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In patients with complicated urinary tract infection, clinical and microbiologic treatment success was significantly better with cefepime–taniborbactam (β-lactam and β-lactamase inhibitor) than with meropenem.

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. 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. 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. Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens. NCT01844856.

Treatment options for antimicrobial-resistant, gram-negative pathogens are limited. Plazomicin is an aminoglycoside antimicrobial agent that is resistant to aminoglycoside-modifying enzymes. In this trial involving 609 patients with complicated urinary tract infections, plazomicin was noninferior to meropenem.

There is a need for additional therapeutic options for serious infections caused by Gram-negative pathogens. In the phase 3, descriptive REVISIT study, we investigated the safety and efficacy of aztreonam–avibactam in the treatment of complicated intra-abdominal infections or hospital-acquired pneumonia or ventilator-associated pneumonia (HAP–VAP) caused, or suspected to be caused, by Gram-negative bacteria. This prospective, multinational, open-label, central assessor-masked study enrolled adults who were hospitalised with a complicated intra-abdominal infection or HAP–VAP. Patients were randomly allocated via block randomisation using interactive response technology stratified by infection type in a 2:1 ratio to aztreonam–avibactam (with metronidazole for complicated intra-abdominal infection) or meropenem with or without colistin for 5–14 days for complicated intra-abdominal infection or 7–14 days for HAP–VAP. The primary endpoint was clinical cure at the test-of-cure visit (within 3 days before or after day 28) in the intention-to-treat (ITT) population. Secondary endpoints included 28-day mortality in the ITT population and safety in patients in the ITT population who received study drug (safety analysis set). No formal hypothesis testing was planned. The study was registered with ClinicalTrials.gov (NCT03329092) and EudraCT (2017–002742–68) and is complete. Between April 5, 2018, and Feb 23, 2023, we screened 461 patients. 422 patients were enrolled and randomly allocated (282 in the aztreonam–avibactam group and 140 in the meropenem group, forming the ITT analysis set), of whom ten patients (seven in the aztreonam–avibactam group and three in the meropenem group) were randomly allocated but did not receive study treatment. 271 (64%) of 422 patients had at least one Gram-negative pathogen from an adequate specimen identified at baseline. The most frequent baseline pathogens were Enterobacterales (252 [93%] of 271). Overall, 19 (24%) of 80 isolates tested for carbapenemases were carbapenemase-positive (serine, metallo-β-lactamase, or both). 193 (68·4%) of 282 patients in the aztreonam–avibactam group and 92 (65·7%) of 140 in the meropenem group had clinical cure at the test-of-cure visit (treatment difference 2·7% [95% CI –6·6 to 12·4]). For patients with complicated intra-abdominal infection, the adjudicated clinical cure rate was 76·4% (159 of 208) for the aztreonam–avibactam group and 74·0% (77 of 104) for the meropenem group. Cure rates in patients with HAP–VAP were 45·9% (34 of 74) for aztreonam–avibactam and 41·7% (15 of 36) for meropenem. 28-day all-cause mortality rates were 4% (12 of 282) for aztreonam–avibactam and 7% (ten of 140) for meropenem; in patients with complicated intra-abdominal infection, mortality was 2% (four of 208) and 3% (three of 104) for aztreonam–avibactam and meropenem, respectively, and in patients with HAP–VAP, mortality was 11% (eight of 74) and 19% (seven of 36), respectively. Aztreonam–avibactam was generally well tolerated, and safety findings were consistent with the known safety profile of aztreonam monotherapy. There were no treatment-related serious adverse events in the aztreonam–avibactam group. These phase 3 efficacy and safety data provide support for aztreonam–avibactam as a potential therapeutic option for complicated intra-abdominal infection or HAP–VAP caused by Gram-negative bacteria. Pfizer.

Background Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. Methods A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7–14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. Results A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of − 2.16 (− 15.59 to 11.26, p  = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p  = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p  = 0.015). Conclusions This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination. Trial registration ClinicalTrials.gov, NCT01292031 . Registered 9 February 2011.

