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: 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 population, respectively. In the intention-to-treat population (ITT), 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), respectively. Rates of clinical cure in the ITT for the C/T arm vs 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), respectively. Small sample sizes in the RI groups resulted in large 95% 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.

Exposure–Efficacy Analyses Support Optimal Dosing Regimens of Ceftolozane/Tazobactam in Participants with Hospital-Acquired/Ventilator-Associated Bacterial Pneumonia in ASPECT-NP

“…In the exposure–efficacy data set, there were differences in the all-cause mortality and clinical response rates between participants with moderate/severe renal impairment (CrCl ≤50 mL/min) and those with mild renal impairment or normal renal function (CrCl >50 mL/min). These results are consistent with a previous secondary analysis of ASPECT-NP that assessed the safety and efficacy of ceftolozane/tazobactam in participants with renal impairment ( 25 ). In that analysis, rates of 28-day all-cause mortality were higher in those with renal impairment compared with those with normal renal function, for both the ceftolozane/tazobactam and the meropenem treatment groups ( 25 ).…”

“…These results are consistent with a previous secondary analysis of ASPECT-NP that assessed the safety and efficacy of ceftolozane/tazobactam in participants with renal impairment ( 25 ). In that analysis, rates of 28-day all-cause mortality were higher in those with renal impairment compared with those with normal renal function, for both the ceftolozane/tazobactam and the meropenem treatment groups ( 25 ). These results likely reflect the established independent association between renal insufficiency and increased risk of mortality ( 26 , 27 ).…”

“…These results likely reflect the established independent association between renal insufficiency and increased risk of mortality ( 26 , 27 ). Huntington et al ( 25 ) also reported that clinical cure rates were lower among participants with moderate/severe renal impairment compared with those with normal renal function for both the ceftolozane/tazobactam and the meropenem treatment groups. Another previously reported secondary analysis of ASPECT-NP participant data examined the relationship between augmented renal function, ceftolozane and tazobactam exposure levels, and clinical outcomes ( 28 ).…”

Ceftolozane/Tazobactam Probability of Target Attainment in Patients With Hospital‐Acquired or Ventilator‐Associated Bacterial Pneumonia

“…At the PK/PD targets of 20% and 35% f T>C T =1 µg/mL, plasma and ELF PTAs for tazobactam were >90% across renal function groups, except for ELF PTA in participants with severe renal impairment, which was only slightly lower than 90%. In the ASPECT‐NP study, similar clinical response rates were seen in the C/T and meropenem treatment groups in the subset of subjects with severe renal impairment, suggesting that the C/T exposures achieved were efficacious 21 …”

“…In the ASPECT-NP study, similar clinical response rates were seen in the C/T and meropenem treatment groups in the subset of subjects with severe renal impairment, suggesting that the C/T exposures achieved were efficacious. 21 Certain limitations should be considered when evaluating the results of this analysis. PK/PD targets were previously defined in plasma using murine thigh infection models, which differs from the site of expected infection in the lungs.…”