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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 -
European Journal of Medicinal Chemistry Dec 2020β-Lactam antibiotics are one of the most relevant drug classes of antibacterial agents worldwide. The discovery and the market of first β-lactam antibiotic (Penicillin... (Review)
Review
β-Lactam antibiotics are one of the most relevant drug classes of antibacterial agents worldwide. The discovery and the market of first β-lactam antibiotic (Penicillin G) is a symbolic landmark of modern chemotherapy. Since then, several other β-lactam antibiotics have been introduced in the therapy, revolutionizing the treatment of bacterial infections. Their antibacterial efficacy has been kept in check by the emergence of bacterial resistance. Among the resistance mechanisms, the expression of β-lactamase enzymes is one of the most studied and prevalent. The combined use of beta-lactamase inhibitors with broad spectrum activity β-lactam antibiotics has been an effective strategy to circumvent the resistance issue. This review discusses, with a focus on structural aspects, the different classes of beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams and penems) in light of their stability, sensitivity to β-lactamases, mechanism of action and spectrum of antimicrobial activity. β-Lactamase inhibitors (structurally correlated and non-correlated to the β-lactam system) and their proposed inhibition mechanisms are also discussed.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Chemistry, Pharmaceutical; Humans; Hydrolysis; Models, Chemical; Molecular Structure; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams
PubMed: 33002736
DOI: 10.1016/j.ejmech.2020.112829 -
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 -
Revista Argentina de Microbiologia 2022The aim of this review is to present an update on the susceptibility of viridans group streptococci (VGS) to β-lactam antimicrobials, with emphasis on the Argentinean... (Review)
Review
The aim of this review is to present an update on the susceptibility of viridans group streptococci (VGS) to β-lactam antimicrobials, with emphasis on the Argentinean scenario. VGS are a heterogeneous group including five groups of species, each one exhibiting peculiar susceptibility patterns to penicillin (PEN). Species of the Streptococcus mitis group are frequently nonsusceptible to PEN. PEN resistance is associated with changes in PEN-binding proteins. In Argentina, one to two thirds of VGS are nonsusceptible to PEN. Third generation cephalosporins and carbapenems are currently more effective in vitro than PEN against VGS. Mortality was associated to nonsusceptibility to PEN in at least two studies involving patients with bacteremia caused by VGS. Treatment of endocarditis due to VGS should be adjusted/to the PEN susceptibility of the isolates. Vancomycin may be an alternative choice for treating endocarditis caused by PEN-resistant isolates (MIC≥4μg/ml).
Topics: Humans; Microbial Sensitivity Tests; Streptococcal Infections; Viridans Streptococci; Penicillins; Monobactams; beta-Lactams; Anti-Bacterial Agents; Endocarditis
PubMed: 36266147
DOI: 10.1016/j.ram.2022.06.004 -
Clinical Infectious Diseases : An... Jun 2021In vitro data support the use of combination of aztreonam (ATM) with ceftazidime-avibactam (CAZ-AVI), but clinical studies are lacking. The aim of our study was to... (Observational Study)
Observational Study
BACKGROUND
In vitro data support the use of combination of aztreonam (ATM) with ceftazidime-avibactam (CAZ-AVI), but clinical studies are lacking. The aim of our study was to compare the outcome of patients with bloodstream infections (BSIs) due to metallo-β-lactamase (MBL)-producing Enterobacterales treated either with CAZ-AVI plus ATM or other active antibiotics (OAAs).
METHODS
This was a prospective observational study including patients admitted to 3 hospitals in Italy and Greece. The primary outcome measure was 30-day all-cause mortality. Secondary outcomes were clinical failure at day 14 and length of stay after BSI diagnosis. Cox regression analysis including a propensity score (PS) for receiving CAZ-AVI + ATM was performed to evaluate primary and secondary outcomes. A PS-based matched analysis was also performed.
RESULTS
We enrolled 102 patients with BSI; 82 had infections caused by NDM-producing (79 Klebsiella pneumoniae and 3 Escherichia coli) and 20 by VIM-producing (14 K. pneumoniae, 5 Enterobacter species, 1 Morganella morganii) strains. The 30-day mortality rate was 19.2% in the CAZ-AVI + ATM group vs 44% in the OAA group (P = .007). The PS-adjusted analysis showed that the use of CAZ-AVI + ATM was associated with lower 30-day mortality (hazard ratio [HR], 0.37 [95% confidence interval {CI}, .13-.74]; P = .01), lower clinical failure at day 14 (HR, 0.30 [95% CI, .14-.65]; P = .002), and shorter length of stay (subdistributional HR, 0.49 [95% CI, .30-.82]; P = .007). The PS-matched analysis confirmed these findings.
CONCLUSIONS
The CAZ-AVI + ATM combination offers a therapeutic advantage compared to OAAs for patients with BSI due to MBL-producing Enterobacterales. Further studies are warranted.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Ceftazidime; Drug Combinations; Greece; Humans; Italy; Microbial Sensitivity Tests; Sepsis; beta-Lactamases
PubMed: 32427286
DOI: 10.1093/cid/ciaa586 -
Expert Review of Anti-infective Therapy Nov 2022OXA-48 and NDM are amongst the most prevalent carbapenemase types associated with worldwide, with an increase in their prevalence in recent years. Knowledge on the... (Review)
Review
INTRODUCTION
OXA-48 and NDM are amongst the most prevalent carbapenemase types associated with worldwide, with an increase in their prevalence in recent years. Knowledge on the treatment of carbapenem-resistant (CRKP) comes from KPC-producing CRKP with limited data available for OXA-48-like and NDM producers. Our aim is to review the literature on the treatment of OXA-48-like and NDM-producing CRKP with the goal of providing an update on the available antibiotic treatment strategies, particularly in light of changing carbapenemase epidemiology and increasing antimicrobial resistance.
