Michael Giladi

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

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.

Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): A phase 3, randomised-controlled, non-inferiority trial

BACKGROUND Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. METHODS This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. FINDINGS 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). INTERPRETATION Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. FUNDING Astellas Pharma Global Development, Basilea Pharmaceutica International.

Reappraisal of Community-Acquired Bacteremia: A Proposal of a New Classification for the Spectrum of Acquisition of Bacteremia

In recent years, dramatic changes in health care systems have shifted much of the care of sick individuals from hospitals to the community. Consequently, infections traditionally classified as community-acquired or hospital-acquired infections cannot now be readily classified into either category. We thus propose a new classification based on a wider spectrum of acquisition. A total of 1028 episodes of bloodstream infection (BSI) were divided into 5 categories: true community-acquired infections (370 episodes [36%]), infections in recently discharged patients (110 [11%]), infections associated with invasive procedures performed just before or at the time of admission (56 [5%]), infections in patients admitted from nursing homes (68 [7%]), and hospital-acquired infections (424 [41%]). Thus, 234 (39%) of the 604 bloodstream infections traditionally defined as community acquired were reclassified into 3 newly defined groups, each of which has distinct epidemiologic, clinical, and bacteriologic characteristics, as well as distinct antimicrobial susceptibility profiles. There is a conceptual and practical need for such a new classification.

Bartonella koehlerae, a New Cat-Associated Agent of Culture-Negative Human Endocarditis

ABSTRACT Bartonella koehlerae is reported for the first time to be a human pathogen that causes culture-negative endocarditis. It is also shown that this species, isolated twice before from domestic cats, can be recovered as well from a stray cat population in Israel. This work follows a recent report of the same case in which the causative agent was misidentified as B. henselae, based on serology and PCR-restriction fragment length polymorphism (RFLP) analysis (A. Schattner, O. Zimhony, B. Avidor, and M. Gilad, Lancet 361:1786, 2003). B. koehlerae was identified in the valvular tissue of an endocarditis patient by DNA sequencing of the PCR products of two Bartonella genes: the genes for citrate synthase (gltA) and riboflavin synthase (ribC). The commonly used PCR-RFLP analysis of the TaqI-digested gltA PCR product did not distinguish between B. koehlerae and B. quintana or between B. elizabethae and B. clarridgeiae. PmlI digestion of the gltA amplification product failed to differentiate between B. quintana, B. clarridgeiae, and B. elizabethae. RFLP analysis of the heat shock protein (htrA) gene by TaqI digestion misidentified B. koehlerae as B. henselae. However, RFLP analysis of the ribC PCR product, digested with TaqI, was able to distinguish between the human endocarditis-associated Bartonella species tested, B. henselae, B. quintana, B. elizabethae, and B. koehlerae, as well as between the cat-associated Bartonella species, B. henselae and B. clarridgeiae. Given the expanding number of Bartonella species emerging as human pathogens, it is suggested that PCR-RFLP analysis for the diagnosis of Bartonella infections target several genes and be coupled with DNA sequencing to avoid species identification.

High Anti-Cytomegalovirus (CMV) IgG Antibody Titer is Associated With Coronary Artery Disease and May Predict Post-Coronary Balloon Angioplasty Restenosis

Recent studies have demonstrated that cytomegalovirus (CMV) DNA was found in atherosclerotic coronary arteries in restenotic lesions, and prior infection with CMV could be a strong independent risk factor for restenosis after coronary atherectomy. We studied the correlation between anti-CMV antibody titer and coronary artery disease. Sixty-five patients (50 men and 15 women) with coronary artery disease were enrolled prospectively. All had symptomatic coronary artery disease with an angiographic documentation of a de novo single coronary lesion. All underwent balloon coronary angioplasty and were followed for 12 months with a thallium perfusion scan 3 months after angioplasty. Patients who had recurrent chest pain and/or a positive thallium scan had another coronary angiography. Blood samples were taken before angiography and 1 and 3 months later. Patients with high anti-CMV titer > or = 1:800 had a higher prevalence of coronary artery disease (p <0.001) than seropositive patients with a lower antibody titer (< or = 1:400); patients with high antibody titer (> or = 1:800) had a higher restenosis rate than seropositive patients with a low antibody titer (< or = 1:400) (p <0.05). High antibody titers against CMV (IgG) may be a strong marker for coronary artery disease, and might predict post-coronary angioplasty restenosis. These findings support the infectious theory of atherosclerosis (especially with prior CMV infection), and also suggest that a chronic immunologic response has a role in atherosclerosis and restenosis.

Pseudomonas aeruginosa Bacteremia: An Analysis of 123 Episodes, with Particular Emphasis on the Effect of Antibiotic Therapy

OBJECTIVES To review current experience with Pseudomonas aeruginosa bacteremia and compare outcome of patients treated with single-drug, versus combination therapy. METHODS The charts of all patients with P. aeruginosa bacteremia between 1990 and 1992 were reviewed, and pertinent demographic, clinical, and bacteriologic data were retrieved. In addition, similar data were collected from a series of patients with P. aeruginosa bacteremia from the literature of the past 20 years. RESULTS One hundred and twenty-three episodes of P. aeruginosa bacteremia in 121 patients were identified. Most patients were older than 70 years, had at least one underlying condition, and had acquired the infection in the hospital. Attributable mortality was 34%. After exclusion for early mortality and inappropriate therapy, 57 patients remained eligible for comparison of outcome according to therapy protocol. Mortality from infection was equal between the group of 42 patients who received monotherapy and the 15 patients who received combination therapy (14% and 13%, respectively). The literature review revealed eight articles describing 21 to 410 episodes of Pseudomonas bacteremia. The clinical characteristics of these series did not differ significantly from those of the present series. CONCLUSIONS Incidence, epidemiology, clinical characteristics, and outcome of pseudomonas sepsis did not change significantly over the past 2 decades. Appropriate monotherapy was as effective as combination drug therapy for individuals with pseudomonas bacteremia surviving the first 2 days of infection.

