Elad Goldberg

Antifungal Prophylaxis in Cancer Patients After Chemotherapy or Hematopoietic Stem-Cell Transplantation: Systematic Review and Meta-Analysis

PURPOSE To evaluate the effect of antifungal prophylaxis on all-cause mortality as primary outcome, invasive fungal infections (IFIs), and adverse events. Many studies have evaluated the role of antifungal prophylaxis in cancer patients, with inconsistent conclusions. METHODS We performed a systematic review and meta-analysis of randomized, controlled trials comparing systemic antifungals with placebo, no intervention, or other antifungal agents for prophylaxis in cancer patients after chemotherapy. The Cochrane Library, MEDLINE, conference proceedings, and references were searched. Two reviewers independently appraised the quality of trials and extracted data. RESULTS Sixty-four trials met inclusion criteria. Antifungal prophylaxis decreased all-cause mortality significantly at end of follow-up compared with placebo, no treatment, or nonsystemic antifungals (relative risk [RR], 0.84; 95% CI, 0.74 to 0.95). In allogeneic hematopoietic stem-cell transplantation (HSCT) recipients, prophylaxis reduced all-cause mortality (RR, 0.62; 95% CI, 0.45 to 0.85), fungal-related mortality, and documented IFI. In acute leukemia patients, there was a significant reduction in fungal-related mortality and documented IFI, whereas the difference in mortality was only borderline significant (RR, 0.88; 95% CI, 0.74 to 1.06). Prophylaxis with itraconazole suspension reduced documented IFI when compared with fluconazole, with no difference in survival, and at the cost of more adverse events. On the basis of two studies, posaconazole prophylaxis reduced all-cause mortality (RR, 0.74; 95% CI, 0.56 to 0.98), fungal-related mortality, and IFI when compared with fluconazole. CONCLUSION Antifungal prophylaxis decreases all-cause mortality significantly in patients after chemotherapy. Antifungal prophylaxis should be administered to patients undergoing allogeneic HSCT, and should probably be administered to high-risk acute leukemia patients.

Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia

OBJECTIVES To document the effects of appropriate and inappropriate empirical antibiotic therapy on mortality in a cohort of patients with bacteraemia due to methicillin-resistant Staphylococcus aureus (MRSA) and to summarize effects with previous studies. METHODS In the retrospective cohort study, episodes of clinically significant MRSA bacteraemia during a 15 year period were included. Polymicrobial episodes were excluded unless MRSA was isolated in more than one bottle and co-pathogens were given appropriate empirical antibiotic treatment. Appropriate empirical treatment was defined as matching in vitro susceptibility and started within 48 h of blood-culture taking, except for single aminoglycosides or rifampicin. We assessed univariate and multivariate associations between appropriate empirical therapy and 30 day all-cause mortality. Multivariable analysis was conducted using backward stepwise logistic regression. We reviewed all studies assessing the effects of appropriate empirical antibiotic treatment on mortality for MRSA infections and compiled adjusted odds ratios (ORs) using a random effects meta-analysis. RESULTS Five hundred and ten episodes of MRSA bacteraemia were included. There were no cases of community-acquired infection. The 30 day mortality was 43.9% (224/510) and was stable throughout the study period. Mortality was significantly higher among patients receiving inappropriate (168/342, 49.1%) compared with those receiving appropriate (56/168, 33.3%) empirical antibiotic treatment, P = 0.001. In the adjusted analysis the OR was 2.15 [95% confidence interval (CI) 1.34-3.46]. Pooling of six studies using adequate methodology for the adjusted analysis resulted in an OR of 1.98 (95% CI 1.62-2.44). CONCLUSIONS Appropriate empirical antibiotic treatment has a significant survival benefit in MRSA bacteraemia. Treatment guidelines should consider this benefit.

