Bacterial infections and antibiotic susceptibility in children with sickle-cell anemia on malaria chemoprevention using Dihydroartemisinin-piperaquine (DP) or Sulfadoxine-pyrimethamine (SP) in Uganda

INTRODUCTION: Over 300,000 babies are born annually with sickle cell anemia (SCA) in sub-Saharan Africa. Despite malaria chemoprevention and early penicillin prophylaxis, these children develop febrile illnesses. The effect of malaria chemoprevention regimens on the incidence of bacterial infections and antimicrobial resistance is unclear. We assessed incidence of bacterial infections and resistance patterns in children with SCA receiving weekly DP or monthly SP. METHODS: This study was nested in a randomized, double-blind clinical trial comparing weekly DP with monthly SP. Participants were children aged 6 months to 15 years with SCA, followed every two months for a median of 14.7 months (IQR 11.2-18.2) and evaluated at all sick visits. Blood cultures were obtained for episodes of fever (axillary temperature >38℃) and processed using the BD BACTEC automated system. Bacterial identification was by phenotypic and genotypic methods. Whole-genome sequencing was performed using Illumina DNA Prep Kit, and antimicrobial resistance genes were characterized using AMRFinderPlus. Analyses were conducted in STATA 18.0 and limited to Ugandan participants. RESULTS: Of 725 enrolled participants, 437 were from Uganda (221 DP; 216 SP). The mean (SD) age was 7.3 (3.8) years, and 52.4% were male. Pathogenic bacteria were rarely isolated, including Escherichia coli (3), Klebsiella pneumoniae (2), Staphylococcus aureus (2), Streptococcus agalactiae. (1), and Enterococcus faecalis (1). The cumulative incidence of bacterial growth over 22 months of follow-up was 2.3% (95% CI: 1.12-4.73). Children with positive cultures tended to have higher fevers and more hospitalizations. All isolates were multidrug-resistant. Multiple resistance genes were identified, including plasmid-mediated sulfonamide resistance via sul2 in both Klebsiella pneumoniae and Escherichia coli. CONCLUSION: Pathogenic bacteria were infrequently isolated from Ugandan children with SCA receiving malaria chemoprevention. The presence of sul2 indicates the possibility of plasmid-mediated sulfonamide resistance.