Tomer Avni

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.

The Safety of Intravenous Iron Preparations: Systematic Review and Meta-analysis

OBJECTIVE To amass all available evidence regarding the safety of intravenous (IV) iron preparations to provide a true balance of efficacy and safety. METHODS Systematic review and meta-analysis of all randomized clinical trials comparing IV iron to another comparator. All electronic databases until January 1, 2014, were reviewed. Primary outcome was occurrence of severe adverse events (SAEs). Secondary outcomes included all-cause mortality and other adverse events (AEs). Subgroup analysis was performed on the basis of type of IV iron, comparator, treated condition, and system involved. RESULTS A total of 103 trials published between 1965 through 2013 were included. A total of 10,390 patients were treated with IV iron compared with 4044 patients treated with oral iron, 1329 with no iron, 3335 with placebo, and 155 with intramuscular iron. There was no increased risk of SAEs with IV iron (relative risk [RR], 1.04; 95% CI, 0.93-1.17; I(2)=9%). Subgroup analysis revealed a decreased rate of SAEs when IV iron was used to treat heart failure (RR, 0.45; 95% CI, 0.29-0.70; I(2)=0%). Severe infusion reactions were more common with IV iron (RR, 2.47; 95% CI, 1.43-4.28; I(2)=0%). There was no increased risk of infections with IV iron. Gastrointestinal AEs were reduced with IV iron. CONCLUSION Intravenous iron therapy is not associated with an increased risk of SAEs or infections. Infusion reactions are more pronounced with IV iron.

Systematic Review and Meta-Analysis of In Vitro Synergy of Polymyxins and Carbapenems

Objectives To examine the evidence on in-vitro synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB) Methods Systematic review and meta-analysis. All studies examining in-vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB. A broad search was conducted with no language, date or publication status restrictions. Synergy rates, defined as fractional inhibitory concentration index ≤0.5 or >2log colony forming unit reduction, were pooled separately for time-kill, checkerboard, and E-test in a mixed-effects meta-analysis of rates. We examined whether synergy rate depended on testing method, type of antibiotic, bacteria and resistance to carbapenems. Pooled rates with 95% confidence intervals are shown. Results 39 published studies and 15 conference proceeding were included, reporting on 246 different tests on 1054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI 64-87) for Acinetobacter baumannii , 44% (95% CI 30-59%) for Klebsiella pneumoniae and 50% (95% CI 30-69%) for Pseudomonas aeruginosa with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii , meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill. Use of combination therapy led to less resistance development in-vitro. Conclusions The combination of a carbapenem with a polymyxin against GNB, especially A. baumannii , is supported in-vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.ABSTRACT Our objective was to examine the evidence of in vitro synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB). A systematic review and meta-analysis were performed. All studies examining in vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concentration index of ≤0.5 or a >2-log reduction in CFU, were pooled separately for time-kill, checkerboard, and Etest methods in a mixed-effect meta-analysis of rates. We examined whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty-nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) for Acinetobacter baumannii, 44% (95% CI, 30 to 59%) for Klebsiella pneumoniae, and 50% (95% CI, 30 to 69%) for Pseudomonas aeruginosa, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill studies. The use of combination therapy led to less resistance development in vitro. The combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.

Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta-analysis.

Over half of chronic heart failure (CHF) patients are anaemic, and iron deficiency is common. Iron replacement therapy (oral or i.v.) might improve exercise capacity and quality of life (QOL).

Prophylactic antibiotics for burns patients: systematic review and meta-analysis

Objective To assess the evidence for prophylactic treatment with systemic antibiotics in burns patients. Design Systematic review and meta-analysis of randomised or quasi-randomised controlled trials recruiting burns inpatients that compared antibiotic prophylaxis (systemic, non-absorbable, or topical) with placebo or no treatment. Data sources PubMed, Cochrane Library, LILACS, Embase, conference proceedings, and bibliographies. No language, date, or publication status restrictions were imposed. Review methods Two reviewers independently extracted data. The primary outcome was all cause mortality. Risk or rate ratios with 95% confidence intervals were pooled with a fixed effect model if no heterogeneity was present. Results 17 trials were included. Trials that assessed systemic antibiotic prophylaxis given for 4-14 days after admission showed a significant reduction in all cause mortality (risk ratio 0.54, 95% confidence interval 0.34 to 0.87, five trials). The corresponding number needed to treat was 8 (5 to 33), with a control event rate of 26%. Perioperative non-absorbable or topical antibiotics alone did not significantly affect mortality. There was a reduction in pneumonia with systemic prophylaxis and a reduction in wound infections with perioperative prophylaxis. Staphylococcus aureus infection or colonisation was reduced with anti-staphylococcal antibiotics. In three trials, resistance to the antibiotic used for prophylaxis significantly increased (rate ratio 2.84, 1.38 to 5.83). The overall methodological quality of the trials was poor. Conclusions Prophylaxis with systemic antibiotics has a beneficial effect in burns patients, but the methodological quality of the data is weak. As such prophylaxis is currently not recommended for patients with severe burns other than perioperatively, there is a need for randomised controlled trials to assess its use.