Effectiveness and safety of colistin: prospective comparative cohort study

BACKGROUND Colistin has re-entered clinical use by necessity. We aimed to assess its effectiveness and safety compared with newer antibiotics. METHODS This was a single-centre, prospective cohort study. Inclusion criteria were microbiologically documented pneumonia, urinary tract infection, surgical site infection, meningitis or bacteraemia treated appropriately with colistin versus imipenem, meropenem or ampicillin/sulbactam (comparators). All consecutive patients were included, only once, between May 2006 and July 2009. The primary outcome was 30 day mortality. Multivariable and Cox regression survival analyses were used to adjust comparisons between groups. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals are reported. RESULTS Two hundred patients treated with colistin and 295 patients treated with comparators were included. Treatment with colistin was associated with older age, admission from healthcare facilities, mechanical ventilation and lower rate of early appropriate antibiotic treatment. The 30 day mortality was 39% (78/200) for colistin versus 28.8% (85/295) for comparators; unadjusted OR 1.58 (1.08-2.31). In the adjusted analysis the OR was 1.44 (0.91-2.26) overall and 1.99 (1.06-3.77) for bacteraemic patients (n = 220). At the end of follow-up, treatment with colistin was significantly associated with cumulative mortality; adjusted HR 1.27 (1.01-1.60) overall and 1.65 (1.18-2.31) among patients with bacteraemia. Nephrotoxicity at the end of treatment was more frequent with colistin; OR adjusted for other risk factors for nephrotoxicity 3.31 (1.54-7.08). Treatment with colistin was followed by increased incidence of Proteus spp. infections during a 3 month follow-up. CONCLUSIONS The need for colistin treatment is associated with poorer survival. Adjusted analyses suggest that colistin is less effective and more toxic than beta-lactam antibiotics.

Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis

OBJECTIVE To compare available antifungal treatments for invasive candidiasis, a leading cause of nosocomial bloodstream infections. METHODS We performed a systematic review and meta-analysis of randomized controlled trials that compared different antifungal agents for the treatment of candidemia and other forms of invasive candidiasis. Two reviewers independently appraised the quality of trials and extracted data. The primary outcome was all-cause mortality, and secondary outcomes were microbiological failure, treatment failure, and adverse events. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled. RESULTS Of the 15 included trials, 9 compared fluconazole with other drugs (amphotericin B, itraconazole, or a combination of fluconazole and amphotericin B), 4 compared echinocandins with other drugs (fluconazole, amphotericin B, liposomal amphotericin B), 1 compared micafungin and caspofungin, and 1 compared amphotericin B plus fluconazole and voriconazole. No difference in mortality was observed with fluconazole vs amphotericin B (RR, 0.92; 95% CI, 0.72-1.17); however, the rate of microbiological failure increased in the fluconazole arm (RR, 1.52; 95% CI, 1.12-2.07). Anidulafungin decreased the rate of microbiological failure compared with fluconazole (RR, 0.50; 95% CI, 0.29-0.86) with fewer adverse events. Caspofungin was comparable to amphotericin B in mortality and efficacy, with fewer adverse events requiring discontinuation (RR, 0.11; 95% CI, 0.04-0.36). Micafungin was comparable to liposomal amphotericin B in mortality. CONCLUSION All assessed antifungal agents showed similar efficacy, but the rate of microbiological failure increased with fluconazole vs amphotericin B or anidulafungin. Amphotericin B is associated with a higher rate of adverse events than fluconazole and echinocandins.

