Does treatment of invasive and persistent non-typhoid Salmonella in HIV-infected African adults cause evolution of antibiotic resistance? (360G-Wellcome-092152_B_10_A)

Multi-drug-resistant non-Typhoid-Salmonella (NTS) are a serious, emerging infection in HIV-infected African adults. In Blantyre, Malawi, NTS are a common cause of bacteraemia with a 25% case-fatality. Survivors are at high risk of recrudescence of invasive NTS (iNTS), necessitating multiple courses of ciprofloxacin, yet the sanctuary site of persistence remains unknown. Resistance (MIC) to ciprofloxacin has risen gradually since it was introduced in 2002, and threatens to spread among NTS and ot her major pathogens. Recent high-throughput whole-genome sequencing has shown that novel epidemic iNTS strains in Sub-Saharan Africa have become more human-adapted, with genetic similarities to S.Typhi. A cohort of HIV-infected adults with iNTS and their spouses will therefore be recruited to: 1) Evaluate mechanisms of persistence and clinical outcomes of iNTS, in the era of rapid anti-retroviral(ARV) roll-out 2) Investigate how iNTS persistence influences the emergence of fluoroquinolon e resistance following repeated ciprofloxacin treatment 3) Determine how iNTS persistence influences further NTS human-adaptation and microevolution. These data, including high-throughput sequencing and SNP-typing of isolates, will inform the design of alternative interventions that prevent episodes of iNTS without promoting antibiotic resistance; and generate locally-implementable molecular tools to further understand the dynamics of molecular evolution of epidemic MDR-NTS in individuals an d populations.