Antimicrobial resistance in paediatric bloodstream infections in Tanzania: a longitudinal comparison of two cohort studies

Background: Paediatric sepsis remains a significant global health issue, with the highest burden in low- and middle-income countries. Widespread antimicrobial resistance makes standard first-line empiric treatment regimens ineffective. To explore potential alternatives, we compared antimicrobial resistance patterns in blood culture isolates from two previous cohort studies on children admitted to hospital with fever in Tanzania, with focus on resistance to the semisynthetic aminoglycosides amikacin and plazomicin. 

Methods: Antimicrobial susceptibility testing was conducted using minimum inhibitory concentration (MIC) strips, with results interpreted according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints. Resistance rates to current recommended empiric sepsis treatments and potential new regimens with ampicillin combined with amikacin or plazomicin were assessed. Whole genome sequencing was performed on Klebsiella, Escherichia, and Salmonella isolates. 

Results: Antimicrobial susceptibility testing was conducted on 449 blood culture isolates from 427 patients, and whole genome sequencing was performed on 216 isolates. Overall resistance rates to gentamicin-ampicillin and ceftriaxone were 46% and 50%, respectively, while resistance to amikacin-ampicillin and plazomicin-ampicillin was 9%. We estimate that by using amikacin-ampicillin instead of gentamicin-ampicillin, we can reduce the risk of ineffective antibiotic treatment by 37 percentage points (95% confidence interval: 32%-42%). Correspondingly, using amikacin-ampicillin instead of ceftriaxone would reduce the risk by 41 percentage points (95% confidence interval: 35%-46%). In Klebsiella pneumoniae and Escherichia coli ceftriaxone resistance primarily resulted from the bla_CTX-M-15 gene, while resistance to gentamicin was mainly due to the aac(3)-II gene. The aac(6′)-Ib-cr gene was found in 33 Klebsiella and E. coli isolates, although only three exhibited amikacin MICs above the clinical breakpoint. 

Conclusion: This in vitro analysis suggest that amikacin-ampicillin is a promising option as first-line empiric treatment of suspected sepsis in children in Tanzania. The clinical efficacy and safety need to be evaluated in clinical trials.