Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial

Abstract

Background: The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function.

Methods: Baseline renal function was categorized as normal renal function (creatinine clearance 80-130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit.

Results: A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [- 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; - 2.6 [- 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; - 2.1 [- 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [- 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [- 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [- 8.7 to 19.0]).

Conclusions: C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Keywords: Hospital-acquired bacterial pneumonia; Multidrug resistance; Pseudomonas aeruginosa; Ventilator-associated bacterial pneumonia.

Conflict of interest statement

AFS reports advisory board membership for Combioxin SA. CJB, ZZ, EJ, WG, H-PF, JAH, BY, EGR, SB, and CDA are employees of MSD and may own stock and/or hold stock options in Merck & Co., Inc., Kenilworth, NJ, USA. MHK reports advisory board and speaker’s bureau fees and institutional research funding from MSD.

© 2021. The Author(s).

Figures

Fig. 1

PTA for ceftolozane and tazobactam in simulated patients with vHABP/VABP by renal function. Panels A and B represent PTA for ceftolozane at a target of 50% fT > MIC. Panels C and D represent PTA for tazobactam at a target of 35% fT > CT. Left panels represent PTA in plasma and right panels represent PTA in ELF. Solid horizontal line on plots represents 90% PTA; vertical line in panels A and B represents an MIC of 4 μg/mL; vertical line in panels C and D represents a CT of 1 μg/mL. CrCl creatinine clearance, CT threshold concentration, ELF epithelial lining fluid, fT > CT time period that the free drug concentration remained above the threshold concentration, fT > MIC time period that the free drug concentration exceeded the MIC value, MIC minimum inhibitory concentration, PD pharmacodynamic, PK pharmacokinetic, PTA probability of target attainment, vHABP/VABP ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia

Fig. 2

28-day ACM in ceftolozane/tazobactam- or meropenem-treated patients by renal function. ACM all-cause mortality, ARC augmented renal clearance, ITT intention-to-treat, mITT microbiologic intention-to-treat

Fig. 3

Clinical cure at the test-of-cure visit in ceftolozane/tazobactam- or meropenem-treated patients by renal function. ARC augmented renal clearance, CE clinically evaluable, ITT intention-to-treat

Fig. 4

Per-patient microbiologic cure at the test-of-cure visit in ceftolozane/tazobactam- or meropenem-treated patients by renal function. ARC augmented renal clearance, mITT microbiologic intention-to-treat