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Mical Paul - One of the best experts on this subject based on the ideXlab platform.
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colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem resistant gram negative bacteria an open label randomised controlled trial
2018Co-Authors: Dafna Yahav, Mical Paul, George L Daikos, Emanuele Durantemangoni, Yehuda Carmeli, Yael Dishon Benattar, Anna SkiadaAbstract:Summary Background Colistin–carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves Clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. Methods A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was Clinical Failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual. Findings Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for Clinical Failure at 14 days after randomisation (risk difference −5·7%, 95% CI −13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83–1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87–1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal Failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury). Interpretation Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve Clinical Failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria. Funding EU AIDA grant Health-F3-2011-278348.
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duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection 7 days or less versus longer treatment systematic review and meta analysis of randomized controlled trials
2013Co-Authors: Noa Eliakimraz, Dafna Yahav, Mical Paul, Leonard LeiboviciAbstract:Background: Acute pyelonephritis is a frequent cause of morbidity, with a wide variation in duration of therapy. We performed a systematic review of all randomized controlled trials (RCTs) comparing ≤7 days treatment with a longer course. Methods: Electronic databases were searched to identify RCTs that assessed adults treated for pyelonephritis, comparing a 7 day or shorter versus longer therapy. Primary outcome was Clinical Failure at the end of the long treatment arm (EOT). Secondary outcomes included Clinical Failure at the end of follow-up (EOF), microbiological Failure, all-cause mortality, the development of resistance and adverse events. Results: Clinical Failure at EOT did not significantly differ between the two treatment arms [relative risk (RR) 0.63, 95% CI 0.33-1.18, I(2) = 41%]. Results did not differ when including studies comparing only fluoroquinolones, reducing the heterogeneity (RR 0.76, 95% CI 0.49-1.17, I(2) = 0%). We found no difference between the short and long treatment arms regarding Clinical Failure at EOF, even in a small subgroup of bacteraemic patients. No difference was found between the arms regarding microbiological Failure at EOF, except in a subgroup of studies with a high percentage of patients with urogenital abnormalities, where microbiological Failure at EOF was significantly higher in the short treatment arm (RR 1.78, 95% CI 1.02-3.10, I(2) = 21%). Adverse events were similar between the arms. Conclusions: Seven days of treatment for acute pyelonephritis is equivalent to longer treatment in terms of Clinical Failure and microbiological Failure, including in bacteraemic patients. In patients with urogenital abnormalities, the evidence, although weak, suggests that longer treatment is required.
Daniel J Skiest - One of the best experts on this subject based on the ideXlab platform.
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prospective randomized trial of empiric therapy with trimethoprim sulfamethoxazole or doxycycline for outpatient skin and soft tissue infections in an area of high prevalence of methicillin resistant staphylococcus aureus
2007Co-Authors: Mary Jo Cenizal, Daniel J Skiest, Samuel D Luber, Roger Bedimo, Pat Davis, Kathleen A Delaney, Doug R HardyAbstract:To evaluate empirical therapy with trimethoprim-sulfamethoxazole or doxycycline for outpatient skin and soft tissue infections in an area of high prevalence of methicillin-resistant Staphylococcus aureus, a randomized, prospective, open-label investigation was performed. The overall Clinical Failure rate was 9%, with all Failures occurring in the trimethoprim-sulfamethoxazole group. However, there was no significant difference between the Clinical Failure rate of empirical trimethoprim-sulfamethoxazole therapy and that of doxycycline therapy.
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treatment Failure resulting from resistance of staphylococcus aureus to daptomycin
2006Co-Authors: Daniel J SkiestAbstract:Daptomycin, a new cyclic lipopeptide, was recently approved for the treatment of infections by gram-positive organisms, including infections with methicillin-resistant Staphylococcus aureus (MRSA). A patient infected with infected with MRSA developed resistance to daptomycin after prolonged exposure, which resulted in Clinical Failure. Clinicians should be aware of the possibility of daptomycin resistance and should consider routine testing for daptomycin susceptibility.
Dafna Yahav - One of the best experts on this subject based on the ideXlab platform.
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colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem resistant gram negative bacteria an open label randomised controlled trial
2018Co-Authors: Dafna Yahav, Mical Paul, George L Daikos, Emanuele Durantemangoni, Yehuda Carmeli, Yael Dishon Benattar, Anna SkiadaAbstract:Summary Background Colistin–carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves Clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. Methods A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was Clinical Failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual. Findings Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for Clinical Failure at 14 days after randomisation (risk difference −5·7%, 95% CI −13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83–1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87–1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal Failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury). Interpretation Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve Clinical Failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria. Funding EU AIDA grant Health-F3-2011-278348.
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duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection 7 days or less versus longer treatment systematic review and meta analysis of randomized controlled trials
2013Co-Authors: Noa Eliakimraz, Dafna Yahav, Mical Paul, Leonard LeiboviciAbstract:Background: Acute pyelonephritis is a frequent cause of morbidity, with a wide variation in duration of therapy. We performed a systematic review of all randomized controlled trials (RCTs) comparing ≤7 days treatment with a longer course. Methods: Electronic databases were searched to identify RCTs that assessed adults treated for pyelonephritis, comparing a 7 day or shorter versus longer therapy. Primary outcome was Clinical Failure at the end of the long treatment arm (EOT). Secondary outcomes included Clinical Failure at the end of follow-up (EOF), microbiological Failure, all-cause mortality, the development of resistance and adverse events. Results: Clinical Failure at EOT did not significantly differ between the two treatment arms [relative risk (RR) 0.63, 95% CI 0.33-1.18, I(2) = 41%]. Results did not differ when including studies comparing only fluoroquinolones, reducing the heterogeneity (RR 0.76, 95% CI 0.49-1.17, I(2) = 0%). We found no difference between the short and long treatment arms regarding Clinical Failure at EOF, even in a small subgroup of bacteraemic patients. No difference was found between the arms regarding microbiological Failure at EOF, except in a subgroup of studies with a high percentage of patients with urogenital abnormalities, where microbiological Failure at EOF was significantly higher in the short treatment arm (RR 1.78, 95% CI 1.02-3.10, I(2) = 21%). Adverse events were similar between the arms. Conclusions: Seven days of treatment for acute pyelonephritis is equivalent to longer treatment in terms of Clinical Failure and microbiological Failure, including in bacteraemic patients. In patients with urogenital abnormalities, the evidence, although weak, suggests that longer treatment is required.
