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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 New England Journal of Medicine Oct 2023Ceftobiprole is a cephalosporin that may be effective for treating complicated bacteremia, including methicillin-resistant . (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ceftobiprole is a cephalosporin that may be effective for treating complicated bacteremia, including methicillin-resistant .
METHODS
In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed.
RESULTS
Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole.
CONCLUSIONS
Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).
Topics: Adult; Humans; Anti-Bacterial Agents; Bacteremia; Cephalosporins; Daptomycin; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Double-Blind Method; Administration, Intravenous; Aztreonam
PubMed: 37754204
DOI: 10.1056/NEJMoa2300220 -
Current Opinion in Infectious Diseases Dec 2023Stenotrophomonas maltophilia is an emerged opportunistic pathogen. Intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical... (Review)
Review
PURPOSE OF REVIEW
Stenotrophomonas maltophilia is an emerged opportunistic pathogen. Intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical challenge. Herein, we provide an update on the most recent literature on treatment options for severe S. maltophilia infections.
RECENT FINDINGS
Trimethoprim-sulfamethoxazole (SXT) is recognized as the first-line therapy for S. maltophilia infections. However, its clinical use is based on good in vitro activity and favorable clinical outcomes, rather than on solid minimum inhibitory concentration (MIC) correlations with pharmacokinetic/pharmacodynamics (PK/PD) and/or clinical outcomes. The same is true for other treatment options like levofloxacin (LVX) and minocycline (MIN). Recent PK/PD studies question the current clinical breakpoints for SXT, LVX, and MIN. Based on this, the latest guidance issued by the Infectious Diseases Society of America (IDSA) recommends using these agents only as part of a combination therapy. Alternatively, novel therapeutic options such as cefiderocol (FDC) and ceftazidime-avibactam plus aztreonam (CZA-ATM) are suggested, based on limited but promising clinical data.
SUMMARY
PK/PD data and controlled clinical studies are needed to optimize current treatment options. Presently, combination therapy of SXT, LVX, MIN, or FDC, or monotherapy with CZA-ATM are recommended therapeutic options for severe-to-moderate S. maltophilia infections.
Topics: Humans; Stenotrophomonas maltophilia; Combined Modality Therapy; Aztreonam; Microbial Sensitivity Tests; Minocycline
PubMed: 37846568
DOI: 10.1097/QCO.0000000000000975 -
Drugs Jul 2023Consolidated data from pharmacokinetic and pharmacodynamic studies support the administration of β-lactam antibiotics in prolonged infusion (i.e., extended or... (Review)
Review
Consolidated data from pharmacokinetic and pharmacodynamic studies support the administration of β-lactam antibiotics in prolonged infusion (i.e., extended or continuous) to optimize therapeutic efficacy by increasing the probability of attaining maximal bactericidal activity. This is the longest possible time during which the free drug concentrations are approximately four-fold the minimum inhibitory concentration between dosing intervals. In the context of antimicrobial stewardship strategies, achieving aggressive pharmacokinetic and pharmacodynamic targets is an important tool in the management of multi-drug resistant (MDR) bacterial infections and in the attainment of mutant preventing concentrations. However, prolonged infusion remains an unexploited resource. Novel β-lactam/β-lactamase inhibitor (βL/βLI) combinations (ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam) have been released in recent years to face the emerging challenge of MDR Gram-negative bacteria. Pre-clinical and real-life evidence has confirmed the promising role of prolonged infusion of these molecules in specific settings and clinical populations. In this narrative review we have summarized available pharmacological and clinical data, future perspectives, and current limitations of prolonged infusion of the novel protected β-lactams, their application in hospital settings and in the context of outpatient parenteral antimicrobial therapy.
Topics: Humans; Anti-Bacterial Agents; Gram-Negative Bacterial Infections; beta-Lactamase Inhibitors; Drug Combinations; Monobactams; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests
PubMed: 37314633
DOI: 10.1007/s40265-023-01893-6 -
Current Opinion in Infectious Diseases Dec 2023This review focuses on the management of severe Pseudomonas aeruginosa infections in critically ill patients. (Review)
Review
PURPOSE OF REVIEW
This review focuses on the management of severe Pseudomonas aeruginosa infections in critically ill patients.
RECENT FINDINGS
Pseudomonas aeruginosa is the most common pathogen in intensive care; the main related infections are nosocomial pneumonias, then bloodstream infections. Antimicrobial resistance is common; despite new antibiotics, it is associated with increased mortality, and can lead to a therapeutic deadlock.
SUMMARY
Carbapenem resistance in difficult-to-treat P. aeruginosa (DTR-PA) strains is primarily mediated by loss or reduction of the OprD porin, overexpression of the cephalosporinase AmpC, and/or overexpression of efflux pumps. However, the role of carbapenemases, particularly metallo-β-lactamases, has become more important. Ceftolozane-tazobactam, ceftazidime-avibactam and imipenem-relebactam are useful against DTR phenotypes (noncarbapenemase producers). Other new agents, such as aztreonam-ceftazidime-avibactam or cefiderocol, or colistin, might be effective for carbapenemase producers. Regarding nonantibiotic agents, only phages might be considered, pending further clinical trials. Combination therapy does not reduce mortality, but may be necessary for empirical treatment. Short-term treatment of severe P. aeruginosa infections should be preferred when it is expected that the clinical situation resolves rapidly.
Topics: Humans; Pseudomonas Infections; Anti-Bacterial Agents; Aztreonam
PubMed: 37823536
DOI: 10.1097/QCO.0000000000000981 -
Expert Review of Anti-infective Therapy Apr 2024Metallo-beta-lactamases (MBLs) are responsible for resistance to almost all beta-lactam antibiotics. Found predominantly in Gram-negative bacteria, they severely limit... (Review)
Review
INTRODUCTION
Metallo-beta-lactamases (MBLs) are responsible for resistance to almost all beta-lactam antibiotics. Found predominantly in Gram-negative bacteria, they severely limit treatment options. Understanding the epidemiology, risk factors, treatment, and prevention of infections caused by MBL-producing organisms is essential to reduce their burden.
AREAS COVERED
The origins and structure of MBLs are discussed. We describe the mechanisms of action that differentiate MBLs from other beta-lactamases. We discuss the global epidemiology of MBL-producing organisms and their impact on patients' outcomes. By exposing the mechanisms of transmission of MBLs among bacterial populations, we emphasize the importance of infection prevention and control.
EXPERT OPINION
MBLs are spreading globally and challenging the majority of available antibacterial agents. Genotypic tests play an important role in the identification of MBL production. Phenotypic tests are less specific but may be used in low-resource settings, where MBLs are more predominant. Infection prevention and control are critical to reduce the spread of organisms producing MBL in healthcare systems. New combinations such as avibactam-aztreonam and new agents such as cefiderocol have shown promising results for the treatment of infections caused by MBL-producing organisms. New antibiotic and non-antibiotic agents are being developed and may improve the management of infections caused by MBL-producing organisms.
Topics: Humans; beta-Lactamases; Anti-Bacterial Agents; Aztreonam; Gram-Negative Bacteria; Bacteria; Microbial Sensitivity Tests; beta-Lactamase Inhibitors
PubMed: 38275276
DOI: 10.1080/14787210.2024.2311213 -
JAMA Jul 2023
Topics: Humans; Anti-Bacterial Agents; beta-Lactams; Critical Illness; Infusions, Intravenous; Monobactams; Sepsis; Treatment Outcome; Time Factors
PubMed: 37326478
DOI: 10.1001/jama.2023.6483