The efficacy and safety of tazobactam/ceftolozane in combination with metronidazole in Japanese patients with complicated intra-abdominal infections

Abstract

a b s t r a c tTazobactam/ceftolozane, a novel antimicrobial therapy, is active against Pseudomonas aeruginosa and most extended-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae. We report the results of the efficacy and safety of tazobactam/ceftolozane in Japanese patients with complicated intra-abdominal infections (cIAI).A multicenter, open-label, noncomparative study (MK-7625A Protocol 013, ClinicalTrials.gov Identifier: NCT02739997) to investigate the efficacy and safety of tazobactam/ceftolozane used in combination with metronidazole in Japanese patients with cIAI was conducted. One hundred Japanese patients with cIAI received tazobactam/ceftolozane 1.5 g (tazobactam 0.5 g/ceftolozane 1 g) plus metronidazole 500 mg intravenously every 8 h for 60 min for 4e14 days. The clinical response rate at the Test-of-Cure visit (TOC; Day 28 ± 2 days) was 92.0% (81/88 subjects). By disease type, the clinical response rates were 92.3% (24/26) for cholecystitis, 100% (6/6) for liver abscess, 93.5% (58/62) for intra-abdominal abscess and 90.2% (55/61) for peritonitis. The per-subject microbiological response rate at the TOC was 90.2% (55/61). Perpathogen microbiological response rates in the most common baseline pathogens were Escherichia coli 90.2% (37/41), Kebsiella pneumoniae 91.7% (11/12), Streptococcus anginosus 100% (11/11), Streptococcus constellatus 90.0% (9/10) and Bacteroides fragilis 95.2% (20/21). The most common drug-related AEs were aspartate aminotransferase increased (11.0%) and alanine aminotransferase increased (9.0%). No serious drug-related AE was reported during the study.The favorable effect of tazobactam/ceftolozane in the treatment of cIAI suggests that the agent will be useful in clinical practice in Japan.

Population pharmacokinetics of tazobactam/ceftolozane in Japanese patients with complicated urinary tract infection and complicated intra-abdominal infection

“…Two multicenter, open-label, noncomparative phase 3 studies in Japanese patients with cUTI (MK-7625A-014, ClinicalTrials.gov Identifier: NCT02728089) [11] and cIAI (MK-7625A-013, ClinicalTrials.gov Identifier: NCT02739997) [12] were conducted. Patients received TAZ/CTLZ 1.5 g (TAZ 0.5 g/CTLZ 1 g) intravenously every 8 h for 1-h for 7 days (for cUTI) and for 4e14 days (for cIAI).…”

“…CLcr was estimated by the Cockcroft-Gault equation [13]. The criteria of diagnose cUTI and cIAI with patients were used the same criteria used in the paper of Arakawa et al [11] and Mikamo et al [12], respectively. For the empirical Bayes analysis, CTLZ and TAZ plasma concentration data from these phase 3 studies in Japanese patients were used.…”

“…In Japan, two phase 3 studies in Japanese patients with cUTI and cIAI were conducted to confirm the safety and efficacy of TAZ/CTLZ in Japanese patients and for an approval application in Japan [11,12]. Furthermore, although there was no PK data that the dose was adjusted based on CLcr during the phase 3 studies in non-Japanese patients, the two phase 3 studies included Japanese patients with moderate renal impairment, and CTLZ and TAZ PK after dose adjustment based on CLcr during these studies in these patients with cUTI and cIAI were confirmed for the first time.…”

The safety of ceftolozane-tazobactam for the treatment of acute bacterial infections: a systemic review and meta-analysis

“…In another single arm study by Mikamo et al, 8 the most common drug-related AEs were AST increase (11.0%), ALT increase (9.0%), diarrhea (3.0%), and nausea (2.0%). All cases of ALT or AST increase were resolved by the end of the treatment or during the study.…”

“…Clinically, ceftolozane-tazobactam has also shown favorable efficacy for the treatment of complicated intra-abdominal infection (cIAI) and uncomplicated/complicated urinary tract infection (cUTI) in Japan. 8 , 9 In addition, several randomized controlled trials (RCTs) have demonstrated that the clinical efficacy of ceftolozane-tazobactam is comparable with other alternative agents for the treatment of acute bacterial infections. 10 – 12 In the ASPECT-cUTI trial, 10 ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (76.9% versus 68.4%, 95% CI 2.3–14.6) for the treatment of complicated lower-UTIs or pyelonephritis.…”