Ronen Ben-Ami

A Multinational Survey of Risk Factors for Infection with Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae in Nonhospitalized Patients

BACKGROUND Infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are increasing in frequency and are associated with high mortality rates. Circulation of CTX-M-type ESBLs in the community is of particular concern, because it may confound standard infection-control measures. METHODS We analyzed the results of epidemiologic studies of infection caused by ESBL-producing Enterobacteriaceae in nonhospitalized patients from 6 centers in Europe, Asia, and North America. Risk factors for infection with an ESBL-producing organism were identified by univariate and multivariate analyses. RESULTS A total of 983 patient-specific isolates were reviewed (890 [90.5%] of which were Escherichia coli, 68 [6.9%] of which were Klebsiella species, and 25 [2.5%] of which were Proteus mirabilis); 339 [34.5%] of the isolates produced ESBLs. CTX-M types were the most frequent ESBLs (accounting for 65%). Rates of co-resistance to ciprofloxacin among ESBL-producing isolates were high (>70%), but significant variation was seen among centers with respect to rates of resistance to gentamicin, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole. Similar risk factors for infection with an ESBL-producing organism were found in the different participating centers. Significant risk factors, identified by multivariate analysis, were recent antibiotic use, residence in a long-term care facility, recent hospitalization, age 65 years, and male sex (area under the receiver-operator characteristic [ROC] curve, 0.80). However, 34% of ESBL-producing isolates (115 of 336 isolates) were obtained from patients with no recent health care contact; the area under the ROC curve for the multivariate model for this group of patients was only 0.70, which indicated poorer predictive value. CONCLUSIONS Community-acquired ESBL-producing Enterobacteriaceae are now prevalent worldwide, necessitating international collaboration. Novel approaches are required to adequately address issues such as empirical treatment for severe community-acquired infection and infection control.

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.

Update on Pseudomonas aeruginosa and Acinetobacter baumannii infections in the healthcare setting

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.

Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: A 20-year autopsy study

Purpose of review Infections with Pseudomonas aeruginosa and Acinetobacter baumannii are of great concern for hospitalized patients, especially with multidrug-resistant strains. This review focuses on recent data that may help us to understand the emergence, spread, and persistence of antibiotic resistance, and summarizes the optional treatment feasible for these resistant bacteria. Recent findings Multidrug-resistant P. aeruginosa and A. baumannii are increasingly causing nosocomial infections; multidrug-resistant clones are spreading into new geographic areas, and susceptible strains are acquiring resistance genes. New extended-spectrum β-lactamases and carbapenemases are emerging, leading to pan-resistant strains. Current studies focus on the effect of antibiotics on gene expression in P. aeruginosa biofilms and their contribution to resistance to therapy. Treatment options for multidrug-resistant P. aeruginosa and A. baumannii infections are limited in most cases to carbapenems. Sulbactam is a treatment option for pan-resistant A. baumannii, and or renewed use of an old drug, colistin, is being entertained for pan-resistant A. baumannii and P. aeruginosa. Immunotherapy is a promising new modality being explored. Prevention of emergence of resistance through combination therapy and pharmacokinetic strategies are studied. Summary The emergence and spread of multidrug-resistant P. aeruginosa and A. baumannii and their genetic potential to carry and transfer diverse antibiotic resistance determinants pose a major threat in hospitals. The complex interplay of clonal spread, persistence, transfer of resistance elements, and cell–cell interaction contribute to the difficulty in treating infections caused by these multidrug-resistant strains. In the absence of new antibiotic agents, new modalities of treatment should be developed.

Immunopharmacology of Modern Antifungals

Autopsy studies remain an essential tool for understanding the patterns of fungal disease not detected ante mortem with current diagnostic approaches. We collected data concerning the microbiological trends, patient clinical characteristics and sites of involvement for invasive fungal infections (IFIs) identified at autopsy in a single large cancer treatment centre over a 20‐year period (1989–2008). The autopsy rate and IFI prevalence both declined significantly during the study period. The prevalence of Aspergillus spp. decreased significantly from the first 15 years of the study (from 0.12 to 0.14 cases per 100 autopsies to 0.07 in 2004–2008; P = 0.04), with only Mucorales accounting for a greater proportion of IFIs over the duration of the study period (0.06 to 0.2 cases per 100 autopsies, P = 0.04). After 2003, moulds accounted for the majority of infections identified at autopsy in the spleen, kidney, heart and gastrointestinal tract. Despite a trend of decreasing prevalence from 1989 to 2004, invasive candidiasis increased in prevalence during later periods 2004–2008 (0.02–0.05 per 100 autopsies) with decreasing kidney, heart and spleen involvement. Despite a declining autopsy rate, these data suggest a decreasing prevalence overall of IFIs with changing patterns of dissemination in patients with haematological malignancies.

