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JAMA Jul 2023Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug...
IMPORTANCE
Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes.
OBJECTIVE
To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis.
DESIGN, SETTING, AND PARTICIPANTS
A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022.
INTERVENTIONS
Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304).
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events.
RESULTS
All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients).
CONCLUSIONS AND RELEVANCE
In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03452839.
Topics: Humans; Female; Middle Aged; Male; Meropenem; Shock, Septic; Critical Illness; Double-Blind Method; Sepsis; Anti-Bacterial Agents; Monobactams; Hypersensitivity
PubMed: 37326473
DOI: 10.1001/jama.2023.10598 -
The Lancet. Infectious Diseases Mar 2018Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in... (Randomized Controlled Trial)
Randomized Controlled Trial
Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial.
BACKGROUND
Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE).
METHODS
Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7-14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21-25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than -12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96).
FINDINGS
Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference -4·2% [95% CI -10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference -0·7% [95% CI -7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related.
INTERPRETATION
Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens.
FUNDING
AstraZeneca.
Topics: Adult; Aged; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Double-Blind Method; Drug Combinations; Female; Humans; Male; Meropenem; Middle Aged; Pneumonia, Ventilator-Associated
PubMed: 29254862
DOI: 10.1016/S1473-3099(17)30747-8 -
Antimicrobial Agents and Chemotherapy Aug 2019Multidrug-resistant (MDR) Gram-negative organisms are a major health concern due to lack of effective therapy. Emergence of resistance to newer agents like...
Evaluation of the Synergy of Ceftazidime-Avibactam in Combination with Meropenem, Amikacin, Aztreonam, Colistin, or Fosfomycin against Well-Characterized Multidrug-Resistant Klebsiella pneumoniae and Pseudomonas aeruginosa.
Multidrug-resistant (MDR) Gram-negative organisms are a major health concern due to lack of effective therapy. Emergence of resistance to newer agents like ceftazidime-avibactam (CZA) further magnifies the problem. In this context, combination therapy of CZA with other antimicrobials may have potential in treating these pathogens. Unfortunately, there are limited data regarding these combinations. Therefore, the objective of this study was to evaluate CZA in combination with amikacin (AMK), aztreonam (AZT), colistin (COL), fosfomycin (FOS), and meropenem (MEM) against 21 carbapenem-resistant and 21 MDR strains. The potential for synergy was evaluated via MIC combination evaluation and time-kill assays. All strains were further characterized by whole-genome sequencing, quantitative real-time PCR, and SDS-PAGE analysis to determine potential mechanisms of resistance. Compared to CZA alone, we observed a 4-fold decrease in CZA MICs for a majority of strains and at least a 2-fold decrease for most isolates in the majority of combinations tested. In both and strains, CZA in combination with AMK or AZT was synergistic (≥2.15-log CFU/ml decrease). CZA-MEM was effective against and CZA-FOS was effective against Time-kill analysis also revealed that the synergy of CZA with MEM or AZT may be due to the previously reported restoration of MEM or AZT activity against these organisms. Our findings show that CZA in combination with these antibiotics has potential for therapeutic options in difficult to treat pathogens. Further evaluation of these combinations is warranted.
Topics: Amikacin; Azabicyclo Compounds; Aztreonam; Ceftazidime; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Fosfomycin; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 31182535
DOI: 10.1128/AAC.00779-19 -
Critical Care (London, England) Aug 2021Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other... (Randomized Controlled Trial)
Randomized Controlled Trial
Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: subset analysis of the ASPECT-NP randomized, controlled phase 3 trial.
BACKGROUND
Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding.
METHODS
ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors.
RESULTS
Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI - 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam.
CONCLUSIONS
There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam.
TRIAL REGISTRATION
clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757.
Topics: Aged; Anti-Bacterial Agents; Cephalosporins; Double-Blind Method; Equivalence Trials as Topic; Female; Healthcare-Associated Pneumonia; Humans; Logistic Models; Male; Meropenem; Middle Aged; Pneumonia, Bacterial; Retrospective Studies; Tazobactam
PubMed: 34380538
DOI: 10.1186/s13054-021-03694-3 -
PloS One 2018Meropenem exhibits time-dependent antimicrobial activity and prolonged infusion (PI) (extended infusion or continuous infusion, EI or CI) of meropenem can better achieve... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Meropenem exhibits time-dependent antimicrobial activity and prolonged infusion (PI) (extended infusion or continuous infusion, EI or CI) of meropenem can better achieve pharmacodynamics target when comparing with intermittent bolus (IB). However, the clinical outcomes between two groups remain inconclusive.
OBJECTIVE
To evaluate current published literatures by meta-analysis to ascertain whether PI of meropenem can improve clinical outcomes.
METHODS
Medline, Cochrane database and EMBASE were searched. Randomized control trails (RCT) and observational studies which compared the clinical outcomes of PI and IB groups were included and evaluated for quality. The data of studies were extracted and meta-analysis was performed using Revman 5.3 software.
RESULTS
Six RCTs and 4 observation studies with relatively high quality were included in this analysis. Compared to IB group, PI group had a higher clinical success rate (odd ratio 2.10, 95% confidence interval 1.31-3.38) and a lower mortality (risk ratio 0.66, 95% confidence interval 0.50-0.88). The sensitivity analysis showed the results were stable.
CONCLUSION
PI of meropenem was associated with a higher clinical improvement rate and a lower mortality. It is recommended for patients with severe infection or infected by less sensitive microbial.
