Selecting the dosage of ceftazidime–avibactam in the perfect storm of nosocomial pneumonia

Abstract

Purpose Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination recently approved in Europe and the USA for the treatment of adults with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), among other indications. In the phase III REPROVE trial (NCT01808092), ceftazidime-avibactam demonstrated non-inferiority to meropenem for the treatment of patients with nosocomial pneumonia (NP), including VAP. As ceftazidime-avibactam was not studied in patients with NP prior to REPROVE, selecting an appropriate dosage regimen in the "perfect storm" of NP required careful consideration of potential determinants and confounders of response specific to the NP patient population. Methods This review describes the series of preclinical studies and pharmacokinetic/pharmacodynamic (PK/PD) analyses that supported ceftazidime-avibactam dosage selection for patients with NP/VAP (2000/500 mg by 2-h intravenous infusion every 8 h, adjusted for renal function). In parallel, important considerations for antibiotic dosage selection in patients with NP are highlighted, including adequate drug penetration into the lungs, the suitability of murine-derived plasma PK/PD targets, evaluation of MIC distributions against clinical bacterial isolates from patients with NP, and consideration of PK in patients with NP, who are often critically ill. These analyses also supported the European approval of ceftazidime-avibactam for adults with HAP, including VAP, before the completion of REPROVE. Conclusions This work serves as a successful practical example of dosage design for a new antibacterial drug therapy in the indication of NP, including VAP, where previous drug therapies have failed, possibly as a result of evaluation of too few variables, thereby limiting the accuracy of pharmacodynamic predictions.

Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man

“…Meropenem T > MIC requirements for stasis, 1 log 10 and 2 log 10 reductions were 30, 35, and 45% fT > MIC against Gram-negatives in the neutropenic thigh infection model; however, vaborbactam required a free area under the curve to MIC (fAUC/MIC) of 38 to enable meropenem to achieve 1 log 10 kill at 35% fT > MIC against K. pneumoniae producing the KPC-carbapenemase (Food and Drug Administration, 2021). For ceftazidime/avibactam, the values used during development were 50% fT > MIC for ceftazidime and free avibactam concentrations that remained above a critical concentration threshold of 1 mg/L for at least 50% of the dosing interval (50% fT > C T 1 mg/L) (Das et al, 2019;Das et al, 2020). Indeed, studies in the neutropenic thigh infection model of humanized ceftazidime/avibactam (2g/0.5 g every 8 h as 2 h infusion) in lung epithelial lining fluid (ELF) demonstrated ≥1 log 10 CFU reductions against P. aeruginosa with MICs up to 32/ 4 mg/L, which corresponded with ceftazidime exposures ≥19% f T > MIC in ELF (Housman et al, 2014).…”

Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia

“…Assessment of drug partitioning into epithelial lining fluid of the human lung along with a compelling PK-PD rationale is a critical step for developing new antibiotics for pneumonia (10). This was the basis for the initial approval of ceftazidime-avibactam for the treatment hospital-acquired pneumonia (HAP) including ventilator associated pneumonia (VAP) prior to completion of Phase III trial for this indication (11). Meropenem-vaborbactam was approved by EMA for use in HAP including VAP based on a statistically powered Phase III trial patients with cUTI including pyelonephritis and a smaller open-label trial which included patients with HAP/VAP (https://www.ema.europa.eu/en/documents/productinformation/vaborem-epar-product-information_en.pdf; accessed 25 th June 2020).…”

Activities of aztreonam in combination with several novel β-lactam-β-lactamase inhibitor combinations against carbapenem-resistant Klebsiella pneumoniae strains coproducing KPC and NDM

“…Antibiotic concentrations used during time-kill experiments represent mean steady-state concentrations of non-protein-bound drug in humans, as calculated from data in the literature (based on the area under the antibiotic concentration–time curve in serum or plasma over 24 h divided by 24 h [AUC 0–24 /24 h]). The following antibiotic concentrations were used: aztreonam, 17 mg/L ( Tangden et al, 2014 ); meropenem, 10 mg/L ( Benitez-Cano et al, 2020 ); polymyxin, 2 mg/L ( Tsuji et al, 2019 ); CZA, 33.5/6 mg/L ( Das et al, 2020 ); aztreonam/avibactam, 17/6 mg/L; MEV, 23.2/25.5 mg/L ( Wenzler et al, 2015 ); and ICR, 11.4/7.5 mg/L ( Rizk et al, 2018 ). Viable colony counts were performed by obtaining samples after 0, 2, 4, 8, 12, and 24 h of antibiotic exposure.…”