Enemy of the (immunosuppressed) state: an update on the pathogenesis of Aspergillus fumigatus infection.

In addition to their in vitro inhibitory and fungicidal effects, modern antifungal agents interact in vivo with host immune functions involved in defense against fungal pathogens. The nature of such interactions is diverse and depends on the drug, the immunological status of the host, and the fungal pathogen. Given the prominent role of the hosts immune response in controlling invasive fungal infection, immunomodulation by antifungal drugs may prove to be clinically significant. Elucidation of the immunopharmacology of these drugs may aid in designing therapeutic regimens for specific clinical scenarios associated with defined immunological dysfunction.

Increased Virulence of Zygomycetes Organisms Following Exposure to Voriconazole: A Study Involving Fly and Murine Models of Zygomycosis

Aspergillus fumigatus is an opportunistic filamentous fungus that is currently the most frequent cause of invasive fungal disease in immunosuppressed individuals. Recent advances in our understanding of the pathogenesis of invasive aspergillosis have highlighted the multifactorial nature of A. fumigatus virulence and the complex interplay between host and microbial factors. In this review, we outline current concepts of immune recognition and evasion, angioinvasion and angiogenesis, secondary metabolism and the fungal stress response, and their respective roles in this often lethal infection.

Fitness and Virulence Costs of Candida albicans FKS1 Hot Spot Mutations Associated With Echinocandin Resistance

BACKGROUND Breakthrough zygomycosis is increasingly observed among patients at high risk for fungal infection who are receiving voriconazole, reflecting either selective pressure or voriconazole-associated alterations in Zygomycetes virulence. We tested the latter hypothesis, using 2 phylogenetically disparate zygomycosis models. METHODS Three Zygomycetes strains were exposed to voriconazole by serial passages on voriconazole-containing medium. The virulence of voriconazole-exposed Zygomycetes strains was compared with that of voriconazole-nonexposed strains in Drosophila and murine models of zygomycosis by assessment of survival curves, pulmonary fungal burdens, and expression of inflammation-associated genes. RESULTS Among Toll-deficient (Tl(-/-)) and wild-type fruit flies, infection with Zygomycetes isolates that had been exposed to voriconazole yielded significantly lower survival rates than infection with Zygomycetes strains grown in drug-free media. In contrast, exposure of Rhizopus oryzae to itraconazole, amphotericin B, or caspofungin and exposure of Aspergillus fumigatus to voriconazole did not alter the virulence of these isolates in fruit flies. In the murine model, infection with a R. oryzae strain preexposed to voriconazole was associated with decreased survival rates and increased pulmonary fungal burdens, compared with infection with a voriconazole-nonexposed R. oryzae strain. In addition, enhanced angioinvasion, inflammation, and expression of genes involved in stress response and tissue repair were found in mouse lungs infected with voriconazole-exposed R. oryzae. CONCLUSIONS Exposure of Zygomycetes organisms to voriconazole selectively enhanced their virulence. The mechanisms underlying these phenotypic changes should be studied further.

Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites.

The identification of FKS1 mutations in Candida albicans associated with echinocandin resistance has raised concerns over the spread of drug-resistant strains. We studied the impact of fks1 mutations on C. albicans virulence and fitness. Compared with wild-type strains for FKS1, echinocandin-resistant C. albicans strains with homozygous fks1 hot-spot mutations had reduced maximum catalytic capacity of their glucan synthase complexes and thicker cell walls attributable to increased cell wall chitin content. The fks1 mutants with the highest chitin contents had reduced growth rates and impaired filamentation capacities. Fks1 mutants were hypovirulent in fly and mouse models of candidiasis, and this phenotype correlated with the cell wall chitin content. In addition, we observed reduced fitness of echinocandin-resistant C. albicans in competitive mixed infection models. We conclude that fks1 mutations that confer echinocandin resistance come at fitness and virulence costs, which may limit their epidemiological and clinical impact.