Although the World Health Organization (WHO) recommends the use of ampicillin plus gentamicin as first-line therapy among individuals with neonatal sepsis residing in low- and middle-income countries (LMIC), results of a recent study showed an increased prevalence of antimicrobial-resistant Gram-negative isolates among those who received these medications, signaling that this recommendation by the WHO may need to be revised. These findings were published in Lancet Infectious Diseases.

Using data from the BARNARDS (Burden of Antibiotic Resistance in Neonates from Developing Societies) study, the researchers examined the effectiveness of empiric antibiotics, as well as potential alternative treatments, among patients aged 60 days or younger with neonatal sepsis  at 12 hospital sites in Bangladesh, Ethiopia, India, Nigeria, Pakistan, Rwanda, and South Africa. They used data from whole-genome sequencing to analyze 457 isolates from 442 neonates who were treated with 1 of the 4 commonly prescribed antibiotic combinations: ampicillin-gentamicin, ceftazidime-amikacin, piperacillin-tazobactam-amikacin, or amoxicillin-clavulanate-amikacin. All countries mentioned above were represented in the final analysis, with the exception of India.

Although no differences in mortality were observed among patients treated with ampicillin-gentamicin vs piperacillin-tazobactam-amikacin or amoxicillin-clavulanate-amikacin, those treated with ceftazidime-amikacin had a decreased mortality rate (adjusted hazard ratio [HR], 0.32; 95% CI, 0.14-0.72; P =.0060). The researchers noted that this data was probably confounded by country-specific factors.


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Of the 390 Gram-negative isolates, 97.2% and 70.3% were resistant to ampicillin and gentamicin, respectively, and 25.9% were resistant to amikacin. Only 28.5% of Gram-negative isolates were found to be susceptible to treatment with ampicillin-gentamicin. The susceptibility rates for the other combination treatments were significantly increased: 73.3% for amoxicillin-clavulanate–amikacin, 77.2% for ceftazidime–amikacin, and 80.0% for piperacillin–tazobactam–amikacin.

Because of the increased prevalence of antimicrobial-resistant isolates found among the included patients, the probability of achieving an 80% or greater target attainment was decreased among those who received ampicillin–gentamicin (33.7%) compared with those who receivedamoxicillin-clavulanate–amikacin (68%), piperacillin–tazobactam–amikacin (85.3%), or ceftazidime–amikacin (92.7%).

An increased frequency of antimicrobial resistant isolates were found among patients treated with fosfomycin (68.4% [78 of 114 isolates]), followed by those treated with colistin (57.3% [55 of 96 isolates]), and then those treated with gentamicin (53.0% [62 of 117 isolates]).

The researchers also collected data on antibiotic costs in LMICs and found that with the exception of South Africa, cost would inevitably affect therapy choice and, consequently, treatment outcomes among patients residing in the other 6 countries included in the study.

Limitations of the study included the number of patients lost to follow-up, potential confounding, country-specific bias, and the absence of patient-level pharmacokinetic measures.

Results of this study “suggest that ceftazidime–amikacin might be an effective potential alternative to ampicillin–gentamicin [for the treatment of patients with neonatal sepsis] in LMICs,” the researchers concluded.

Reference

Thomson KM, Dyer C, Liu F, et al; BARNARDS Group. Effects of antibiotic resistance, drug target attainment, bacterial pathogenicity and virulence, and antibiotic access and affordability on outcomes in neonatal sepsis: an international microbiology and drug evaluation prospective substudy (BARNARDS). Lancet Infect Dis. Published online August 9, 2021. doi:10.1016/S1473-3099(21)00050-5