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BACKGROUND: There is a substantial overlap in the epidemiology of chronic hepatitis B (HBV), hepatitis C (HCV) and tuberculosis (TB) due to overlapping risk factors. Testing for viral hepatitis is not widely recommended for patients with TB. The aim of this systematic review was to evaluate the global prevalence of chronic viral hepatitis infection among patients with TB. METHODS: MEDLINE, EMBASE, Web of Science, Cochrane Library, African Journals Online, LILACS, and country TB reports were searched for studies published between January 1st, 2011 and June 17th 2021. Random-effects meta-analyses for proportions were conducted to obtain pooled prevalences. The prevalence of chronic HBV/HCV infection among patients with TB was also compared to that in the general population. The protocol was registered on PROSPERO (CRD42021276468). FINDINGS: This analysis included 127 studies (83 for both HBV and HCV, 28 for HBV only, and 25 for HCV only) and data from 94,936 patients. The global pooled seroprevalence was 5.8% (95% CI 5.0–6.8) for HBs-antigen and 10.3% (95% CI 8.4–12.3) for HCV-antibodies. Pooled prevalence was highest in the WHO African Region for HBV at 7.8% (95% CI 5.2–10.9) and in the WHO European Region at 17.5% (95% CI 12.2–23.5) for HCV. In studies among TB patients who inject drugs, HCV prevalence was 92.5% (95% CI 80.8–99.0). Pooled HCV-antibody seroprevalence among patients with TB was higher than in the general population in all six WHO regions while HBs-antigen seroprevalence was higher in 3/6 regions. INTERPRETATION: This review highlights the syndemicity of chronic viral hepatitis and TB and suggests that routine testing for hepatitis upon TB diagnosis may be justified. The prevalence of chronic HBV and HCV infections was higher among patients with TB than in the general population. FUNDING: This study was study was funded by the Global Tuberculosis Programme, 10.13039/100004423World Health Organization.

Background: Chlamydia trachomatis(CT) and Neisseria gonorrhoeae (NG) are the most common bacterial sexually transmitted infections (STIs) worldwide. In the absence of affordable point-of-care STI tests, WHO recommends STI testing based on risk factors. This study aimed to develop a prediction tool with a sensitivity of >90% and efficiency (defined as the percentage of individuals that are eligible for diagnostic testing) of

This study aims to assess antimicrobial consumption in the pediatric department of a tertiary care public hospital in Zimbabwe. Clinical records of pediatric inpatients admitted to Harare Central Hospital over a 3-week period were reviewed prospectively. Antimicrobial consumption was described as days of therapy per 100 inpatient days (DOT/100 PD). Adherence of antimicrobial drug prescriptions to the National Guidelines was also evaluated. A total of 121 (93.1%) children were prescribed at least one antimicrobial out of 130 children admitted. The median age was 14 months (IQR: 3 – 48 months). Overall antimicrobial consumption was 155.4 DOT / 100 PD (95% CI 146-165.2). The most frequently prescribed antimicrobials were benzylpenicillin, gentamicin and ceftriaxone. Prescriptions were adherent to national guidelines in 57.7% of children. This study shows that there is high antimicrobial drug usage in hospitalized children in Zimbabwe and a considerable proportion of prescriptions are non-adherent with national guidelines.

Background Overuse of antibiotics is one of the main drivers for antimicrobial resistance (AMR). Globally, most antibiotics are prescribed in the outpatient setting. This survey aimed to explore attitudes and practices with regards to microbiology tests, AMR and antibiotic prescribing among healthcare providers at public primary health clinics in Harare, Zimbabwe. Methods This cross-sectional survey was conducted in nine primary health clinics located in low-income suburbs of Harare between October and December 2020. In Zimbabwe, primary health clinics provide nurse-led outpatient care for acute and chronic illnesses. Healthcare providers who independently prescribe antibiotics and order diagnostic tests were invited to participate. The survey used self-administered questionnaires. A five-point Likert scale was used to determine attitudes and beliefs. Results A total of 91 healthcare providers agreed to participate in the survey. The majority of participants (62/91, 68%) had more than 10 years of work experience. Most participants reported that they consider AMR as a global (75/91, 82%) and/or national (81/91, 89%) problem, while 52/91 (57%) considered AMR to be a problem in their healthcare facilities. A fifth of participants (20/91, 22%) were unsure if AMR was a problem in their clinics. Participants felt that availability of national guidelines (89/89, 100%), training sessions on antibiotic prescribing (89/89, 100%) and regular audit and feedback on prescribing (82/88, 93%) were helpful interventions to improve prescribing. Conclusions These findings support the need for increased availability of data on AMR and antibiotic use in primary care. Educational interventions, regular audit and feedback, and access to practice guidelines may be useful to limit overuse of antibiotics.