Diagnostic Accuracy of PCR Alone Compared to Galactomannan in Bronchoalveolar Lavage Fluid for Diagnosis of Invasive Pulmonary Aspergillosis: a Systematic Review

ABSTRACT PCR in bronchoalveolar lavage (BAL) fluid has not been accepted as a diagnostic criterion for invasive pulmonary aspergillosis (IPA). We conducted a systematic review assessing the diagnostic accuracy of PCR in BAL fluid with a direct comparison versus galactomannan (GM) in BAL fluid. We included prospective and retrospective cohort and case-control studies. Studies were included if they used the EORTC/MSG consensus definition criteria of IPA and assessed ≥80% of patients at risk for IPA. Two reviewers abstracted data independently. Risk of bias was assessed using QUADAS-2. Summary sensitivity and specificity values were estimated using a bivariate model and reported with a 95% confidence interval (CI). Nineteen studies published between 1993 and 2012 were included. The summary sensitivity and specificity values (CIs) for diagnosis of proven or probable IPA were 90.2% (77.2 to 96.1%) and 96.4% (93.3 to 98.1%), respectively. In nine cohort studies strictly adherent to the 2002 or 2008 EORTC/MSG criteria for reference standard definitions, the summary sensitivity and specificity values (CIs) were 77.2% (62 to 87.6%) and 93.5% (90.6 to 95.6%), respectively. Antifungal treatment before bronchoscopy significantly reduced sensitivity. The diagnostic performance of PCR was similar to that of GM in BAL fluid using an optical density index cutoff of 0.5. If either PCR or GM in BAL fluid defined a positive result, the pooled sensitivity was higher than that of GM alone, with similar specificity. We conclude that the diagnostic performance of PCR in BAL fluid is good and comparable to that of GM in BAL fluid. Performing both tests results in optimal sensitivity with no loss of specificity. Results are dependent on the reference standard definitions.

Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis

Objective International guidelines recommend dopamine or norepinephrine as first-line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin are considered second-line agents. Our objective was to assess the evidence for the efficiency and safety of all vasopressors in septic shock. Methods Systematic review and meta-analysis. We searched electronic database of MEDLINE, CENTRAL, LILACS and conference proceedings up to June 2014. We included randomized controlled trials comparing different vasopressors for the treatment of adult patients with septic shock. Primary outcome was all-cause mortality. Other clinical and hemodynamic measurements were extracted as secondary outcomes. Risk ratios (RR) and mean differences with 95% confidence intervals (CI) were pooled. Results Thirty-two trials (3,544 patients) were included. Compared to dopamine (866 patients, 450 events), norepinephrine (832 patients, 376 events) was associated with decreased all-cause mortality, RR 0.89 (95% CI 0.81-0.98), corresponding to an absolute risk reduction of 11% and number needed to treat of 9. Norepinephrine was associated with lower risk for major adverse events and cardiac arrhythmias compared to dopamine. No other mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine and vasopressin / terlipressin. Hemodynamic data were similar between the different vasopressors, with some advantage for norepinephrine in central venous pressure, urinary output and blood lactate levels. Conclusions Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in the treatment of septic shock.

β-Lactam/β-lactamase inhibitors versus carbapenems for the treatment of sepsis: systematic review and meta-analysis of randomized controlled trials

BACKGROUND Data on the relative efficacy of β-lactam/β-lactamase inhibitors (BL/BLIs) versus carbapenems are scant. METHODS This is a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing any BL/BLI versus any carbapenem for the treatment of sepsis. The primary outcome was all-cause mortality. A broad search was conducted with no restrictions on language, publication status or date. Two reviewers independently applied the inclusion criteria and extracted the data. Assessment of risk of bias was performed using the domain-based approach. Subgroup analyses were used to investigate heterogeneity and focus on patient groups more likely to harbour ESBL-positive bacteria. Risk ratios (RRs) with 95% CIs were calculated and pooled. RESULTS Thirty-one RCTs were included. There was no difference between BL/BLIs and carbapenems in terms of mortality (RR 0.98, 95% CI 0.79-1.20), without heterogeneity. No differences were observed with regard to clinical or microbiological failure and bacterial superinfections. The results were not affected by risk of bias. No differences were detected in the subgroups of patients with nosocomial infections, Gram-negative infections and neutropenic fever. Adverse events requiring discontinuation were more common with BL/BLIs, on account of an increased incidence of diarrhoea. However, Clostridium difficile-associated diarrhoea (RR 0.29, 95% CI 0.10-0.87) was more frequent with carbapenems and seizures were more frequent with imipenem (RR 0.21, 95% CI 0.05-0.93). CONCLUSIONS No differences in efficacy between BL/BLIs and carbapenems exist in RCTs including patient populations with a certain, albeit unknown, rate of ESBL-positive bacteria causing infections.

Cost–benefit of infection control interventions targeting methicillin-resistant Staphylococcus aureus in hospitals: systematic review

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) incur significant costs. We aimed to examine the cost and cost-benefit of infection control interventions against MRSA and to examine factors affecting economic estimates. We performed a systematic review of studies assessing infection control interventions aimed at preventing spread of MRSA in hospitals and reporting intervention costs, savings, cost-benefit or cost-effectiveness. We searched PubMed and references of included studies with no language restrictions up to January 2012. We used the Quality of Health Economic Studies tool to assess study quality. We report cost and savings per month in 2011 US

Fecal calprotectin for the prediction of small-bowel Crohn's disease by capsule endoscopy: a systematic review and meta-analysis.

. We calculated the median save/cost ratio and the save-cost difference with interquartile range (IQR) range. We examined the effects of MRSA endemicity, intervention duration and hospital size on results. Thirty-six studies published between 1987 and 2011 fulfilled inclusion criteria. Fifteen of the 18 studies reporting both costs and savings reported a save/cost ratio >1. The median save/cost ratio across all 18 studies was 7.16 (IQR 1.37-16). The median cost across all studies reporting intervention costs (n = 31) was 8648 (IQR 2025-19 170) US