Vincent H Tam - One of the best experts on this subject based on the ideXlab platform.
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cefepime free minimum concentration to minimum inhibitory concentration fcmin mic ratio predicts Clinical Failure in patients with gram negative bacterial pneumonia
2015Co-Authors: Samuel L Aitken, Jerry Altshuler, David J Guervil, Elizabeth B Hirsch, Luis Ostroskyzeichner, Charles D Ericsson, Vincent H TamAbstract:Abstract Cefepime is an antibiotic commonly used in nosocomial infections. The objective of this study was to elucidate the relationship between cefepime exposure and Clinical outcome in patients with Gram-negative bacterial pneumonia. A previously published population pharmacokinetic model of cefepime was validated in 12 adult patients with normal renal function by measuring plasma concentrations at steady-state. Additionally, Clinical outcomes for 33 patients with Gram-negative bacterial pneumonia who received cefepime monotherapy were determined. The free minimum concentration ( f C min ) to MIC ratio for each patient was determined by conditioning the validated pharmacokinetic model using patient-specific creatinine clearance (CL Cr ), dosing regimen and cefepime MIC of the organism isolated, and was subsequently correlated with Clinical Failure. Classification and regression tree (CART) analysis was used to determine the most significant drug exposure breakpoint. Mean±S.D. CL Cr and cefepime C min in the 12 patients were 87.5±21.2mL/min and 6.2±3.8mg/L, respectively. In comparison, the C min predicted by the pharmacokinetic model was 5.8mg/L using a CL Cr of 90mL/min. MICs of organisms ranged from 0.5mg/L to 8mg/L. Percent time free drug above MIC of 100% was achieved in 32/33 patients, but 12 patients experienced Clinical Failure. CART analysis determined patients with an f C min /MIC≥2.1 had a significantly lower risk of Clinical Failure (OR=0.11, 95% CI 0.02–0.67; P =0.017). The f C min /MIC ratio is a useful predictor of Clinical Failure in Gram-negative bacterial pneumonia. The Clinical utility of f C min /MIC in therapeutic drug monitoring should be further explored.
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Clinical outcomes for patients with bacteremia caused by vancomycin resistant enterococcus in a level 1 trauma center
2002Co-Authors: Thomas P Lodise, Vincent H Tam, Peggy S Mckinnon, Michael J RybakAbstract:To assess the degree of morbidity and mortality attributable to vancomycin resistance in enterococcal bacteremia (EB), a matched case-control study was conducted. Patients with bacteremia due to vancomycin-resistant enterococcus (VRE) were matched to control patients with bacteremia due to vancomycin-susceptible enterococcus. During 1996--2000, 65 patients with cases of Clinically significant VRE bacteremia were identified, and 53 of these patients were successfully matched. In this group of patients, VRE bacteremia was found to be an independent predictor of crude mortality (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.2--13.3) and the infection-related mortality rate (OR, 5.2; 95% CI, 1.4--20.0). It was also an independent predictor of the rate of Clinical Failure at day 7 after the onset of EB (OR, 4.6; 95% CI, 1.2--17.3) and overall Clinical Failure (OR, 4.3; 95% CI, 1.3--14.5) and was associated with a longer mean length of hospitalization after the onset of EB, compared with that for control patients (22.7plus minus1.88 vs. 15.9 +/- 1.7, P=.006). These observations indicate that vancomycin resistance in EB independently affects outcomes.
John Ferguson - One of the best experts on this subject based on the ideXlab platform.
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antibiotic therapy for inducible ampc β lactamase producing gram negative bacilli what are the alternatives to carbapenems quinolones and aminoglycosides
2012Co-Authors: Patrick N A Harris, John FergusonAbstract:a b s t r a c t Some bacteria that possess chromosomally determined AmpC -lactamases may express these enzymes at a high level following exposure to -lactams, either by induction or selection for derepressed mutants. This may lead to Clinical Failure even if an isolate initially tests susceptible in vitro, a phenomenon best characterised by third-generation cephalosporin therapy for Enterobacter bacteraemia or meningitis. Several other Enterobacteriaceae, such as Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (often termed the 'ESCPM' group), may also express high levels of AmpC. However, the risk of Clinical Failure with -lactams that test susceptible in vitro is less clear in these species than for Enterobacter. Laboratories frequently do not report -lactam or -lactamase inhibitor combination drug susceptibilities for ESCPM organisms, encouraging alternative therapy with quinolones, aminoglyco- sides or carbapenems. However, quinolones and carbapenems present problems with selective pressure for multiresistant organisms, and aminoglycosides with potential toxicity. The risk of emergent AmpC- mediated resistance for non-Enterobacter spp. appears rare in Clinical studies. Piperacillin/tazobactam may remain effective and may be less selective for AmpC derepressed mutants than cephalosporins. The potential roles for agents such as cefepime or trimethoprim/sulfamethoxazole are also discussed. Clinical studies that better define optimal treatment for this group of bacteria are required.