Topics: Anti-Bacterial Agents; Drug Administration Schedule; Humans; Infections; Infusions, Intravenous; Meropenem; Observational Studies as Topic; Randomized Controlled Trials as Topic; Severity of Illness Index; Time Factors; Treatment Outcome
PubMed: 30059536
DOI: 10.1371/journal.pone.0201667 -
Clinical Infectious Diseases : An... Sep 2022In the CREDIBLE-CR and APEKS-NP studies, cefiderocol treatment was effective against gram-negative bacteria producing metallo-B-lactamases; rates of clinical cure (70.8%... (Randomized Controlled Trial)
Randomized Controlled Trial
In the CREDIBLE-CR and APEKS-NP studies, cefiderocol treatment was effective against gram-negative bacteria producing metallo-B-lactamases; rates of clinical cure (70.8% [17/24]), microbiological eradication (58.3% [14/24]), and day 28 all-cause mortality (12.5% [3/24]) compared favorably with comparators of best-available therapy and high-dose meropenem (40.0% [4/10], 30.0% [3/10], and 50.0% [5/10], respectively).
Topics: Anti-Bacterial Agents; Cephalosporins; Gram-Negative Bacteria; Humans; Meropenem; Microbial Sensitivity Tests; beta-Lactamases; Cefiderocol
PubMed: 35148378
DOI: 10.1093/cid/ciac078 -
Advances in Clinical and Experimental... Aug 2020The antibiotic meropenem is commonly administered to patients with sepsis and septic shock. The aim of this study was to conduct a meta-analysis to evaluate the clinical... (Meta-Analysis)
Meta-Analysis
The antibiotic meropenem is commonly administered to patients with sepsis and septic shock. The aim of this study was to conduct a meta-analysis to evaluate the clinical efficacy and safety of continuous compared to intermittent meropenem infusion for the treatment of sepsis. Electronic databases such as PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI) were researched to collect clinical trials comparing continuous and intermittent infusion of meropenem in patients with sepsis. After data extraction and quality assessment of the included studies, Stata v. 12.0 software (Stata Corporation LLC, College Station, USA) was used for a meta-analysis of mortality, clinical cure, microbiological eradication, and safety. Seven studies with a total of 1,191 participants met the inclusion criteria and were included in the meta-analysis. The meta-analysis showed that continuous meropenem infusion was superior to intermittent infusion in terms of mortality (combined risk ratio (RR) = 0.66, 95% confidence interval (95% CI) = 0.46-0.98, p = 0.03), clinical cure rate (combined RR = 1.15, 95% CI = 1.02-1.30, p = 0.026) and microbiological eradication (combined RR = 1.20, 95% CI = 1.01-1.42, p = 0.04), although it may increase the incidence of some adverse events (AEs). Compared with intermittent dosing, administration of meropenem antibiotics through continuous infusion in patients with sepsis is associated with decreased hospital mortality, increased clinical cure rates and greater microbiological eradication. Further high-quality studies should be conducted to confirm our findings.
Topics: Anti-Bacterial Agents; China; Humans; Infusions, Intravenous; Meropenem; Sepsis
PubMed: 32783408
DOI: 10.17219/acem/121934 -
Clinical Infectious Diseases : An... Aug 2019Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae.
METHODS
IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated.
RESULTS
Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively.
CONCLUSIONS
Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens.
CLINICAL TRIALS REGISTRATION
NCT01844856.
Topics: Anti-Bacterial Agents; Disease Management; Female; Humans; Intraabdominal Infections; Male; Meropenem; Tetracyclines; Time-to-Treatment; Treatment Outcome
PubMed: 30561562
DOI: 10.1093/cid/ciy1029 -
Critical Care (London, England) Nov 2020Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often... (Observational Study)
Observational Study
Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study.
BACKGROUND
Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO.
METHODS
Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints.
RESULTS
The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem.
CONCLUSIONS
ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.
Topics: Adult; Aged; Anti-Bacterial Agents; Ceftazidime; Drug Monitoring; Extracorporeal Membrane Oxygenation; Female; Germany; Humans; Intensive Care Units; Linezolid; Male; Meropenem; Middle Aged; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Renal Replacement Therapy
PubMed: 33239110
DOI: 10.1186/s13054-020-03397-1 -
Journal of Postgraduate Medicine 2023Drug-induced hemolytic anemia (DIHA) is a rare complication of drug therapy and usually underdiagnosed. Cefoperazone/sulbactam is a compound prepared from the third...
Drug-induced hemolytic anemia (DIHA) is a rare complication of drug therapy and usually underdiagnosed. Cefoperazone/sulbactam is a compound prepared from the third generation of cephalosporin and β-lactamase inhibitor. There are limited data of DIHA induced from cefoperazone/sulbactam. A 93-year-old female patient, who had an operation on the biliary tract 3 months ago, was admitted to our hospital with an abdominal infection. After cefoperazone/sulbactam was given as anti-infection treatment, the patient developed hemolytic anemia on the third day. Cefoperazone/sulbactam was discontinued and replaced with meropenem. Subsequently the level of red blood cells, hemoglobin, and hematocrit returned to normal. Clinicians should pay attention to monitoring the possible adverse reactions during the use of cefoperazone/sulbactam and should be aware of the occurrence of DIHA, so as to give timely treatment.
Topics: Female; Humans; Aged, 80 and over; Cefoperazone; Sulbactam; Anti-Bacterial Agents; Meropenem; Anemia, Hemolytic; Microbial Sensitivity Tests
PubMed: 34528516
DOI: 10.4103/jpgm.JPGM_1335_20