By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: Gram-negative rods are responsible for most neonatal sepsis in low- and middle-income countries. Ampicillin-gentamicin usually has been recommended for presumptive treatment pending bacteriology results (when such tests are available). A multinational study in Africa and Asia suggests that resistance to standard therapy is widespread and that ceftazidime-amikacin might be a better option.
SOURCE: Thomson KM, Dyer C, Liu F, et al. 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 2021;21:1677-1688.
Each year, approximately 2.5 million babies die during their first month of life, mostly in sub-Saharan Africa and Asia. Sepsis is a major contributor to this mortality. Standard international recommendations suggest that combined treatment with ampicillin and gentamicin be used for presumed neonatal sepsis. Appropriate empirical selection of an antimicrobial regimen is especially important in low- and middle-income countries since bacteriologic testing is not always available in such settings.
Whether from a lack of antimicrobial stewardship or from appropriate concerns for resistance to first-line antibiotics, alternate empirical antibiotic choices often are employed. Unnecessary use of newer or broader-coverage antibiotics risks fostering further spread of resistance.
With funding from the Bill and Melinda Gates Foundation, an observational cohort study followed 36,285 babies with concern for possible bacterial infection during the first 60 days of life at 12 sites in seven countries (Bangladesh, Ethiopia, India, Nigeria, Pakistan, Rwanda, and South Africa) between November 2015 and February 2018. The focus of this part of an overall larger study was on antibiotic use, effectiveness, and resistance.
Of the overall cohort, 9,874 had clinically diagnosed sepsis; 5,749 had antibiotic data available, and 2,483 had a positive blood culture. Ampicillin-gentamicin was used in African sites and in Bangladesh. Ceftazidime-amikacin was used mostly in Bangladesh but also sometimes in Nigeria and Pakistan. Piperacillin-tazobactam-amikacin was used in Pakistan and sometimes in South Africa and India. In Nigeria, amoxicillin-clavulanate-amikacin was used. These four combinations accounted for 77% of treatment courses.
Mortality was lowest (9%) in neonates treated with ceftazidime-amikacin, and this was significantly better (P = 0.006) than treatment with ampicillin-gentamicin (16% mortality). Amoxicillin-clavulanate-amikacin was associated with 24% mortality, and piperacillin-tazobactam-amikacin with 28% mortality.
Gram-negative isolates were frequently resistant to ampicillin (97%) and gentamicin (70%), and these rates of resistance were similar in African and Asian sites. There was less resistance to amikacin than to other aminoglycosides, but the resistance rate still was 26%. Resistance to imipenem (16%) and meropenem (14%) was lower than to most other antibiotics.
Most sites (but not Nigeria) offered gentamicin-amikacin without charge. Non-first-line antibiotics were more expensive and required payment by patient families in most other settings.
The authors pointed out that group B streptococcus infection and Listeria infection are less common in lower-income than in higher-income countries. Thus, for settings such as the study sites in Africa and Asia, it seems that ampicillin-gentamicin might need to be replaced by different first-line regimens for newborns with presumed sepsis. Specifically, ceftazidime-amikacin could be a more effective first choice in treating neonatal sepsis.
COMMENTARY
In North America, the combinations of ampicillin-gentamicin and ampicillin-ceftazidime are widely used as initial presumptive therapy for infants with possible sepsis or bacteremia. However, the 2021 American Academy of Pediatrics clinical practice guideline for the management of well-appearing febrile infants was consistent with these new findings in suggesting that the selection of antimicrobial agents should be based on knowledge of local and regional bacterial epidemiology and susceptibility patterns.1 Specifically, ampicillin might not be needed in areas where Listeria is not a significant concern, and resistance patterns of gram-negative rods will inform the selection of gram-negative germ coverage.
Thomson and colleagues wisely noted that their findings could relate to country and regional factors separate from simple microbiologic issues. For instance, dosing of antibiotics could alter effectiveness of treatments, and supportive care measures also might vary between sites and could influence outcomes. Nonetheless, the investigators considered these factors, and their results clearly show differences in outcomes related to antibiotic selection. Thus, clinicians in low-resource African and Asian countries, even without bacterial culture and susceptibility results being available, could wisely use these data as a reason to consider switching to ceftazidime-amikacin as presumptive treatment for neonatal sepsis.
In past years, either ampicillin or gentamicin was effective against most group B streptococci, and the combination was synergistic with even better killing of these bacteria. Now, however, group B streptococcus is less frequently a cause of neonatal sepsis in many areas,1 and there is emergence of resistance of group B streptococcus to aminoglycosides.2 Combining ceftazidime and an aminoglycoside still provides adequate streptococcal coverage (through the cephalosporin) as well as improved gram-negative coverage.
Of course, cost and availability of antibiotics also are important considerations. As Thomson and colleagues noted, many patients in resource-limited settings are unable to feasibly access some medications.
The initial selection of antibiotic therapy is only one aspect of antimicrobial stewardship.3 Whatever antimicrobial agents are used initially, excessively long treatment durations also should be avoided.3
REFERENCES
- Pantell RH, Roberts KB, Adams WG, et al. Clinical practice guideline: Evaluation and management of well-appearing febrile infants 8 to 60 days old. Pediatrics 2021;148:e2021052228.
- Hays C, Louis M, Plainvert C, et al. Changing epidemiology of group B streptococcus susceptibility to fluoroquinolones and aminoglycosides in France. Antimicrob Agents Chemother 2016;60:7424-7430.
- Klatte JM, Knee A, Szcerba F, Horton ER. Identification of high-yield targets for antimicrobial stewardship program efforts within a nonfreestanding children’s hospital. Hosp Pediatr 2019;9:355-364.
Gram-negative rods are responsible for most neonatal sepsis in low- and middle-income countries. Ampicillin-gentamicin usually has been recommended for presumptive treatment, pending bacteriology results (when such tests are available). The results of a multinational study in Africa and Asia suggest resistance to standard therapy is widespread and that ceftazidime-amikacin might be a better option.
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