Outcomes in Participants with Renal Impairment from a Phase 3 Clinical Trial for Ceftolozane/Tazobactam Treatment of Nosocomial Pneumonia (ASPECT-NP)

Abstract

In the phase 3 ASPECT-NP trial (NCT02070757), ceftolozane/tazobactam (C/T) was noninferior to meropenem for treatment of Gram-negative ventilated hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (vHABP/VABP). Here, we report outcomes in participants from ASPECT-NP with renal impairment (RI). Participants were categorized by their baseline renal function as follows: normal renal function (NRF; creatinine clearance [CLCR], ≥80 ml/min), mild RI (CLCR, >50 to <80 ml/min), moderate RI (CLCR, ≥30 to ≤50 ml/min), and severe RI (CLCR, ≥15 to <30 ml/min). Dosing of both study drugs was adjusted based on renal function. The following C/T doses were administered every 8 h: NRF or mild RI, 3 g; moderate RI, 1.5 g; and severe RI, 0.75 g. The primary and key secondary endpoints were day 28 all-cause mortality (ACM) and clinical response at the test-of-cure visit in the intention-to-treat (ITT) population, respectively. In the ITT population, day 28 ACM rates for the C/T arm versus the meropenem arm were 17.6% versus 19.1% (NRF), 36.6% versus 28.6% (mild RI), 31.4% versus 38.5% (moderate RI), and 35.3% versus 61.9% (severe RI). Rates of clinical cure in the ITT population for the C/T arm versus the meropenem arm were 58.1% versus 58.5% (NRF), 54.9% versus 45.5% (mild RI), 37.1% versus 42.3% (moderate RI), and 41.2% versus 47.6% (severe RI). Small sample sizes in the RI groups resulted in large 95% confidence intervals (CIs), limiting conclusive interpretation of the analysis. Both drugs were well tolerated across all renal function groups. Overall, these results support the use of the study dosing regimens of C/T for treatment of vHABP/VABP in patients with RI. (This study has been registered at ClinicalTrials.gov under identifier NCT02070757.).

Keywords: Pseudomonas aeruginosa; hospital-acquired pneumonia; multidrug resistance; renal insufficiency; ventilator-associated pneumonia.

Copyright © 2020 American Society for Microbiology.

Figures

FIG 1

(A and B) Day 28 ACM by renal function group in the intention-to-treat (A) and microbiological intention-to-treat (B) populations. Participants were classified by renal function groups as follows: normal renal function (CLCR, ≥80 ml/min), mild RI (CLCR, >50 to <80 ml/min), moderate RI (CLCR, ≥30 to ≤50 ml/min), and severe RI (CLCR, ≥15 to <30 ml/min). Mortality rates (n/N, %) for each renal function group are provided below the graphs, and percentage differences between treatment groups (95% CI) are indicated above each renal function group. ACM, all-cause mortality; CI, confidence interval; CLCR, creatinine clearance; C/T, ceftolozane/tazobactam; MEM, meropenem; n, number of participants who died by day 28; N, number of participants in the treatment group; RI, renal impairment.

FIG 2

(A and B) Clinical cure rates at the test-of-cure visit by renal function group for the intention-to-treat (A) and clinically evaluable (B) populations. Participants were classified by renal function groups as follows: normal renal function (CLCR, ≥80 ml/min), mild RI (CLCR, >50 to <80 ml/min), moderate RI (CLCR, ≥30 to ≤50 ml/min), and severe RI (CLCR, ≥15 to <30 ml/min). Clinical cure rates (n/N, %) for each renal function group are provided below the graphs, and percentage differences between treatment groups (95% CI) are indicated above each renal function group. CI, confidence interval; CLCR, creatinine clearance; C/T, ceftolozane/tazobactam; MEM, meropenem; n, number of participants who experienced clinical cure; N, number of participants in the treatment group; RI, renal impairment.

FIG 3

Ceftolozane and tazobactam steady-state exposures by renal function group. (A to D) The ceftolozane AUC0–8 (A) and Cmax (B) and tazobactam AUC0–8 (C) and Cmax (D) are shown. Participants were classified by renal function groups as follows: normal renal function (CLCR, ≥80 ml/min), mild RI (CLCR, >50 to <80 ml/min), moderate RI (CLCR, ≥30 to ≤50 ml/min), and severe RI (CLCR, ≥15 to <30 ml/min). Boxes are the 25th, 50th, and 75th percentiles; whiskers are the 5th to 95th percentiles. Asterisks show data points outside this range. Participant numbers are indicated above each box. AUC0–8, area under the concentration-time curve for the first 8 h after dosing; CLCR, creatinine clearance; Cmax, maximum plasma concentration; RI, renal impairment.

FIG 4

ASPECT-NP study design. ACM, all-cause mortality; CE, clinically evaluable; C/T, ceftolozane-tazobactam; CLCR, creatinine clearance; EOT, end of treatment; ITT, intention-to-treat; MEM, meropenem; mITT, microbiological intention-to-treat; q8h, every 8 h; TOC, test of cure; VABP, ventilator-associated bacterial pneumonia; vHABP, ventilated hospital-acquired bacterial pneumonia.