A new study finds that piperacillin-tazobactam doesn’t improve mortality compared to meropenem in patients with ceftriaxone-resistant blood poisoning caused by E. coli or K. pneumoniae. The findings were so striking that the study was ended early.
Courtesy: JAMA
“These findings do not support use of piperacillin-tazobactam in this setting,” wrote the authors. The report was published Sept. 11 in JAMA (2018;320[10]:984-94.)
According to the Centers for Disease Control and Prevention, an estimated 1,700 deaths in the United States in 2011 were caused by gram-negative bacteria that produce extended-spectrum beta-lactamase enzymes.
While carbapenems such as meropenem (Merrem) are “regarded as the treatment of choice for serious infections,” the MERINO trial (NCT02176122) authors wrote, their rising use could lead to drug resistance.
One alternate option is to embrace beta-lactam/beta-lactamase inhibitors such as piperacillin-tazobactam (Zosyn), the researchers noted, but research has produced conflicting results.
Piperacillin-tazobactam is an injected penicillin antibiotic used to treat conditions such as severe pneumonia, complicated urinary tract infections and complicated skin and soft tissue infections.
For the new study, researchers led by Patrick N. A. Harris, MBBS, of the University of Queensland, randomly assigned 188 patients to intravenous piperacillin-tazobactam (4.5 g every 6 hours) and 191 patients to meropenem (1 g every 8 hours) for 4-14 days, depending on clinician’s preference. (12 other patients did not continue with the study after initial randomization due to factors such as errors).
All patients were adults and had at least one blood test showing they were positive for E. coli or K. pneumoniae. They all had to be nonsusceptible to ceftriaxone (Rocephin) but susceptible to piperacillin-tazobactam.
The study was ceased prior to enrollment because of the risk of harm. Interim findings suggested the study was unlikely to show higher effectiveness for piperacillin-tazobactam
The primary analysis included 379 patients (mean age 67 years, 48% were women), and the primary outcome analysis included 378 patients.
A total of 23 (12.3%) of 187 patients in the piperacillin-tazobactam group died by 30 days compared to 7 (3.7%) of 191 in the meropenem group (risk difference: 8.6%, P = .90 for noninferiority).
By day 4, 68% of the piperacillin-tazobactam group and 75% of the meropenem group achieved clinical and microbiological resolution.
Serious adverse effects other than death were rare, occurring in around 3% of the piperacillin-tazobactam group and nearly 2% of the meropenem group.
The researchers note various limitations, including the unblinded nature of the study and the fact that it’s not known if extended or continuous infusions of piperacillin-tazobactam would boost the drug’s effectiveness. They also note that delays resulted in some patients initially receiving treatment with one of the study’s two drugs before being randomized to the other.
The study authors caution that it’s not clear if newer beta-lactam/beta-lactamase inhibitors agents such as ceftolozane-tazobactam or ceftazidime-avibactam may be effective in this population.
The study was funded by the University of Queensland, Australian Society for Antimicrobials, International Society for Chemotherapy, and National University Hospital Singapore. Various organizations funded the researchers and the study’s whole-genome sequencing. The study authors report various disclosures, including funding from drugmakers such as Pfizer, maker of Zosyn (through its subsidiary Wyeth) and Merrem.
SOURCE: Harris PNA et al. JAMA 2018 Sep 11;320[10]:984-94. doi: 10.1001/jama.2018.12163.