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Bacteremia mortality rate similar with monotherapy, combination therapy
Pediatric patients with gram-negative bacteremia treated with beta-lactam monotherapy have reduced nephrotoxicity, according to recent study findings published in JAMA Pediatrics.
“Our study demonstrates that the risk of mortality is similar in pediatric patients with gram-negative bacteremia treated with beta-lactam monotherapy and those treated with combination (beta-lactam and aminoglycoside) therapy,” researchers wrote. “However, the use of combination therapy may predispose pediatric patients to acute renal injury.”
The retrospective cohort study included 879 children aged 18 years or younger with gram-negative bacteremia hospitalized at the Johns Hopkins Children’s Center between 2002 and 2011. Participants were assigned to either combination therapy (61.1%) or monotherapy (38.9%).
Researchers did not find an association with combination therapy and 30-day mortality (OR=0.98; 95% CI, 0.93-1.02). Acute kidney injury was evident in 19.3% of participants, 25.1% in the combination therapy group and 10.2% in the monotherapy group. Nephrotoxicity was two times more likely in the combination therapy group compared with the monotherapy group (OR=2.15; 95% CI, 2.09-2.21).
“In conclusion, we have identified an important problem in pediatrics that can help change our paradigm for treating gram-negative bacteremia in pediatric patients,” researchers wrote. “Combining our results with the large body of evidence supporting beta-lactam monotherapy for gram-negative bacteremia in the adult literature, we believe that beta-lactam monotherapy in pediatric patients with gram-negative can decrease the development of nephrotoxicity without compromising clinical outcomes.”
Disclosure: The study was funded in part by Johns Hopkins Hospital and NIH.
Perspective
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When discussing combination antimicrobial use, it is important to distinguish between empiric therapy (prior to pathogen identification) and definitive therapy (after identification and susceptibility results). Prior studies suggest that patients receiving early appropriate empiric antibiotics (those active against the organism ultimately identified) fare better than those who received delayed active therapy. Therefore, for extremely ill patients with presumed gram-negative bacteremia, combination empiric therapy is often warranted to increase the likelihood of covering the pathogen.
Definitive combination therapy is a different story. Theoretical advantages such as synergy or the prevention of antimicrobial resistance during therapy are generally not evidence-based, and studies of adult patients do not support the use of definitive combination therapy for gram-negative bacteremia. However, similar pediatric studies have not been performed and many patients—more than half at the large, academic medical center in the current study—receive two drugs for their entire treatment course.
This well-done and important study addresses this gap in the literature and (at least) local practice variation. Comparing outcomes between children treated with combination beta-lactam/aminoglycoside therapy and beta-lactams alone, investigators show that two drugs are not better than one, and may be more harmful given the higher incidence of renal failure in children receiving combination therapy. Although a single center study, the large number (more than 800 episodes) and propensity score matching (to adjust for differences in comorbid conditions and severity of illness) are significant strengths.
Tamma and colleagues provide strong evidence for limiting definitive antibiotic therapy for gram-negative bacteremia to a single active agent, which supports the principles of antimicrobial stewardship: optimizing clinical outcomes while avoiding the potential for direct patient harm and antibiotic resistance pressure from unnecessary antibiotic exposure.