AREAS COVERED
We reviewed studies looking at the antibiotic treatment and outcome of OXA-48-like and/or NDM-producing CRKP.
EXPERT OPINION
The best available treatment option for OXA-48 producers is ceftazidime-avibactam, where available and when the price permits its use. Colistin remains as the second-line option if susceptibility is demonstrated with an appropriate method. There is not enough evidence to support the use of meropenem-containing combination therapies for meropenem-resistant OXA-48 producers. Treatment of NDM producers is an unmet need. Ceftazidime-avibactam and aztreonam combination or cefiderocol can be used for NDM producers, where available. Higher cefiderocol MICs against NDM producers is concerning. Aztreonam-avibactam provides hope for the treatment of NDM producers.
Topics: Humans; Klebsiella pneumoniae; Aztreonam; Colistin; Meropenem; Azabicyclo Compounds; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Microbial Sensitivity Tests; Anti-Bacterial Agents; Bacterial Proteins; Drug Combinations; Klebsiella Infections; Cefiderocol
PubMed: 36150216
DOI: 10.1080/14787210.2022.2128764 -
Clinical Microbiology and Infection :... Apr 2023The aim of the guidelines is to provide recommendations on perioperative antibiotic prophylaxis (PAP) in adult inpatients who are carriers of multidrug-resistant...
SCOPE
The aim of the guidelines is to provide recommendations on perioperative antibiotic prophylaxis (PAP) in adult inpatients who are carriers of multidrug-resistant Gram-negative bacteria (MDR-GNB) before surgery.
METHODS
These evidence-based guidelines were developed after a systematic review of published studies on PAP targeting the following MDR-GNB: extended-spectrum cephalosporin-resistant Enterobacterales, carbapenem-resistant Enterobacterales (CRE), aminoglycoside-resistant Enterobacterales, fluoroquinolone-resistant Enterobacterales, cotrimoxazole-resistant Stenotrophomonas maltophilia, carbapenem-resistant Acinetobacter baumannii (CRAB), extremely drug-resistant Pseudomonas aeruginosa, colistin-resistant Gram-negative bacteria, and pan-drug-resistant Gram-negative bacteria. The critical outcomes were the occurrence of surgical site infections (SSIs) caused by any bacteria and/or by the colonizing MDR-GNB, and SSI-attributable mortality. Important outcomes included the occurrence of any type of postsurgical infectious complication, all-cause mortality, and adverse events of PAP, including development of resistance to targeted (culture-based) PAP after surgery and incidence of Clostridioides difficile infections. The last search of all databases was performed until April 30, 2022. The level of evidence and strength of each recommendation were defined according to the Grading of Recommendations Assessment, Development and Evaluation approach. Consensus of a multidisciplinary expert panel was reached for the final list of recommendations. Antimicrobial stewardship considerations were included in the recommendation development.
RECOMMENDATIONS
The guideline panel reviewed the evidence, per bacteria, of the risk of SSIs in patients colonized with MDR-GNB before surgery and critically appraised the existing studies. Significant knowledge gaps were identified, and most questions were addressed by observational studies. Moderate to high risk of bias was identified in the retrieved studies, and the majority of the recommendations were supported by low level of evidence. The panel conditionally recommends rectal screening and targeted PAP for fluoroquinolone-resistant Enterobacterales before transrectal ultrasound-guided prostate biopsy and for extended-spectrum cephalosporin-resistant Enterobacterales in patients undergoing colorectal surgery and solid organ transplantation. Screening for CRE and CRAB is suggested before transplant surgery after assessment of the local epidemiology. Careful consideration of the laboratory workload and involvement of antimicrobial stewardship teams before implementing the screening procedures or performing changes in PAP are warranted. High-quality prospective studies to assess the impact of PAP among CRE and CRAB carriers performing high-risk surgeries are advocated. Future well-designed clinical trials should assess the effectiveness of targeted PAP, including the monitoring of MDR-GNB colonization through postoperative cultures using European Committee on Antimicrobial Susceptibility Testing clinical breakpoints.
Topics: Male; Adult; Humans; Gram-Negative Bacterial Infections; Antibiotic Prophylaxis; Prospective Studies; Gram-Negative Bacteria; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Carbapenems; Cephalosporins; Monobactams; Fluoroquinolones
PubMed: 36566836
DOI: 10.1016/j.cmi.2022.12.012 -
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 -
Defining the Role of Novel β-Lactam Agents That Target Carbapenem-Resistant Gram-Negative Organisms.Journal of the Pediatric Infectious... Jul 2019With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and... (Review)
Review
With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and traditional salvage agents (eg, colistin, tigecycline, etc) confer high toxicity and/or have low efficacy. However, several β-lactam agents with activity against carbapenem-resistant organisms were approved recently by the US Food and Drug Administration, and more are anticipated to be approved in the near future. The primary goal of this review is to assist infectious disease practitioners with preferentially selecting 1 agent over another when treating patients infected with a carbapenem-resistant organism. However, resistance to some of these antibiotics has already developed. Antibiotic stewardship programs can ensure that they are reserved for situations in which other options are lacking and are paramount for the survival of these agents.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Boronic Acids; Carbapenems; Ceftazidime; Cephalosporins; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Meropenem; Tazobactam; Cefiderocol
PubMed: 30793757
DOI: 10.1093/jpids/piz002