IntroductionSub-Saharan Africa shoulders the highest burden of global sepsis and associated mortality. In high HIV and tuberculosis (TB) prevalent settings such as sub-Saharan Africa, TB is the leading cause of sepsis. However, anti-TB therapy is often delayed and may not achieve adequate blood concentrations in patients with sepsis. Accordingly, this multisite randomised clinical trial aims to determine whether immediate and/or increased dose anti-TB therapy improves 28-day mortality for participants with HIV and sepsis in Tanzania or Uganda.Methods and analysisThis is a phase 3, multisite, open-label, randomised controlled clinical 2×2 factorial superiority trial of (1) immediate initiation of anti-TB therapy and (2) sepsis-specific dose anti-TB therapy in addition to standard of care antibacterials for adults with HIV and sepsis admitted to hospital in Tanzania or Uganda. The primary endpoint is 28-day mortality. A sample size of 436 participants will provide 80% power for testing each of the main effects of timing and dose on 28-day mortality with a two-sided significance level of 5%. The expected main effect for absolute risk reduction is 13% and the expected OR for risk reduction is 1.58.Ethics and disseminationThis clinical trial will determine the optimal content, dosing and timing of antimicrobial therapy for sepsis in high HIV and TB prevalent settings. The study is funded by the National Institutes of Health in the US. Institutional review board approval was conferred by the University of Virginia, the Tanzania National Institute for Medical Research, and the Uganda National Council for Science and Technology. Study results will be published in peer-reviewed journals and in the popular press of Tanzania and Uganda. We will also present our findings to the Community Advisory Boards that we convened during study preparation.Trial registration numberClinicalTrials.gov (NCT04618198).
Background
This study aimed to determine the association between pre-hospital antibiotic exposure and level of bacterial resistance among adult and paediatric patients.
Methods:
In the study, 79 antibiotic pre-exposed patients (cases) were compared with 79 non-pre-exposed patients (controls) hospitalized at medical and paediatric wards at Mbarara Regional Referral Hospital (MRRH) for various bacterial diagnoses. Data collected included participant demographics, previous medications and bacterial culture and sensitivity results. Data was analysed to determine the odds ratios for the occurrence of bacterial resistance between the cases and controls.
Results:
Results from the study showed that there was no statistically significant difference in terms of antibiotic resistance between pre-exposed and non-pre-exposed participants (OR: 0.5, 95%CI: 0.045 - 5.51, P = 0.571), whereby “no resistance” was defined as zero antibiotics resisted and “resistance” defined as 1 or more antibiotics resisted. However, when we adjusted the definition of “no resistance” and “resistance” to mean “one or less antibiotics resisted” and “two or more antibiotics resisted” respectively, there was a statistically significant more resistance in pre-exposed participants (cases) compared to non-pre-exposed participants (OR: 7, 95% CI: 1.59 - 30.8; p = 0.010). When the definition of resistance was further adjusted upwards to “three or more antibiotics resisted”, the resistance in cases was still significantly higher compared to controls (OR: 5.4, 95%CI: 2.42 - 12.2, p = 0.000) and when the definition of resistance was further adjusted to “four or more antibiotics resisted”, the OR increased even further (OR: 7.14, 95%CI: 3.24 - 15.8, p = 0.000). Ceftriaxone (17.6%) and amoxicillin (14.1%) were the commonest antibiotics to which participants were pre-exposed.
Conclusion:
The study showed that pre-hospital antibiotic exposure is strongly associated with resistance to one or more antibiotics. Strategies should be sought to reduce the level of such exposures and to enforce proper screening of patients during admission to facilitate rational prescription of antibiotics, improve quality of care, and slow the emergence of antimicrobial resistance in the management of infections.
Registration: This study was approved and registered by Mbarara University Research Ethics Committee (MUREC) and its number is 53/03-20
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