to involve other patients in the hospital, and ultimately reaches the community. These events are initially localized geographically; however, via spread from region to region, resistant bacterial strains eventually establish global endemicity. This pattern has been observed with penicillin-resistant staphylococci, methicillinresistant Staphylococcus aureus (MRSA), and extendedspectrum -lactamase (ESBL)–producing Enterobacteriaceae. In each case, adequate preventive measures to contain the spreadof resistantpathogenswerenot implemented in time. In this Commentary, we discuss the implications of a new resistance threat to public health: the global spread of carbapenem-resistant Enterobacteriaceae (CRE). Bacteria from the family Enterobacteriaceae are among the most common pathogens in humans, affecting all populations and causing syndromes ranging in severity from simple cystitis to pneumonia, peritonitis, bacteremia, and meningitis. Historically, these bacteria were susceptible to a wide range of antibiotics. During the past 25 years, however, multidrug resistance has emerged and become widespread, mediated primarily via acquired genes that code for ESBLs, other enzymes, and additional resistance mechanisms. In response to this broad-spectrum resistance, antibiotics from the carbapenem class have been established as the agents of last resort in treating these infections, and carbapenems have been increasingly used in recent decades as the only effective therapy. Yet during the past decade, carbapenem resistance in Enterobacteriaceae has emerged, and in recent years widespread outbreaks of CRE have been increasingly reported. Carbapenem-resistant Enterobacteriaceae differ from most other multidrug-resistant bacterial pathogens in that there is no reliable treatment. The spread of CRE has potentially devastating consequences for global public health and should be addressed with urgency by the international medical community and policy makers. Resistance to carbapenems in Enterobacteriaceae is generally caused by hydrolyzing enzymes. The most important among these are carbapenemases, primarily the serine -lactamase KPC and the metallo– -lactamase VIM. The genes coding for these enzymes are carried by plasmids that often carry other resistance factors as well, resulting in extensively drug-resistant (XDR) bacteria. Moreover, plasmids carrying resistance genes also may carry virulence factors, thus leading to severe infections. Since plasmids are readily transferred, these resistance genes can easily spread within species and even from species to species of Enterobacteriaceae. When such plasmids enter a rapidly disseminating bacterial strain, the result may be a widespread outbreak of a virulent XDR pathogen. Until recently, CRE were rare. During the past few years, however, the incidence has been increasing, with outbreaks reported in the northeastern United States and spread of CRE described in other countries as well. This dissemination is cause for concern. Since Enterobacteriaceae constitute normal human intestinal flora, the reservoir of potential spreaders, by fecal-oral and contact routes, extends to every individual. Carriage may persist for years, and therefore these XDR organisms may eventually spread to the healthy population in the community, with attendant long-term risk of infection to the carriers, similar to the current experience with ESBL-producing bacteria. These organisms are opportunistic pathogens, and once intestinal carriage is established individuals are at risk of infection under the right conditions. As these organisms become increasingly prevalent, treatment of health care–associated infections most likely will become more difficult or even impossible. These circumstances eventually may limit the ability to offer therapeutic interventions associated with a high risk of infection, such as solid organ and bone marrow transplantation and chemotherapy, and could make the hospital environment unsafe even to the general population undergoing simple and elective procedures. In addition, infections acquired in the community, even those occurring in young, healthy individuals, including such conditions as pyelonephritis and perforated appendicitis, may become untreatable and therefore life-threatening.

First Report on a Hyperepidemic Clone of KPC-3-Producing Klebsiella pneumoniae in Israel Genetically Related to a Strain Causing Outbreaks in the United States

We previously determined that all 6 Staphylococcus aureus strains with confirmed intermediate-level resistance to glycopeptides (glycopeptide intermediate S. aureus [GISA]) from the United States that we tested belonged to accessory gene regulator (agr) group II. In the present study, we found that 56% of surveyed bloodstream methicillin-resistant S. aureus isolates (n = 148) at our hospital were agr group II, whereas only 24% of methicillin-susceptible S. aureus isolates (n = 33) were agr group II (P = .001). Population analysis of genetically engineered agr-null and parent wild-type strains of groups I, II, and IV revealed that, when agr function is lost, the agr group II knockout S. aureus was most likely to develop glycopeptide heteroresistance after growth in 1 microg/mL but not 16 microg/mL vancomycin. This strain was unique in showing decreased autolysis after growth in these conditions. This study suggests that some S. aureus strains have an intrinsic survival advantage under a glycopeptide selective pressure, which is possibly related to reduced autolysis after exposure to subinhibitory concentrations of glycopeptide.