Empirical antifungal therapy for patients with neutropenia and persistent fever: systematic review and meta-analysis

OBJECTIVES To assess the evidence for the current standard of practice of using empirical antifungal treatment in febrile neutropenic cancer patients. METHODS Systematic review and meta-analysis of randomised controlled trials comparing empirical or preemptive antifungal treatment with placebo, no intervention, or another antifungal. The primary outcomes were all-cause mortality and invasive fungal infections (IFI) (documented or probable). Relative risks (RR) with 95% confidence intervals (CI) were pooled. RESULTS Six trials assessed the efficacy of empirical treatment compared to no treatment and one compared empirical to preemptive therapy. Empirical treatment did not decrease mortality significantly (RR 0.82, 95% CI 0.50-1.34), but significantly decreased IFIs (RR 0.25, 0.12-0.54). Twenty-three trials assessed the efficiency of different antifungals. All-cause mortality was lower with azoles compared to amphotericin B (AB) (RR 0.81, 0.65-1.01); IFI rates were not different while adverse events were less frequent with azoles (RR 0.40; 0.34-0.66). Liposomal AB was associated with lower mortality and IFIs than other AB formulations (RR 1.57, 1.10-2.23 and 1.48, 0.98-2.25, respectively). Caspofungin was associated with fewer adverse events, but otherwise comparable to liposomal AB. All trials included patients with haematological malignancies. Major limitations included per-protocol analysis, non-blinded design and inconsistent definitions of IFIs. CONCLUSIONS Empirical antifungal treatment is associated with a lower rate of IFIs but no significant difference in overall mortality. The assessment of IFIs in these trials may have been biased, offering only weak support to standard practice. Azoles, liposomal amphotericin B or caspofungin should be preferred. Pre-emptive antifungal therapy should be considered and further investigated.

Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial

Objective To show non-inferiority of trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of severe infections due to meticillin resistant Staphylococcus aureus (MRSA). Design Parallel, open label, randomised controlled trial. Setting Four acute care hospitals in Israel. Participants Adults with severe infections caused by MRSA susceptible to trimethoprim-sulfamethoxazole and vancomycin. Patients with left sided endocarditis, meningitis, chronic haemodialysis, and prolonged neutropenia were excluded. Interventions Trimethoprim-sulfamethoxazole 320 mg/1600 mg twice daily versus vancomycin 1 g twice daily for a minimum of seven days and then by indication. Main outcome measures The primary efficacy outcome was treatment failure assessed at day 7, consisting of death, persistence of haemodynamic instability or fever, stable or worsening Sequential Organ Failure Assessment score, and persistence of bacteraemia. The primary safety outcome was all cause mortality at day 30. Non-inferiority was defined by a difference of less than 15% for treatment failure. Results 252 patients were included in the trial, of whom 91 (36%) had bacteraemia. No significant difference in treatment failure was seen for trimethoprim-sulfamethoxazole (51/135, 38%) versus vancomycin (32/117, 27%)—risk ratio 1.38 (95% confidence interval 0.96 to 1.99). However, trimethoprim-sulfamethoxazole did not meet the non-inferiority criterion—absolute difference 10.4% (95% confidence interval −1.2% to 21.5%). For patients with bacteraemia, the risk ratio was 1.40 (0.91 to 2.16). In a multivariable logistic regression analysis, trimethoprim-sulfamethoxazole was significantly associated with treatment failure (adjusted odds ratio 2.00, 1.09 to 3.65). The 30 day mortality rate was 32/252 (13%), with no significant difference between arms. Among patients with bacteraemia, 14/41 (34%) treated with trimethoprim-sulfamethoxazole and 9/50 (18%) with vancomycin died (risk ratio 1.90, 0.92 to 3.93). Conclusions High dose trimethoprim-sulfamethoxazole did not achieve non-inferiority to vancomycin in the treatment of severe MRSA infections. The difference was particularly marked for patients with bacteraemia. Trial registration Clinical trials NCT00427076.

Infection and type 1 diabetes mellitus - a two edged sword?

Infection by various viral and bacterial pathogens has long been proposed as one of the etiologies of autoimmune diabetes. Many theories, ranging from direct cytolysis of pancreatic islet cells to immunological processes such as antigen mimicry and polyclonal lymphocyte activation, tried to explain the epidemiological correlation between infections and diabetes, supported by information from human and animal studies. However, a direct correlation and exact mechanism continue to elude investigators due to scarce and conflicting data. Interestingly, there is also data to support an opposite role for infection in the development of type 1 diabetes, as several pathogens demonstrated a protective effect from this disease. This article reviews the current data available from clinical studies and animal models, while trying to explain the different mechanisms underlying these findings.

