Leonard Leibovici

β lactam monotherapy versus β lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials

Abstract Objective To compare β lactam monotherapy with β lactam-aminoglycoside combination therapy for severe infections. Data sources Medline, Embase, Lilacs, Cochrane Library, and conference proceedings, to 2003; references of included studies; contact with all authors. No restrictions, such as language, year of publication, or publication status. Study selection All randomised trials of β lactam monotherapy compared with β lactam-aminoglycoside combination therapy for patients without neutropenia who fulfilled criteria for sepsis. Data selection Two reviewers independently applied selection criteria, performed quality assessment, and extracted the data. The primary outcome assessed was all cause fatality by intention to treat. Relative risks were pooled with the random effect model (relative risk < 1 favours monotherapy). Results 64 trials with 7586 patients were included. There was no difference in all cause fatality (relative risk 0.90, 95% confidence interval 0.77 to 1.06). 12 studies compared the same β lactam (1.02, 0.76 to 1.38), and 31 studies compared different β lactams (0.85, 0.69 to 1.05). Clinical failure was more common with combination treatment overall (0.87, 0.78 to 0.97) and among studies comparing different β lactams (0.76, 0.68 to 0.86). There was no advantage to combination therapy among patients with Gram negative infections (1835 patients) or Pseudomonas aeruginosa infections (426 patients). There was no difference in the rate of development of resistance. Nephrotoxicity was significantly more common with combination therapy (0.36, 0.28 to 0.47). Heterogeneity was not significant for these comparisons. Conclusions In the treatment of sepsis the addition of an aminoglycoside to β lactams should be discouraged. Fatality remains unchanged, while the risk for adverse events is increased.

Systematic Review and Meta-Analysis of the Efficacy of Appropriate Empiric Antibiotic Therapy for Sepsis

ABSTRACT Quantifying the benefit of early antibiotic treatment is crucial for decision making and can be assessed only in observational studies. We performed a systematic review of prospective studies reporting the effect of appropriate empirical antibiotic treatment on all-cause mortality among adult inpatients with sepsis. Two reviewers independently extracted data. Risk of bias was assessed using the Newcastle-Ottawa score. We calculated unadjusted odds ratios (ORs) with 95% confidence intervals for each study and extracted adjusted ORs, with variance, methods, and covariates being used for adjustment. ORs were pooled using random-effects meta-analysis. We examined the effects of methodological and clinical confounders on results through subgroup analysis or mixed-effect meta-regression. Seventy studies were included, of which 48 provided an adjusted OR for inappropriate empirical antibiotic treatment. Inappropriate empirical antibiotic treatment was associated with significantly higher mortality in the unadjusted and adjusted comparisons, with considerable heterogeneity occurring in both analyses (I2 > 70%). Study design, time of mortality assessment, the reporting methods of the multivariable models, and the covariates used for adjustment were significantly associated with effect size. Septic shock was the only clinical variable significantly affecting results (it was associated with higher ORs). Studies adjusting for background conditions and sepsis severity reported a pooled adjusted OR of 1.60 (95% confidence interval = 1.37 to 1.86; 26 studies; number needed to treat to prevent one fatal outcome, 10 patients [95% confidence interval = 8 to 15]; I2 = 46.3%) given 34% mortality with inappropriate empirical treatment. Appropriate empirical antibiotic treatment is associated with a significant reduction in all-cause mortality. However, the methods used in the observational studies significantly affect the effect size reported. Methods of observational studies assessing the effects of antibiotic treatment should be improved and standardized.

