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.

Ruthenium complexes as prospective inhibitors of metallo-ß-lactamases to reverse carbapenem resistance.

The widespread prevalence of metallo-ß-lactamase (MßL)-mediated pathogens has seriously caused a loss of efficacy of carbapenem antibacterials, the last resort for the treatment of severe infectious diseases. The development of effective MßL inhibitors is an ideal alternative to restore the efficacy of carbapenems. Here we report that Ru complexes can irreversibly inhibit clinically relevant B1 subclass MßLs (NDM-1, IMP-1 and VIM-2) and potentiate meropenem efficacy against MßL-expressing bacteria in vitro and in a mice infection model. The Cys208 residue at the Zn(ii)-binding site and Met67 residue at the ß-hairpin loop of an enzyme active pocket are critical for Ru complexes to inhibit NDM-1, which was verified by enzyme kinetics, thermodynamics, NDM-1-C208A mutation and MALDI-TOF-MS analysis. This study will undoubtedly aid efforts to develop metal-based MßL inhibitors in combination with carbapenems to deal with the clinical crisis of carbapenem-resistant E. coli harboring MßLs.

A validated LC-MSMS method for the simultaneous quantification of meropenem and vaborbactam in human plasma and renal replacement therapy effluent and its application to a pharmacokinetic study.

A simple method for the simultaneous quantification of meropenem and the recently approved ß-lactamase inhibitor, vaborbactam, in human plasma and renal replacement therapy effluent (RRTE) was developed and validated. This antibiotic combination protects a primary ß-lactam, meropenem, with a new ß-lactamase inhibitor, and expands the limited options for treatment of multidrug-resistant Gram-negative infections. Meropenem, vaborbactam, and the internal standards [2H6]-meropenem and sulbactam in plasma and RRTE were processed using acetonitrile followed by a chromatographic separation on a Poroshell HPH-C18 column with a gradient elution of the mobile phases and monitored using mass spectrometry detection. The calibration range was 0.05 to 100 µg mL-1 for both meropenem and vaborbactam. The intra-day and inter-day precision and accuracy were less than 15% for both meropenem and vaborbactam and the recovery from plasma was 96% for both meropenem and vaborbactam and the recovery from RRTE was 93% and 103% for meropenem and vaborbactam, respectively. This methodology was successfully applied to an ex vivo characterisation study of the effects of renal replacement therapy modalities on the pharmacokinetics of meropenem and vaborbactam (Antimicrob Agents Chemother 62(10), 2018). Graphical abstract.

Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial.

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.