Abstract Background Nephrotoxins contribute to 20%–40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations. Methods The study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups. Results The overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85–1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71–1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09). Conclusion Short courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations. Findings suggest that nephrotoxicity occurs after 3–5 days of piperacillin-tazobactam/vancomycin therapy. We found in a large observational study of intensive care unit patients that brief (<72-hour) empiric use of this combination was no more nephrotoxic than other such combinations.

The search for new agents to treat multidrug-resistant gram-negative bacterial infections has been ongoing. Specifically, carbapenem-resistant Enterobacteriaceae (CRE) infections often exhibit multiple resistance mechanisms, including alterations in drug structure, bacterial efflux pumps, and drug permeability. Vaborbactam, a cyclic boronic acid pharmacophore, has the highest potency in vitro with meropenem as an inhibitor of class A carbapenemases, including Klebsiella pneumoniae carbapenemase (KPC). This combination product was approved by the US Food and Drug Administration for complicated urinary tract infections (cUTIs) in August 2017, and recent Phase III trial data have expanded the literature available. This article aimed to describe the literature regarding spectrum of activity, dosing and administration, including pharmacokinetic and pharmacodynamics properties, safety profile, and efficacy end points. The terms meropenem, vaborbactam, RPX7009, and meropenem-vaborbactam were used to search for literature via PubMed, ClinicalTrials.gov, and published abstracts from 2013 to July 2019. Abstracts from IDWeek 2019 were also searched via these terms. Results were limited to availability in English. Meropenem-vaborbactam covers a spectrum of gram-negative bacterial pathogens, including K pneumoniae, Escherichia coli, and Enterobacter cloacae complex. Although the addition of vaborbactam to meropenem results in MIC lowering for KPC-positive Enterobacteriaceae, in vitro data reveal limited activity against resistant strains of Acinetobacter species and Pseudomonas aeruginosa. Data from 2 Phase III studies compare the drug with available therapies for the following indications: cUTIs, acute pyelonephritis, hospital-acquired and ventilator-acquired bacterial pneumonia, bacteremia, and complicated intra-abdominal infections. Outcomes include an improvement in clinical success when compared with piperacillin-tazobactam (98.4% vs 94%; 95% CI, 0.7%–9.1%; P < 0.001 for noninferiority) for overall treatment of cUTIs and acute pyelonephritis and clinical cure (64.3% vs 33.3%; P = 0.04) when compared with best available therapy for CRE infections in various sites of infection. Adverse events have been described as mild to moderate, with few events requiring discontinuation of the drug therapy. Currently, meropenem-vaborbactam is approved for treatment of cUTIs and acute pyelonephritis; however, off-label use, in particular for CRE infections, appears beneficial. Clinical trials to date have found an improvement in clinical cure and potentially an improved tolerability compared with standard therapies. Most of the evidence for meropenem-vaborbactam activity and the role in therapy focuses on KPC-producing organisms; however, because in vitro activity has been found with some non–KPC-producing CRE, its role may be further described from upcoming in vivo cases and postmarketing research.

Tazobactam/piperacillin and meropenem are commonly used as an empiric treatment in patients with severe bacterial infections. However, few studies have investigated the cause of tazobactam/piperacillin- or meropenem-induced liver injury in them. Our objective was to evaluate the association between tazobactam/piperacillin or meropenem and liver injury in the intensive care unit patients. We evaluated the expression profiles of antibiotics-induced liver injury using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Further, in the retrospective observational study, data of patients who initiated tazobactam/piperacillin or meropenem in the intensive care unit were extracted. In FAERS database, male, age, the fourth-generation cephalosporin, carbapenem, β -lactam and β -lactamase inhibitor combination, and complication of sepsis were associated with liver injury ( p  < 0.001). In the retrospective observational study, multivariate logistic regression analyses indicated that the risk factors for liver injury included male ( p  = 0.046), administration period ≥ 7 days ( p  < 0.001), and alanine aminotransferase ( p  = 0.031). Not only administration period but also sex and alanine aminotransferase should be considered when clinicians conduct the monitoring of liver function in the patients receiving tazobactam/piperacillin or meropenem.

The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged <90 days with LOS. NeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.