β lactam monotherapy versus β lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis

Abstract Objective To compare the effectiveness of β lactam monotherapy versus β lactam-aminoglycoside combination therapy in the treatment of patients with fever and neutropenia. Data sources Medline, Embase, Lilacs, the Cochrane Library, and conference proceedings to 2002. References of included studies and contact with authors. No restrictions on language, year of publication, or publication status. Study selection All randomised trials of β lactam monotherapy compared with β lactam-minoglycoside combination therapy as empirical treatment for patients with fever and neutropenia. Data selection Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. An intention to treat approach was used. Relative risks were pooled with the random effect model. Main outcome measure All cause fatality. Results Forty seven trials with 7807 patients met inclusion criteria. Nine trials compared the same β lactam. There was no significant difference in all cause fatality (relative risk 0.85, 95% confidence interval 0.72 to 1.02). For success of treatment there was a significant advantage with monotherapy (0.92, 0.85 to 0.99), though there was considerable heterogeneity among trials. There was no significant difference between monotherapy and combination treatment in trials that compared the same β lactam, whereas there was major advantage with monotherapy in trials that compared different β lactams (0.87, 0.80 to 0.93). Rates of superinfection were similar. Adverse events, including those associated with severe morbidity, were significantly more common in the combination treatment group. Detected flaws in methods did not affect results. Conclusions For patients with fever and neutropenia there is no clinical advantage in treatment with β lactam-aminoglycoside combination therapy. Broad spectrum β lactams as monotherapy should be regarded as the standard of care for such patients.

Prophylaxis of Pneumocystis Pneumonia in Immunocompromised Non-HIV-Infected Patients: Systematic Review and Meta-analysis of Randomized Controlled Trials

OBJECTIVE To assess the efficacy of prophylaxis for Pneumocystis pneumonia (PCP), caused by Pneumocystis jirovecii (formerly Pneumocystis carinii), for immunocompromised non-HIV-infected patients by conducting a systematic review and meta-analysis. METHODS We searched for randomized controlled trials that compared prophylaxis using antibiotics effective against P jirovecii, given orally or intravenously, vs placebo, no intervention, or antibiotics with no activity against P jirovecii. In addition, we included trials that compared different PCP prophylactic regimens or administration schedules. The search included the Cochrane Central Register of Controlled Trials, PubMed, Latin American and Caribbean Health Sciences Literature, and conference proceedings. No language, year, or publication restrictions were applied. Two reviewers (H.G. and M.P.) independently searched, selected trials, extracted data, and performed methodological quality assessment. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis was performed using the random-effects model. RESULTS Twelve randomized trials were identified, including 1245 patients (50% children) who had undergone autologous bone marrow or solid organ transplant or who had hematologic cancer. When trimethoprim-sulfamethoxazole was administered, a 91% reduction was observed in the occurrence of PCP (RR, 0.09; 95% CI, 0.02-0.32); the number needed to treat was 15 (95% CI, 13-20) patients, with no heterogeneity. Pneumocystis pneumonia-related mortality was significantly reduced (RR, 0.17; 95% CI, 0.03-0.94), whereas all-cause mortality did not differ significantly (RR, 0.79; 95% CI, 0.18-3.46). Adverse events that required discontinuation occurred in 3.1% of adults and none of the children, and all were reversible. No differences between once-daily and thrice-weekly administration schedules were found. CONCLUSION Balanced against severe adverse events, PCP prophylaxis is warranted when the risk for PCP is higher than 3.5% for adults. Adverse events are less frequent in children, for whom prophylaxis might be warranted at lower PCP incidence rates.

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.