BACKGROUND: Clinically suspected and laboratory-confirmed bloodstream infections are frequent causes of morbidity and mortality during neonatal care. The most effective infection prevention and control interventions for neonates in low- and middle-income countries (LMIC) are unknown. AIM: To identify effective interventions in the prevention of hospital-acquired bloodstream infections in LMIC neonatal units. METHODS: Medline, PUBMED, the Cochrane Database of Systematic Reviews, EMBASE and PsychInfo (January 2003 to October 2020) were searched to identify studies reporting single or bundled interventions for prevention of bloodstream infections in LMIC neonatal units. RESULTS: Our initial search identified 5206 articles; following application of filters, 27 publications met the inclusion and Integrated Quality Criteria for the Review of Multiple Study Designs assessment criteria and were summarized in the final analysis. No studies were carried out in low-income countries, only 1 in Sub-Saharan Africa and just 2 in multiple countries. Of the 18 single-intervention studies, most targeted skin (n = 4) and gastrointestinal mucosal integrity (n = 5). Whereas emollient therapy and lactoferrin achieved significant reductions in proven neonatal infection, glutamine and mixed probiotics showed no benefit. Chlorhexidine gluconate for cord care and kangaroo mother care reduced infection in individual single-center studies. Of the 9 studies evaluating bundles, most focused on prevention of device-associated infections and achieved significant reductions in catheter- and ventilator-associated infections. CONCLUSIONS: There is a limited evidence base for the effectiveness of infection prevention and control interventions in LMIC neonatal units; bundled interventions targeting device-associated infections were most effective. More multisite studies with robust study designs are needed to inform infection prevention and control intervention strategies in low-resource neonatal units.

Background The AID line probe assay has shown promising evaluation data on the detection of Mycobacterium tuberculosis as well as 1st- and 2nd-line drug resistance, using isolates and selected clinical samples in previous studies. Methods The diagnostic performance of three AID-modules (AID INH/RIF, AID FQ/EMB and AID AG) was analyzed in sputum samples from patients with presumed tuberculosis against culture methods and phenotypic drug resistance as reference standards. Results 59 patients had culture-confirmed tuberculosis. All AID modules showed moderate sensitivity (46/59, 78.0%, 65.3–87.7) and very good specificity (100%, 95.5%, 93.7%). There was a high proportion of invalid tests, resulting in 32.6%, 78.3% and 19.6% of 46 AID-positive tuberculosis cases, who could not be assessed for drug resistance by the AID INH/RIF-, AID FQ/EM- and AID AG-module, respectively. A small number of patients showed drug resistance by reference standards: Three MDR-TB cases plus three, one and one patients with resistance to streptomycin, fluoroquinolones and aminoglycosides, respectively. The AID-assay detected all MDR-TB cases, two of three streptomycin-resistant TB cases, one of one of fluoroquinolone-resistant and missed one aminoglycoside-resistant TB case. Discussion The high proportion of invalid results precludes the use of the AID-assay from direct sputum-based tuberculosis and drug-resistance testing.

