Antibiotic regimens proven safe in premature infants with intra-abdominal infections

Three antibiotic regimens have been found safe and tolerable in critically ill premature infants with complicated intra-abdominal infections (CIAIs), a study has shown. No differences are seen in mortality, adverse events (AEs), or serious AEs between any of the commonly used antimicrobial regimens.

“This study provides important safety data to guide recommended label changes in the premature neonate population with CIAIs,” the researchers said.

This study randomized infants ≤33 weeks gestational age and <121 days postnatal age with CIAIs to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam, and gentamicin (group 3) at doses stratified by postmenstrual age.

Due to slow enrolment, the researchers amended the protocol to allow eligible infants already receiving study regimens to enrol without randomization.

Mortality within 30 days of study drug completion was the primary outcome, while secondary ones included AEs, outcomes of special interest (OSI), and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion.

Of the 180 infants enrolled (128 randomized [R], 52 nonrandomized [NR]), 63 were assigned to group 1 (45 R, 18 NR), 47 to group 2 (41 R, six NR), and 70 to group 3 (42 R, 28 NR). Thirty-day mortality was 8 percent in group 1, 7 percent in group 2, and 9 percent in group 3. No differences in safety outcomes were noted between these antibiotic regimens. [Pediatr Infect Dis J 2021;40:550-555]

Mortality rates at follow-up were 4.22 (95 percent confidence interval [CI], 1.39–4.53) for group 1, 4.53 (95 percent CI, 1.21–15.50) for group 2, and 4.07 (95 percent CI, 1.22–12.70) for group 3 after adjusting for treatment group and gestational age.

A previous randomized controlled trial found an increased risk of intestinal strictures and no survival benefit when adding clindamycin to ampicillin and gentamicin for the treatment of necrotizing enterocolitis (NEC). [J Pediatr 1988;112:271-277]

In a subsequent propensity-matched retrospective cohort study, the results showed a small increase in the development of strictures among infants with NEC who received any anaerobic therapy relative to anaerobic-free regimens. However, no association was seen between strictures and any particular agent. [Pediatrics 2015;135:e117-e125]

“Development of strictures was an OSI that was collected, monitored, and adjudicated based on prospectively collected radiology, clinical notes, and operative reports,” the researchers said.

“Even when using this rigorous definition, we arrived at a low estimate for stricture similar to that reported in a recent large retrospective cohort, and no regimen was associated with increased rates of stricture,” they added. [Pediatrics 2015;135:e117-e125]

NEC aetiology is multifactorial and involves a combination of intestinal immaturity, hypoperfusion, and mucosal colonization with pathologic bacteria. While it may not be a primarily infectious process, affected infants are usually treated with antibiotics; recommendations for antimicrobial management of NEC are included in the IDSA CIAI guidelines. [Clin Infect Dis 2010;50:133-164]

“Despite these guidelines, there is no clear consensus on antibiotic regimens for NEC,” the researchers noted. [Cochrane Database Syst Rev 2012:CD007448]

The present study had certain limitations. First, it was underpowered to detect small but clinically meaningful differences between treatment regimens. Second, the protocol amendment might have introduced differences between randomized and nonrandomized infants that were not accounted for in the modeling. Finally, not every regimen was randomly assigned.