Rapid and accurate drug susceptibility testing (DST) is essential for the treatment of multi- and extensively drug-resistant tuberculosis (M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using Bactec 960 MGIT or Löwenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TB drugs. Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs; Hain GenoType MTBDR plus 2.0 and MTBDR sl 2.0) and whole-genome sequencing (WGS) were translated into individual algorithm-derived treatment regimens for each patient. We further analyzed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results. Compared with pDST, the average agreement in the number of drugs prescribed in genotypic regimens ranged from just 49% (95% confidence interval [CI], 39 to 59%) for Xpert and 63% (95% CI, 56 to 70%) for LPAs to 93% (95% CI, 88 to 98%) for WGS. Only the WGS regimens did not contain any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high. WGS can be used to rule in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be reexamined to avoid systematic false-susceptible results in low-level resistant isolates.

Introduction: There are positive aspects regarding the prescribing of fixed dose combinations (FDCs) versus prescribing the medicines separately. However, these have to be balanced against concerns including increased costs and their irrationality in some cases. Consequently, there is a need to review their value among lower- and middle-income countries (LMICs) which have the greatest prevalence of both infectious and noninfectious diseases and issues of affordability. Areas covered: Review of potential advantages, disadvantages, cost-effectiveness, and availability of FDCs in high priority disease areas in LMICs and possible initiatives to enhance the prescribing of valued FDCs and limit their use where there are concerns with their value. Expert commentary: FDCs are valued across LMICs. Advantages include potentially improved response rates, reduced adverse reactions, increased adherence rates, and reduced costs. Concerns include increased chances of drug:drug interactions, reduced effectiveness, potential for imprecise diagnoses and higher unjustified prices. Overall certain FDCs including those for malaria, tuberculosis, and hypertension are valued and listed in the country’s essential medicine lists, with initiatives needed to enhance their prescribing where currently low prescribing rates. Proposed initiatives include robust clinical and economic data to address the current paucity of pharmacoeconomic data. Irrational FDCs persists in some countries which are being addressed.

Background: Antimicrobial resistance is an increasing challenge in low and middle-income countries as it is widespread in these countries and is linked to an increased mortality. Apart from human and environmental factors, animal-related drivers of antimicrobial resistance in low- and middle-income countries have special features that differ from high-income countries. The aim of this narrative review is to address the zoonotic sources and the spread of antimicrobial resistance from the perspective of low- and middle-income countries. Main body: Contamination with extended-spectrum beta-lactamase (ESBL)-producing Escherichiacoli is highest in poultry (Africa: 8.9–60%, Asia: 53–93%) and there is a risk to import ESBL-producing E.coli through poultry meat in Africa. In aquacultures, the proportion of ESBL-producers among E.coli can be high (27%) but the overall low quality of published studies limit the general conclusion on the impact of aquacultures on human health. ESBL-producing E.coli colonization of wildlife is 1–9% in bats or 2.5–63% birds. Since most of them are migratory animals, they can disperse antimicrobial resistant bacteria over large distances. So-called ‘filth flies’ are a relevant vector not only of enteric pathogens but also of antimicrobial resistant bacteria in settings where sanitary systems are poor. In Africa, up to 72.5% of ‘filth flies’ are colonized with ESBL-producing E.coli, mostly conferred by CTX-M (24.4–100%). While methicillin-resistant Staphylococcus aureus plays a minor role in livestock in Africa, it is frequently found in South America in poultry (27%) or pork (37.5–56.5%) but less common in Asia (poultry: 3%, pork: 1–16%). Conclusions: Interventions to contain the spread of AMR should be tailored to the needs of low- and middle-income countries. These comprise capacity building of diagnostic facilities, surveillance, infection prevention and control in small-scale farming. Graphical

People living with HIV (PLWH) are at increased risk of infections with resistant organisms due to more frequent healthcare utilisation. investigate the association between HIV and antimicrobial resistance (AMR). we searched MEDLINE, EMBASE, Web of Science, LILACS and African Journals Online. Studies reporting on AMR for colonisation or infection with bacterial pathogens excluding mycobacteria and bacteria causing sexual transmitted infections stratified by HIV status, species and antimicrobials tested. any. none. Pooled odds ratios were used to evaluate the association between HIV and resistance. A total of 92 studies published between 1995 and 2020 were identified. The studies included the following organisms: Staphylococcus (n=47), Streptococcus pneumoniae (n=28), Escherichia coli (n=6) and other Gram-negative bacteria. PLWH had a 2.12 (95% CI 1.36-3.30) higher odds for colonization and 1.90 (95%CI 1.45-2.48) higher odds for infection with methicillin-resistant S. aureus; a 2.28 (95%CI 1.75-2.97) higher odds of infections with S. pneumoniae with decreased penicillin susceptibility and a 1.59 (95%CI 0.83-3.05) higher odds of resistance to third-generation cephalosporins in E. coli and Klebsiella pneumoniae. . This review shows an increased risk of AMR in PLWH across a range of bacterial pathogens and multiple drug classes. The lack of laboratory capacity for identifying AMR and limited access to alternative treatment options in countries with the highest burden of HIV highlights the need for more research on AMR in PLWH. Overall, the quality of studies was moderate or low which may impact the findings of this review.

Background: The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB.Methods: Adult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points.Results: 50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9–0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%; p<0.001) and the MDR-RVC (mean reduction of 161.0 days, 23.4%; p=0.001).Conclusion: Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.