s: Background: By the end of July 2021 Zimbabwe, has reported over 100,000 SARS-CoV-2 infections. The true number of SARS-CoV-2 infections is likely to be much higher. We conducted a seroprevalence survey to estimate the prevalence of past SARS-CoV-2 in three high-density communities in Harare, Zimbabwe before and after the second wave of SARS-CoV-2. Methods: Between November 2020 and April 2021 we conducted a cross-sectional study of randomly selected households in three high-density communities (Budiriro, Highfield and Mbare) in Harare. Consenting participants answered a questionnaire and a dried blood spot sample was taken. Samples were tested for anti-SARS-CoV-2 nucleocapsid antibodies using the Roche e801 platform. Findings: A total of 2340 individuals participated in the study. SARS-CoV-2 antibody results were available for 70·1% (620/885) and 73·1% (1530/2093) of eligible participants in 2020 and 2021. The median age was 22 (IQR 10-37) years and 978 (45·5%) were men. SARS-CoV-2 seroprevalence was 19·0% (95% CI 15·1-23·5%) in 2020 and 53·0% (95% CI 49·6-56·4) in 2021. The prevalence ratio was 2·47 (95% CI 1·94-3·15) comparing 2020 with 2021 after adjusting for age, sex, and community. Almost half of all participants who tested positive reported no symptoms in the preceding six months. Interpretation: Following the second wave, one in two people had been infected with SARS-CoV-2 suggesting high levels of community transmission. Our results suggest that 184,800 (172,900-196,700) SARS-CoV-2 infections occurred in these three communities alone, greatly exceeding the reported number of cases for the whole city. Further seroprevalence surveys are needed to understand transmission during the current third wave despite high prevalence of past infections. Funding: GCRF, Government of Canada, Wellcome Trust, Bavarian State Ministry of Sciences, Research, and the Arts

BackgroundThe 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.MethodsAdult 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.Results50 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%; pConclusionBiomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.

ObjectiveUrinary tract infections (UTIs) are common in primary care. The yield of urine cultures in patients with UTI symptoms can be considerably different between high-income and low-income settings. This study aimed to explore possible causes of negative urine cultures in patients presenting with symptoms of UTI to primary health clinics in Harare.DesignCross-sectional study.SettingNine primary health clinics in Harare, Zimbabwe.ParticipantsAdults presenting with symptoms of UTIs between March and July 2020.Primary outcome measuresUrine samples underwent dipstick testing, microscopy, culture, and testing for sexually transmitted infections (STIs) using GeneXpert and for the presence of antibiotic residues using an antibiotic bioassay. The primary outcomes were the number and proportion of participants with evidence of STIs, prior antibiotic exposure, leucocyturia and UTIs.ResultsThe study included 425 participants with a median age of 37.3 years, of whom 275 (64.7%) were women. Leucocyturia was detected in 130 (30.6%, 95% CI 26.2% to 35.2%) participants, and 96 (22.6%, 95% CI 18.7% to 26.9%) had a positive urine culture for a uropathogen. Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis were detected in 43/425 (10.1%, 95% CI 7.4% to 13.4%), 37/425 (8.7%, 95% CI 6.2% to 11.8%) and 14/175 (8.0%, 95% CI 4.4% to 13.1%) participants, respectively. Overall, 89 (20.9%, 95% CI 17.2% to 25.1%) participants reported either having taken prior antibiotics or having had a positive urine bioassay. In 170 (40.0%, 95% CI 35.3% to 44.8%) participants, all of the tests that were performed were negative.ConclusionsThis study found a high prevalence of STIs and evidence of prior antimicrobial use as possible explanations for the low proportion of positive urine cultures.

OBJECTIVE: To perform a nationwide inventory of diagnostic mycobacteriology services in Germany.METHOD: A survey was conducted among participants of the national mycobacteriology external quality assurance scheme asking for smear microscopy techniques, molecular assays, culture systems and drug susceptibility testing (DST) capacities for Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM), and numbers of processed/culture-positive samples, and DSTs performed in 2016.RESULTS: We found that 170/238 laboratories (71.4%) provided data. Numbers of samples processed for culture varied between 35 and 40 000 (median 1856, interquartile range [IQR] 761-3500). Specimen numbers culture-positive for MTBC or NTM ranged from 0 to 1895 (median 46, IQR 17-116), and from 0 to 833 (median 30, IQR 13-71), respectively. Numbers of performed first-line susceptibility tests varied between 3 and 1400 (median 36, IQR 28-78). Eight laboratories performed DST for NTM. Also, 26.9% of all laboratories did not offer rapid genotypic DST (gDST) from primary samples.CONCLUSION: The landscape of diagnostic mycobacteriology in Germany is highly heterogenic with considerable variations in sample numbers and testing methodologies. Shortcomings exist with respect to fluorochrome staining of primary samples, rapid gDST of MTBC, and DST of NTM. National guidelines need to be adapted accordingly.

