Safety and Efficacy of Ceftolozane/Tazobactam for Nosocomial Pneumonia

According to data presented at the 29th European Congress of Clinical Microbiology & Infectious Diseases, held April 13-16, 2019 in Amsterdam, The Netherlands, the novel combination antibacterial agent ceftolozane/tazobactam had comparable clinical and microbiologic response rates to meropenem in treating gram-negative ventilator-related nosocomial pneumonia.

The ASPECT-NP trial was a randomized, controlled, double-blind, multicenter, noninferiority trial (Clinicaltrials.gov number NCT02070757) conducted to compare ceftolozane/tazobactam vs meropenem in ventilator-related nosocomial pneumonia. Patients received either 3 g of the combination agent, consisting of 2 g ceftolozane and 1 g tazobactam or 1 g meropenem. Both treatment options were administered as 1-hour infusions every 8h for 8 to 14 days.

The microbiologic intent-to-treat (mITT) population consisted of 264 ceftolozane/tazobactam and 247 meropenem patients, all of whom were in the intent-to-treat population with at least 1 dose of study treatment and at least 1 eligible respiratory pathogen susceptible to at least 1 study drug. A subset of the mITT population, comprising 115 ceftolozane/tazobactam patients and 118 patients who received meropenem, was identified as the microbiologically evaluable (ME) population. The ME population were mITT patients who adhered to the protocol; had an evaluable clinical response at test of cure 7 to 14 days after therapy ended; and had eligible baseline lower respiratory tract pathogen counts of ≥105 CFU/mL for endotracheal aspirate, ≥104 CFU/mL for bronchoalveolar lavage (BAL/mini-BAL), and ≥103 CFU/mL for protected specimen brush (PSB).

The main causative baseline lower respiratory tract gram-negative pathogens in the mITT population were Enterobacteriaceae (74.4%) and Pseudomonas aeruginosa (25.0%). In the pool of mITT isolates of Enterobacteriaceae, ceftolozane/tazobactam showed a minimum inhibitory concentration (MIC) range of <0.064 to ≥256 μg/mL (MIC₅₀ 0.5 μg/mL, MIC₉₀ 16 μg/mL), whereas meropenem had an MIC range of <0.064 to 16 μg/mL (MIC₅₀ <0.064 μg/mL, MIC₉₀ 0.125 μg/mL). The MIC ranges for P aeruginosa in the mITT group were 0.125 to ≥256 μg/mL (MIC₅₀ 1 μg/mL, MIC₉₀ 2 μg/mL) and <0.064 to 128 μg/mL (MIC₅₀ 0.5 μg/mL, MIC₉₀ 8 μg/mL) for ceftolozane/tazobactam and meropenem, respectively. The mITT population analysis also showed that 87% of baseline gram-negative lower respiratory tract isolates were susceptible to ceftolozane/tazobactam and 93.3% to meropenem.

The 2 treatment options also had comparable per-pathogen clinical cure and microbiologic eradication rates and there was high concordance between clinical cure and per-pathogen microbiologic eradication at test of cure in both the mITT and ME populations. Clinical failure and per-patient microbiologic persistence in the ME population also showed high concordance, while clinical failure and per-patient microbiologic persistence showed generally lower concordance in the mITT population.

According to the study investigators, these data demonstrate additional support for the use of ceftolozane/tazobactam 3 g every 8h, which is double the currently approved dose, as an efficacious treatment option for gram-negative nosocomial pneumonia.

Reference

Martin-Loeches I, Kivistik Ü, Nováček M, et al. (2019). Clinical and microbiologic outcomes by causative pathogen in the ASPECT-NP randomized, controlled, phase 3 trial evaluating ceftolozane/tazobactam for treatment of ventilated nosocomial pneumonia. 29th European Congress of Clinical Microbiology & Infectious Diseases. Amsterdam, Netherlands. ePoster O0302.