Evaluating the relationship between ciprofloxacin prescription and non-susceptibility in Salmonella Typhi in Blantyre, Malawi: an observational study

Ashton, P. M. et al. (2024) Evaluating the relationship between ciprofloxacin prescription and non-susceptibility in Salmonella Typhi in Blantyre, Malawi: an observational study. Lancet Microbe, 5(3), E226-E234. (doi: 10.1016/S2666-5247(23)00327-0) (PMID:38387472)

Abstract

Background Ciprofloxacin is the first-line drug for treating typhoid fever in many countries in Africa with a high disease burden, but the emergence of non-susceptibility poses a challenge to public health programmes. Through enhanced surveillance as part of vaccine evaluation, we investigated the occurrence and potential determinants of ciprofloxacin non-susceptibility in Blantyre, Malawi. Methods We conducted systematic surveillance of typhoid fever cases and antibiotic prescription in two health centres in Blantyre, Malawi, between Oct 1, 2016, and Oct 31, 2019, as part of the STRATAA and TyVAC studies. In addition, blood cultures were taken from eligible patients presenting at Queen Elizabeth Central Hospital, Blantyre, as part of routine diagnosis. Inclusion criteria were measured or reported fever, or clinical suspicion of sepsis. Microbiologically, we identified Salmonella enterica serotype Typhi (S Typhi) isolates with a ciprofloxacin non-susceptible phenotype from blood cultures, and used whole-genome sequencing to identify drug-resistance mutations and phylogenetic relationships. We constructed generalised linear regression models to investigate associations between the number of ciprofloxacin prescriptions given per month to study participants and the proportion of S Typhi isolates with quinolone resistance-determining region (QRDR) mutations in the following month. Findings From 46 989 blood cultures from Queen Elizabeth Central Hospital, 502 S Typhi isolates were obtained, 30 (6%) of which had either decreased ciprofloxacin susceptibility, or ciprofloxacin resistance. From 11 295 blood cultures from STRATAA and TyVAC studies, 241 microbiologically confirmed cases of typhoid fever were identified, and 198 isolates from 195 participants sequenced (mean age 12·8 years [SD 10·2], 53% female, 47% male). Between Oct 1, 2016, and Aug 31, 2019, of 177 typhoid fever cases confirmed by whole-genome sequencing, four (2%) were caused by S Typhi with QRDR mutations, compared with six (33%) of 18 cases between Sept 1 and Oct 31, 2019. This increase was associated with a preceding spike in ciprofloxacin prescriptions. Every additional prescription of ciprofloxacin given to study participants in the preceding month was associated with a 4·2% increase (95% CI 1·8–7·0) in the relative risk of isolating S Typhi with a QRDR mutation (p=0·0008). Phylogenetic analysis showed that S Typhi isolates with QRDR mutations from September and October, 2019, belonged to two distinct subclades encoding two different QRDR mutations, and were closely related (4–10 single-nucleotide polymorphisms) to susceptible S Typhi endemic to Blantyre. Interpretation We postulate a causal relationship between increased ciprofloxacin prescriptions and an increase in fluoroquinolone non-susceptibility in S Typhi. Decreasing ciprofloxacin use by improving typhoid diagnostics, and reducing typhoid fever cases through the use of an efficacious vaccine, could help to limit the emergence of resistance.

• Item Type: Articles
• Additional Information: This research was funded in part by the Wellcome Trust (grant numbers 200901/Z/16/Z to PM; 206545/Z/17/Z to Malawi-Liverpool-Wellcome Programme and supporting, in part, MYRH; and 106158/Z/14/Z to the STRATAA Consortium). This work was supported by grants (OPP1151153, to the Typhoid Vaccine Acceleration Consortium; and OPP1141321 to the STRATAA Consortium) from the Bill & Melinda Gates Foundation. MAG, ACC, and PMA were supported by a research professorship (NIHR300039) from the National Institute for Health and Care Research, UK Department of Health and Social Care.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacPherson, Professor Peter

Creator Roles

MacPherson, P.: Formal analysis, Writing – review and editing

• Authors: Ashton, P. M., Chirambo, A. C., Meiring, J. E., Patel, P. D., Mbewe, M., Silungwe, N., Chizani, K., Banda, H., Heyderman, R. S., Dyson, Z. A., MacPherson, P., Henrion, M. Y.R., STRATAA Study Group, , Holt, K. E., and Gordon, M. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
• Journal Name: Lancet Microbe
• Publisher: Elsevier
• ISSN: 2666-5247
• ISSN (Online): 2666-5247
• Published Online: 19 February 2024
• Copyright Holders: Copyright: © 2023 The Author(s)
• First Published: First published in Lancet Microbe 5(3):E226-E234
• Publisher Policy: Reproduced under a Creative Commons licence