PCR Diagnosis of Invasive Candidiasis: Systematic Review and Meta-Analysis

ABSTRACT Invasive candidiasis (IC) is a significant cause of morbidity and mortality. Diagnosis relies on culture-based methods, which lack sensitivity and delay diagnosis. We conducted a systematic review assessing the diagnostic accuracy of PCR-based methods to detect Candida spp. directly in blood samples. We searched electronic databases for prospective or retrospective cohort and case-control studies. Two reviewers abstracted data independently. Meta-analysis was performed using a hierarchical logistic regression model. Random-effects metaregression was performed to assess the effects of study methods and infection characteristics on sensitivity or specificity values. We included 54 studies with 4,694 patients, 963 of whom had proven/probable or possible IC. Perfect (100%) sensitivity and specificity for PCR in whole-blood samples was observed when patients with cases had candidemia and controls were healthy people. When PCR was performed to evaluate patients with suspected invasive candidiasis, the pooled sensitivity for the diagnosis of candidemia was 0.95 (confidence interval, 0.88 to 0.98) and the pooled specificity was 0.92 (0.88 to 0.95). A specificity of >90% was maintained in several analyses considering different control groups. The use of whole-blood samples, rRNA, or P450 gene targets and a PCR detection limit of ≤10 CFU/ml were associated with improved test performance. PCR positivity rates among patients with proven or probable IC were 85% (78 to 91%), while blood cultures were positive for 38% (29 to 46%). We conclude that direct PCR using blood samples had good sensitivity and specificity for the diagnosis of IC and offers an attractive method for early diagnosis of specific Candida spp. Its effects on clinical outcomes should be investigated.

Antimicrobial Lock Solutions for the Prevention of Infections Associated with Intravascular Catheters in Patients Undergoing Hemodialysis: Systematic Review and Meta-analysis of Randomized, Controlled Trials

BACKGROUND Prevention of catheter-related bloodstream infections in patients undergoing hemodialysis by use of antimicrobial catheter lock solutions has been examined in several trials, but no consensus is available for clinical practice. METHODS A systematic review and meta-analysis were performed of randomized controlled trials that compared single or combination antimicrobial catheter lock solutions with heparin or another antimicrobial for the prevention of infections in patients undergoing hemodialysis. The primary outcomes assessed were bloodstream infections, catheter-related bloodstream infections, and the need for catheter removal. Relative risks with 95% confidence intervals (CIs) for individual trials were pooled. RESULTS Eleven trials (924 patients) that assessed antibiotic catheter lock solutions and 5 trials (661 patients)that assessed non antibiotic antimicrobial catheter lock solutions met inclusion criteria. None of the trials assessed all bloodstream infections. Antibiotic catheter lock solutions significantly reduced catheter-related bloodstream infections (relative risk, 0.44; 95% CI, 0.38-0.50). Significant heterogeneity for this outcome could be explained by smaller effect estimates in larger trials that reported adequate randomization methods (relative risk, 0.60; 95%CI, 0.54-0.67). Efficacy was higher when additional preventive measures were used and to prevent the first episode of catheter-related bloodstream infection. Catheter removal rates were significantly reduced (relative risk, 0.35;95% CI, 0.23-0.55). Resistance development was documented in a single patient. Data concerning nonantibiotic antimicrobial lock solutions were limited and heterogeneous. High-quality trials that used additional preventive measures showed a significant reduction in catheter-related bloodstream infections (relative risk, 0.25; 95% CI,0.13-0.50). CONCLUSIONS Antibiotic catheter lock solutions reduce catheter-related bloodstream infections, with a number needed to treat of 4 patients (95% CI, 4-5), and catheter removal rates in patients undergoing hemodialysis. The use of antibiotic catheter lock solutions should be considered in routine clinical practice in conjunction with other prevention modalities.

Comparative meta-analysis of the effect of Lactobacillus species on weight gain in humans and animals

BACKGROUND Obesity is associated with alteration of the gut microbiota. In order to clarify the effect of Lactobacillus-containing probiotics (LCP) on weight we performed a meta-analysis of clinical studies and experimental models. We intended to assess effects by Lactobacillus species. METHODS A broad search with no date or language restriction was performed. We included randomized controlled trials (RCTs) and comparative clinical studies in humans and animals or experimental models assessing the effect of Lactobacillus-containing probiotics on weight. We primarily attempted to extract and use change from baseline values. Data were extracted independently by two authors. Results were pooled by host and by Lactobacillus species and are summarized in a meta-analysis of standardized difference in means (SMDs). RESULTS We identified and included 17 RCTs in humans, 51 studies on farm animals and 14 experimental models. Lactobacillus acidophilus administration resulted in significant weight gain in humans and in animals (SMD 0.15; 95% confidence intervals 0.05-0.25). Results were consistent in humans and animals. Lactobacillus fermentum and Lactobacillus ingluviei were associated with weight gain in animals. Lactobacillus plantarum was associated with weight loss in animals and Lactobacillus gasseri was associated with weight loss both in obese humans and in animals. CONCLUSIONS Different Lactobacillus species are associated different effects on weight change that are host-specific. Further studies are needed to clarify the role of Lactobacillus species in the human energy harvest and weight regulation. Attention should be drawn to the potential effects of commonly marketed lactobacillus-containing probiotics on weight gain.

Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions.

New evidence shows that antibiotic prophylaxis in neutropenic patients reduces mortality, febrile episodes, and bacterial infections. For patients with acute leukemia or those who undergo bone marrow transplantation, prophylaxis with fluoroquinolones diminished the risk of death from any cause by 33% (95% confidence interval [95% CI], 2–54%). Thus, 55 patients who have acute leukemia or who undergo bone marrow transplantation must receive prophylaxis to prevent 1 death. In 4 studies that included patients with solid tumors or lymphoma, prophylaxis reduced the rate of death during the first month (relative risk, 0.51; 95% CI, 0.27–0.97), and 82 patients had to receive prophylaxis to prevent 1 death. The main argument brought against prophylaxis is the induction of resistance. Patients who received prophylaxis did not experience more infections caused by resistant strains than patients in the control group. The recent GIMEMA study was conducted in a population with a nearly 50% resistance to fluoroquinolones in all pathogens and 20% resistance in gram‐negative isolates, thus indicating that prophylaxis should be offered in settings with similar or less resistance. Prophylaxis with fluoroquinolones was efficacious in reducing infections caused by gram‐positive bacteria. Patients who are treated for acute leukemia should be offered prophylaxis with ciprofloxacin or levofloxacin. Prophylaxis to cover the expected period of neutropenia may be considered for the first cycle of treatment in patients with solid tumors or lymphoma who regularly receive regimens that cause severe neutropenia. Excessive local levels of resistance to fluoroquinolones or high local incidence of infections caused by Clostridium difficile and related to fluoroquinolones should prompt a reconsideration of this policy. Cancer 2006.

Effects of remote, retroactive intercessory prayer on outcomes in patients with bloodstream infection: randomised controlled trial

Abstract Objective: To determine whether remote, retroactive intercessory prayer, said for a group of patients with a bloodstream infection, has an effect on outcomes. Design: Double blind, parallel group, randomised controlled trial of a retroactive intervention. Setting: University hospital. Subjects: All 3393 adult patients whose bloodstream infection was detected at the hospital in 1990-6. Intervention: In July 2000 patients were randomised to a control group and an intervention group. A remote, retroactive intercessory prayer was said for the well being and full recovery of the intervention group. Main outcome measures: Mortality in hospital, length of stay in hospital, and duration of fever. Results: Mortality was 28.1% (475/1691) in the intervention group and 30.2% (514/1702) in the control group (P for difference=0.4). Length of stay in hospital and duration of fever were significantly shorter in the intervention group than in the control group (P=0.01 and P=0.04, respectively). Conclusions: Remote, retroactive intercessory prayer said for a group is associated with a shorter stay in hospital and shorter duration of fever in patients with a bloodstream infection and should be considered for use in clinical practice. What is already known on this topic Two randomised controlled trials of remote intercessory prayer (praying for persons unknown) showed a beneficial effect in patients in an intensive coronary care unit A recent systematic review found that 57% of the randomised, placebo controlled trials of distant healing showed a positive treatment effect What this study adds Remote intercessory prayer said for a group of patients is associated with a shorter hospital stay and shorter duration of fever in patients with a bloodstream infection, even when the intervention is performed 4–10 years after the infection