Infrared Detection of Low-Mass Secondaries in Spectroscopic Binaries

This paper outlines an infrared spectroscopic technique to measure the radial velocities of faint secondaries in known single-lined binaries. The paper presents our H-band observations with the Cryogenic Echelle (CSHELL) and the Phoenix spectrographs and describes detections of three low-mass secondaries in main-sequence binaries, G147-36, G164-67, and HD 144284, with mass ratios of 0.562 ± 0.011, 0.423 ± 0.042, and 0.380 ± 0.013, respectively. The latter is one of the smallest mass ratios derived to date for detached main-sequence stars.

The need for macrolides in hospitalised community-acquired pneumonia: propensity analysis

The present study compared β-lactam macrolide (“combination”) therapy versus β-lactam alone (“monotherapy”) for hospitalised community-acquired pneumonia, using propensity scores to adjust for the differences between patients. A prospective multinational observational study was carried out. Baseline patient and infection characteristics were used to develop a propensity score for combination therapy. Patients were matched by the propensity score (three decimal point precision) and compared with 30-day mortality and hospital stay. The propensity score was used as a covariate in a logistic model for mortality. Patients treated with monotherapy (n = 169) were older (mean±sd age 70.6±17.3 versus 65.0±19.6 yrs), had a higher chronic diseases score and a different clinical presentation compared with patients treated with combination therapy (n = 282). Unadjusted mortality was significantly higher with monotherapy (37 (22%) out of 169 versus 21 (7%) out of 282). Only 27 patients in the monotherapy group could be matched to 27 patients in the combination group using the propensity score. The mortality in these groups was identical, with three (11%) demises each. The multivariable odds ratio for mortality associated with combination therapy, adjusted for the propensity score and the Pneumonia Severity Index, was 0.69 (95% confidence interval 0.32–1.48). The benefit of combination therapy versus monotherapy cannot be reliably assessed in observational studies, since the propensity to prescribe these regimens differs markedly.

Co-trimoxazole versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteraemia: a retrospective cohort study

OBJECTIVES To evaluate the efficacy and safety of co-trimoxazole versus that of vancomycin in adults with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. PATIENTS AND METHODS Retrospective matched cohort study. Thirty-eight patients with MRSA bacteraemia, treated with co-trimoxazole as the main therapeutic agent, were matched with 76 patients treated with vancomycin as the main agent. The groups were matched for age, sex, functional status, endovascular source of infection, appropriateness of empirical antibiotic therapy, presence of a foreign body, sepsis severity and Charlson score. The outcomes collected were 30 day mortality, persistent bacteraemia [defined as positive blood culture (BC) >14 days after the first positive BC, but within 30 days], relapse (defined as recurrence of the same phenotype >30 days after the first positive BC within 12 months) and adverse events. RESULTS The groups were well matched. Thirty day mortality was not significantly different between the groups [co-trimoxazole 13/38 (34.2%); vancomycin 31/76 (40.8%); odds ratio 0.76, 95% confidence interval 0.34-1.7]. There was only one case of relapse in the co-trimoxazole group (2.6%) compared with nine cases in the vancomycin group (11.8%). Incidence of relapse or persistent bacteraemia was lower in the co-trimoxazole group (3/38, 7.9%) than in the vancomycin group (13/76, 17.1%), although the difference was not statistically significant (P = 0.182). Development of renal failure was similar [co-trimoxazole 11/38 (28.9%); vancomycin 21/76 (27.6%)]. CONCLUSIONS Within the limitations of a small retrospective study, co-trimoxazole had a safety and efficacy profile similar to that of vancomycin and may offer an attractive additional therapeutic option for MRSA bacteraemia. A prospective, randomized controlled trial is warranted.