National Multicenter Study of Predictors and Outcomes of Bacteremia upon Hospital Admission Caused by Enterobacteriaceae Producing Extended-Spectrum β-Lactamases

ABSTRACT Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are pathogens that may lead to a spectrum of clinical syndromes. We aimed to identify predictors and outcomes of ESBL bacteremia upon hospital admission (UHA) in a nationwide prospective study. Thus, a multicenter prospective study was conducted in 10 Israeli hospitals. Adult patients with bacteremia due to Enterobacteriaceae diagnosed within 72 h of hospitalization were included. Patients with ESBL producers (cases) were compared to those with non-ESBL producers (controls), and a 1:1 ratio was attempted in each center. A case-control study to identify predictors and a cohort study to identify outcomes were conducted. Bivariate and multivariate logistic regressions were used for analyses. Overall, 447 patients with bacteremia due to Enterobacteriaceae were recruited: 205 cases and 242 controls. Independent predictors of ESBL were increased age, multiple comorbid conditions, poor functional status, recent contact with health care settings, invasive procedures, and prior receipt of antimicrobial therapy. In addition, patients presenting with septic shock and/or multiorgan failure were more likely to have ESBL infections. Patients with ESBL producers suffered more frequently from a delay in appropriate antimicrobial therapy (odds ratio [OR], 4.7; P, <0.001) and had a higher mortality rate (OR, 3.5; P, <0.001). After controlling for confounding variables, both ESBL production (OR, 2.3; P, 9.1) and a delay in adequate therapy (OR, 0.05; P, 0.001) were significant predictors for mortality and other adverse outcomes. We conclude that among patients with bacteremia due to Enterobacteriaceae UHA, those with ESBL producers tend to be older and chronically ill and to have a delay in effective therapy and severe adverse outcomes. Efforts should be directed to improving the detection of patients with ESBL bacteremia UHA and to providing immediate appropriate therapy.

Long-Term Serological Analysis and Clinical Follow-Up of Patients with Cat Scratch Disease

A highly specific enzyme immunoassay (EIA) was recently described for use in the diagnosis of cat scratch disease (CSD). However, data regarding EIA antibody kinetics or its correlation with long-term clinical follow-up data are lacking. The association between antibody kinetics, clinical spectrum, and disease duration were studied in 98 patients with CSD. The median duration of follow-up was 35.3 weeks (range, 2-211.3 weeks). Results of EIA testing for detection of anti-Bartonella henselae immunoglobulin M (IgM) antibodies (detected in 53% of the patients) remained positive for < or =3 months. Therefore, the presence of IgM indicated acute infection. Titers of immunoglobulin G (IgG) also decreased over time; 25% of the patients remained seropositive for >1 year after the onset of CSD. Onset of CSD in patients with an IgG titer with an optical density of > or =1.0 occurred within the prior 12 months. No association was found between antibody titers or their kinetics and the clinical manifestations or duration of disease. EIA allows for the identification of atypical manifestations of CSD that were unrecognized before the use of serological assays. Complete recovery from these manifestations may take months. Results of this study provide additional data supporting the utility of EIA in the serodiagnosis of CSD.

Hospital-Acquired Infective Endocarditis: Should the Definition be Broadened?

Hospital-acquired infective endocarditis (IE) is a growing health-care problem. Hospital-acquired IE, according to the commonly used definition, is IE manifesting > or =72 h after admission to the hospital or within several weeks after a hospital-based invasive procedure. To assess the validity of this definition, we evaluated 87 episodes of IE, with special attention to recent hospitalizations. The incidence rate of IE in the 6-month period after discharge from the hospital was 27 cases per 100,000 person-years, compared with 1.1 cases per 100,000 person-years in a population with no recent hospitalizations. Furthermore, episodes of IE manifesting during this 6-month period were notable for a high proportion of typically hospital-acquired pathogens (26% vs. 0%; P=.001) and a low proportion of viridans streptococci (0% vs. 36%; P<.001), compared with community-acquired episodes that did not involve recent hospitalization. We conclude that characteristics of hospital-acquired IE extend to episodes arising within 6 months after discharge from the hospital and suggest that the definition of hospital-acquired IE be broadened to include these episodes.

Time to Blood Culture Positivity as a Marker for Catheter-Related Candidemia

ABSTRACT Candida spp. are important causes of nosocomial bloodstream infections. Around 80% of patients with candidemia have an indwelling central venous catheter (CVC). Determining whether the CVC is the source of candidemia has implications for patient management. We assessed whether the time to detection of Candida species in peripheral blood (time to positivity [TTP]) can serve as a marker for catheter-related candidemia. Prospective surveillance of Candida bloodstream infection was conducted in two medical centers. TTP was recorded by the BacT/Alert automated system. Sixty-four candidemia episodes were included. Fifty patients (78%) had an indwelling CVC. Thirteen patients (20.3%) had definite catheter-related candidemia. TTP was shorter for definite catheter-related candidemia (17.3 ± 2 h) than that for candidemia from other sources (38.2 ± 3 h; P < 0.001). A TTP cutoff of 30 h was 100% sensitive and 51.4% specific for catheter-related candidemia (area under the receiver-operator characteristic curve of 0.76). We conclude that TTP in peripheral blood is a sensitive but nonspecific marker for catheter-related candidemia and that a TTP of more than 30 h can help exclude an intravascular catheter as the possible source of candidemia.