A novel framework for quantifying the clinical impact of substandard and falsified antimicrobials: Application to typhoid fever
9 affiliations
- 1Nuffield Department of Medicine, Drug Resistant Infections and Disease Dynamics (DRIaDD) Research Group, NDM Centre for Global Health Research, University of Oxford, Oxford, United Kingdom
- 2Nuffield Department of Medicine, Medicine Quality Research Group (MQRG), NDM Centre for Global Health Research, University of Oxford, Oxford, United Kingdom
- 3Nuffield Department of Medicine, Infectious Diseases Data Observatory, NDM Centre for Global Health Research, University of Oxford, Oxford, United Kingdom
- 4Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- 5Nuffield Department of Medicine, Antimicrobial resistance, antimicrobial consumption and burden estimation (MICRoBE) research group, NDM Centre for Global Health Research, University of Oxford, Oxford, United Kingdom
- 6Nuffield Department of Medicine, Modernizing Medical Microbiology, University of Oxford, Oxford, United Kingdom
- 7NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Nuffield Department of Medicine, Oxford, United Kingdom
- 8NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom
- 9Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom
Abstract
Substandard and falsified (SF) medicines are a neglected public health threat, with an estimated 7% of antimicrobials in low- and middle-income countries being SF. However, quantifying their clinical impact remains challenging. We developed a general framework for estimating population-level impacts of SF antimicrobials on patient outcomes and apply it to SF fluoroquinolones in typhoid treatment. The framework combines two data sources: published surveys of antimicrobial quality to characterize the distribution of active pharmaceutical ingredient (API) content and individual-level patient data to estimate dose-response relationships. These are synthesized to evaluate population-level impacts. We extracted data from surveys of fluoroquinolone quality and fitted generalized additive models to data from seven clinical trials to estimate the causal effect of ofloxacin dose on typhoid outcomes. Application to typhoid demonstrated that while dose had negligible overall effect within trial dose ranges, lower doses worsened outcomes for non-susceptible strains. When the minimum inhibitory concentration was 1 mg/L, ofloxacin matching observed ofloxacin quality (mean %API = 102.8%) improved fever clearance by 4.1 hours (90% CrI: 0.75–8.7) compared to 100% API. At the same minimum inhibitory concentration, ofloxacin whose %API instead matched the ciprofloxacin surveys (mean %API = 93.6%) worsened fever clearance by 11 hours (90% CrI: 1.9–25). This framework can quantify the impact of SF antimicrobials on different pathogen–antimicrobial pairs. For typhoid, it demonstrates that SF fluoroquinolones likely have a substantial impact on treatment outcomes in settings like South Asia where non-susceptible strains are prevalent. Increased vigilance around antimicrobial quality is important in such settings.
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BibTeX
@article{cavany2026novel,
title = {{A novel framework for quantifying the clinical impact of substandard and falsified antimicrobials: Application to typhoid fever}},
author = {Sean Cavany and Lawrence Adipo and Kerlijn van Assche and Celine Caillet and Christiane Dolecek and Cathrin Hauk and Jessica Mendes and Stella Nanyonga and Nicole Stoesser and Paul N. Newton and Christopher M. Parry and Ben S. Cooper},
journal = {PLOS Global Public Health},
year = {2026},
month = aug,
doi = {10.1371/journal.pgph.0007207},
url = {https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0007207},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A novel framework for quantifying the clinical impact of substandard and falsified antimicrobials: Application to typhoid fever
AU - Sean Cavany
AU - Lawrence Adipo
AU - Kerlijn van Assche
AU - Celine Caillet
AU - Christiane Dolecek
AU - Cathrin Hauk
AU - Jessica Mendes
AU - Stella Nanyonga
AU - Nicole Stoesser
AU - Paul N. Newton
AU - Christopher M. Parry
AU - Ben S. Cooper
PY - 2026
DA - 2026/08/31
JO - PLOS Global Public Health
DO - 10.1371/journal.pgph.0007207
UR - https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0007207
AB - Substandard and falsified (SF) medicines are a neglected public health threat, with an estimated 7% of antimicrobials in low- and middle-income countries being SF. However, quantifying their clinical impact remains challenging. We developed a general framework for estimating population-level impacts of SF antimicrobials on patient outcomes and apply it to SF fluoroquinolones in typhoid treatment. The framework combines two data sources: published surveys of antimicrobial quality to characterize the distribution of active pharmaceutical ingredient (API) content and individual-level patient data to estimate dose-response relationships. These are synthesized to evaluate population-level impacts. We extracted data from surveys of fluoroquinolone quality and fitted generalized additive models to data from seven clinical trials to estimate the causal effect of ofloxacin dose on typhoid outcomes. Application to typhoid demonstrated that while dose had negligible overall effect within trial dose ranges, lower doses worsened outcomes for non-susceptible strains. When the minimum inhibitory concentration was 1 mg/L, ofloxacin matching observed ofloxacin quality (mean %API = 102.8%) improved fever clearance by 4.1 hours (90% CrI: 0.75–8.7) compared to 100% API. At the same minimum inhibitory concentration, ofloxacin whose %API instead matched the ciprofloxacin surveys (mean %API = 93.6%) worsened fever clearance by 11 hours (90% CrI: 1.9–25). This framework can quantify the impact of SF antimicrobials on different pathogen–antimicrobial pairs. For typhoid, it demonstrates that SF fluoroquinolones likely have a substantial impact on treatment outcomes in settings like South Asia where non-susceptible strains are prevalent. Increased vigilance around antimicrobial quality is important in such settings.
SN - 2767-3375
ER -