Characteristics and Outcomes of Complicated Intra-abdominal Infections Involving Pseudomonas aeruginosa from a Randomized, Double-Blind, Phase 3 Ceftolozane-Tazobactam Study

Abstract

c Ceftolozane-tazobactam is active against Gram-negative pathogens, including multidrug-resistant Pseudomonas aeruginosa. In a subgroup analysis of patients with complicated intra-abdominal infections (cIAIs) involving P. aeruginosa from a phase 3 program, ceftolozane-tazobactam demonstrated potent in vitro activity against P. aeruginosa. Clinical cure in the microbiologically evaluable population was 100% (26/26) for ceftolozane-tazobactam plus metronidazole and 93.1% (27/29) for meropenem. These findings support the use of ceftolozane-tazobactam in the management of cIAI when P. aeruginosa is suspected or confirmed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01445665 and NCT01445678.) C omplicated intra-abdominal infections (cIAIs) are caused by Gram-negative bacteria, with Enterobacteriaceae being the most common pathogen. Pseudomonas aeruginosa is the thirdmost-common Gram-negative bacteria in cIAI (1), and increasing rates of P. aeruginosa resistance are a global concern (2, 3).Ceftolozane-tazobactam, in combination with metronidazole, is approved for the treatment of cIAI (4). Ceftolozane-tazobactam has potent activity against many drug-resistant Gram-negative pathogens, including most extended-spectrum ␤-lactamase (ESBL)-producing Enterobacteriaceae (5, 6), and is minimally affected by common P. aeruginosa resistance mechanisms (7). Compared with approved ␤-lactam antibiotics, including meropenem and piperacillin-tazobactam, ceftolozane-tazobactam displays more potent in vitro activity against P. aeruginosa (8).The Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-Abdominal Infections (ASPECT-cIAI) study was a global phase 3 program that demonstrated the efficacy of ceftolozane-tazobactam plus metronidazole to be similar to that of meropenem in patients with cIAI (NCT01445665 and NCT01445678) (9). This analysis was conducted to determine the characteristics and clinical outcomes of the subgroup of patients with P. aeruginosa infection.( In ASPECT-cIAI, patients (age, Ն18 years) with cIAI were randomly assigned 1:1 to receive intravenous ceftolozane-tazobactam (1.5 g containing 1,000 mg ceftolozane and 500 mg tazobactam) plus metronidazole (500 mg) every 8 h or intravenous meropenem (1 g every 8 h) plus placebo for 4 to 14 days. Efficacy was assessed at the test-of-cure visit 24 to 32 days after initiation of the study drug. Clinical cure was defined as the resolution of or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or intervention was necessary. Descriptive statistics were used to compare baseline characteristics (microbiological intent-to-treat [MITT] population) and clinical outcomes (microbiologically evaluable [ME] population) of patients with and without P. aeruginosa infection. Descriptions of inclusion/exclusion criteria and study design were published previously (9).MIC cutoffs for susceptibility to ceftolozane-tazobactam and meropenem were based ...

Multicenter Evaluation of the Etest Gradient Diffusion Method for Ceftolozane-Tazobactam Susceptibility Testing of Enterobacteriaceae and Pseudomonas aeruginosa

“…C/T was approved by the U.S. Food and Drug Administration in 2014 for the treatment of complicated intra-abdominal infections (cIAI, in combination with metronidazole) and complicated urinary tract infections (cUTI) (1). In clinical trials, C/T demonstrated noninferiority to meropenem when used in combination with metronidazole for the treatment of cIAIs (2,3). Additionally, C/T was noninferior to levofloxacin for the treatment of cUTIs, including pyelonephritis (4), which was mainly attributable to high rates of levofloxacin-resistant isolates among cUTI-causing bacteria (5,6).…”

Compassionate Use of Cefiderocol in the Treatment of an Intraabdominal Infection Due to Multidrug‐Resistant Pseudomonas aeruginosa: A Case Report

“…Lack of therapeutic options for the treatment of P. aeruginosa infections has been an increasing concern as antibiotic resistance continues to evolve. Specifically with regards to intraabdominal infections, resistance has led to the study and recent FDA approval of two new cephalosporin/β‐lactamase inhibitor combinations, ceftazidime‐avibactam and ceftolozane‐tazobactam . These agents initially represented advancements in the ability to treat organisms with few other therapeutic options secondary to antimicrobial resistance.…”

“…Specifically with regards to intraabdominal infections, resistance has led to the study and recent FDA approval of two new cephalosporin/ b-lactamase inhibitor combinations, ceftazidimeavibactam and ceftolozane-tazobactam. 10,11 These agents initially represented advancements in the ability to treat organisms with few other therapeutic options secondary to antimicrobial resistance. Despite the promise of these two newer agents for complicated intraabdominal infections caused by MDR gram-negative bacilli, resistance is being increasingly encountered.…”

Ceftolozane/tazobactam for febrile UTI due to multidrug-resistant Pseudomonas aeruginosa in a patient with neurogenic bladder

“…In the study from Wagenlehner et al 6 on C/T and UTI, 23 PSA were involved but their antimicrobial susceptibilities are unknown. Miller et al 8 studied cIAI due to PSA; among them 26 MDR PSA were involved and treated by CT with a cure rate of 93%. Also, Castón et al 7 found that CT as salvage therapy for pneumonia due to MDR PSA was effective.…”