Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: subset analysis of the ASPECT-NP randomized, controlled phase 3 trial

Abstract

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.

HAP and VAP after Guidelines

“…Interestingly, some new antibiotics have also been discovered that might provide a better survival benefit in patients with vHAP compared with those with VAP. [20][21][22] Fig. 2 Classification of lower respiratory tract infection in ICU patients, with a distinction between tracheobronchitis and pneumonia.…”

Comparison between meropenem and ceftolozane/tazobactam: possible influence of CRRT

“…In their recent study [ 1 ], Timsit et al conclude that mortality risk with ventilator hospital-acquired bacterial pneumonia (vHABP) was over twice as high when treated with meropenem compared to ceftolozane/tazobactam (C/T). However, the percentage of patients in the database with vHABP who had a creatinine clearance (CrCl) between 15 and 30 ml/min was 12% in both groups [ 1 ]. Of these, around 40% had a sequential organ failure assessment (SOFA) score > 7 with vasopressor use in more than 50% in both groups.…”

“…Of these, around 40% had a sequential organ failure assessment (SOFA) score > 7 with vasopressor use in more than 50% in both groups. Consequently, it is reasonable to assume that most of these patients were undergoing renal replacement therapy (RRT), most likely continuous RRT (CRRT) though this was not reported [ 1 ]. While a dose of C/T of 3 gr (2 g ceftolozane and 1 g tazobactam) three times a day will surely be above the minimal inhibitory concentration (MIC) most of the time even on CRRT [ 2 ], this is not the case for meropenem 1 gr three times a day, as in a number of cases this dose will fall below the MIC when undergoing CRRT [ 1 ].…”

“…Consequently, it is reasonable to assume that most of these patients were undergoing renal replacement therapy (RRT), most likely continuous RRT (CRRT) though this was not reported [ 1 ]. While a dose of C/T of 3 gr (2 g ceftolozane and 1 g tazobactam) three times a day will surely be above the minimal inhibitory concentration (MIC) most of the time even on CRRT [ 2 ], this is not the case for meropenem 1 gr three times a day, as in a number of cases this dose will fall below the MIC when undergoing CRRT [ 1 ]. Kothekar et al concluded that in septic shock patients, extended infusions (EI) of 1000 mg of meropenem over 3 h, administered every 8 h, provided adequate coverage against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii [ 3 ].…”

“…If drug dose adaptation was not adhered to in CRRT patients and continuous infusion (CI) not used in cases of pathogens with a MIC ≥ 4, as recommended [ 4 ] some patients may have been underdosed, even with 1 g every 8 h [ 3 , 4 ], as meropenem is significantly eliminated by CRRT [ 4 ]. In addition, in the same study adjunctive therapy with amikacin 15 mg/kg was permitted for the first 72 h of study treatment where ≥ 15% of Pseudomonas aeruginosa were known to be meropenem resistant [ 1 ]. Under CRRT, the recommended dose of amikacin to avoid failure is 25 mg/kg [ 5 ].…”