Azithromycin Prophylaxis Reduces Postcesarean Infections

Bridget M. Kuehn

September 28, 2016

Adding the broad-spectrum antibiotic azithromycin to routine antibiotic prophylaxis regimens used for unscheduled cesarean deliveries may reduce maternal infections without apparent harm to newborns, according to a results of a large, randomized controlled trial.

Maternal infections after unscheduled cesarean deliveries remain a substantial cause of death and illness in the United States, despite routine use of prophylactic antibiotics (usually cephalosporins) before the surgical incision, according to Alan T. N. Tita, MD, PhD, professor of obstetrics and gynecology at the University of Alabama at Birmingham, and colleagues. Dr Tita and colleagues reported the results in an article published in the September 29 issue of the New England Journal of Medicine.

In fact, as many as 12.0% of women undergoing nonelective cesarean sections experience infections despite such prophylaxis. However, previous studies, including a single-center randomized trial from the same research group, had suggested that adding azithromycin to these prophylactic regimens could reduce the risk for maternal infection.

Therefore, Dr Tita and colleagues conducted a multicenter trial to further assess the value of adding prophylactic azithromycin precesarean. In the trial, 2013 women having an unplanned cesarean at one of 14 US hospitals were randomly assigned to receive either standard prophylaxis plus azithromycin or standard prophylaxis plus a placebo.

The women who received azithromycin were significantly less likely to experience a composite of endometritis, wound infection, or other infections within 6 weeks of delivery than women receiving standard antibiotic prophylaxis plus placebo (6.1% vs 12.0%; relative risk, 0.51; 95% confidence interval, 0.38 - 0.68; P < .001). Endometritis (3.8% vs 6.1%; P = .02) and wound infection (2.4% vs 6.6%; P < .001) were also less frequent in the azithromycin group when considered individually. In addition, serious maternal adverse events were less common in the azithromycin group (1.5% vs 2.9%; P = .03).

"Our findings are consistent with those of previous studies supporting a lower risk of infection after cesarean section with the use of prophylatic extended-spectrum coverage than with standard antibiotic prophylaxis," the authors write.

Women with scheduled cesareans and with chorioamnionitis were not included in the study, so the results may not be generalizable to them, the authors note.

According to the results, 17 women would have to be treated with azithromycin plus standard antibiotic prophylaxis to prevent a woman from developing endometritis, wound infection, or other infections. To prevent only endometritis, 43 would need to receive this additional broad-spectrum antibiotic. To prevent only wound infections, 24 would need to be treated.

"The mechanism by which azithromycin reduces the rate of infection after cesarean section remains unclear," the authors note.

However, in an accompanying editorial, Robert Weinstein, MD, and Kenneth M. Boyer, MD, from Rush University Medical Center and the Cook Country Health and Hospitals System, Chicago, Illinois, suggest azithromycin may have provided antimicrobial protection against common bacteria found in the reproductive tract that the standard prophylactic regimen does not act against. However, the study did not collect the culture data necessary to confirm this, they write.

One concern about wider use of azithromycin for precesarean prophylaxis is that it could select for resistant strains for bacteria, the authors caution, although a single dose is unlikely to drive such selection.

"Our findings from clinical maternal cultures are reassuring, but ongoing monitoring for changes in resistance profiles is needed," they write.

The addition of the broad-spectrum antibiotic did not appear to pose additional risks to the newborns of women treated with azithromycin. Adverse events among newborns in both groups were comparable (14.3% vs 13.6%; P = .63). The concentration and persistence of azithromycin in the maternal myometrium and fat tissue, and limited fetal exposure to the drug, may explain why the drug was effective for the treated women without apparent immediate adverse effects for the newborn, the editorial authors explain.

"Pharmacologic data indicating that azithromycin only minimally crosses the placenta into the fetal circulation suggest limited exposure for the infant," write Dr Weinstein and Dr Boyer.

Longer-term follow-up of the newborns could provide additional "reassurance" that infants of treated mothers did not experience adverse effects, such as pyloric stenosis or hearing impairment, that have been linked to macrolide antibiotic exposure, the editorialists continue.

Although the results are promising, Dr Weinstein and Dr Boyer write that it was too early to tell whether the results would change practice. First, they suggested studies of higher doses of standard prophylactic antibiotics or studies that confirm the mechanism of azithromycin's apparent protection may be warranted.

"Time will tell whether such findings result in changes in routine antibiotic prophylaxis before cesarean deliveries," write Dr Weinstein and Dr Boyer. However, on the basis of the results, the addition of azithromycin "would reduce a number of infectious complications for some women without established infections who are undergoing nonelective cesarean section."

Pfizer donated the azithromycin used in the study, but had no other role in the study design or conduct. One coauthor reports receiving grant and nonfinancial support from Airstrip. Another coauthor reports receiving grants and personal fees from Teva Neuroscience and personal fees from the Consortium of Multiple Sclerosis Centers; Biogen Idec; EMD Serono; Novartis; Pfizer; Sanofi; Questcor; Genzyme; MedImmune; Receptos; Gilead Sciences; Neuren; Apotex/Modigenetec; Opko;; Ono/Merck; Genentech; GlaxoSmithKline; Transparency Life Sciences; Roche; Opexa; Janssen; Somahlution; Savara; Nivalis; Horizon Pharma; Reata Pharma; Munck WIlson; and PTC Therapeutics. Another coauthor reports being a member of the scientific advisory board of Sera Prognostics and holds stock in that company. Dr Weinstein reports owning stock in Merck. Dr Boyer has disclosed no relevant financial relationships.

N Engl J Med. 2016;375:1231-1241, 1284-1286. Article full text, Editorial

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