Background: The primary goal was to estimate the seroprevalence of autochthonous hepatitis E virus (HEV) infection in adult Romanian population. Additionally, we aimed to identify the risk factors associated with the HEV seropositive status. Methods: Between January 2015 and December 2016, 201 adult patients were tested for antiHEV-IgG. Multivariate logistic regression was used to examine for factors associated with a positive HEV-IgG test. The level of significance was set at α = 0.05. Results: The final analysis included 175 patients who followed the study protocol. Forty-sex (26.3%) had positive, 121 (69.1%) had negative, and 8 (4.6%) had indeterminate antiHEV-IgG results. Patients with positive anti-HEV-IgG were older [median age: 54.5 years (IQR 43-65)] compared to patients with negative anti-HEV-IgG [median age: 37.5 years (IQR 28-57.5)], p Conclusions: In conclusion, we found that autochthonous HEV seropositivity is common in our study population, especially in older patients, previous blood transfusions, presence of immunosuppressive conditions, and positive HBsAg.

ObjectivesTo assess the performance of antigen-based rapid diagnostic tests (Ag-RDTs) for SARS CoV-2 when implemented for large-scale universal screening of asymptomatic individuals.MethodsThis study presents data from a pragmatic implementation study for universal Ag-RDT-based screening at a tertiary care hospital in Germany where all incoming patients without symptoms suggestive of SARS-CoV-2 were screened with an Ag-RDT prior to admission since October 2020.ResultIn total, 49,542 RDTs were performed in 27,199 asymptomatic individuals over a duration of five months. Out of 222 positive results, 196 underwent in-house confirmatory testing with PCR, out of which 170 were confirmed positive, indicating a positive predictive value (PPV) of 86.7%. Negative Ag-RDTs were not routinely tested with PCR, but a total of 94 cases of false negative Ag-RDTs were detected due to PCR tests being performed within the following five days with a median CT-value of 33.ConclusionsThis study provides evidence that Ag-RDTs can have a high diagnostic yield for transmission relevant infections with limited false-positives when utilized at the point of care on asymptomatic patients and thus can be a suitable public-health test for universal screening.

Background: Treatment for urinary tract infections (UTIs) is usually empiric and is based on local antimicrobial resistance data. These data, however, are scarce in low-resource settings. The aim of this study is to determine the impact of antibiotic treatment on clinical and bacteriological outcomes in patients presenting with UTI symptoms to primary care in Harare. Methods: This cohort study enrolled participants presenting with UTI symptoms to 10 primary healthcare clinics in Harare between July 2019 and July 2020. A questionnaire was administered and a urine sample was collected for culture. If the urine culture showed growth of ≥105 colony forming units/mL of a uropathogen, a follow up visit at 7-21 days was conducted. Results: The analysis included 168 participants with a median age of 33.6 years (IQR 25.1-51.4) and of whom 131/168 (78.0%) were female. Effective treatment was taken by 54/168 (32.1%) participants. The urine culture was negative at follow up in 41/54 (75.9%) of participants who took appropriate treatment and in 33/114 (28.9%, p Conclusion: The findings of this study show that effective treatment leads to symptom resolution and bacterial clearance in people presenting with UTIs to primary care. Although UTIs are not life-threatening and can resolve without treatment, they do impact on quality of life, highlighting the need for optimised treatment recommendations.

Background Neonatal sepsis accounts for a large proportion of neonatal deaths in sub-Saharan Africa. The lack of access to diagnostic testing and excessively long turnaround times to result contributes to delays in sepsis identification and initiation of appropriate treatment. This study aims to evaluate the novel InTrays COLOREX Screen and extended-spectrum beta-lactamase for rapid identification of bacterial pathogens causing sepsis and detection of resistance. Methods Neonates with suspected sepsis admitted to the Harare Central Hospital were prospectively enrolled. One blood culture was collected and incubated using the BacT/ALERT automated system. Positive blood cultures with potential pathogens identified by Gram stain were inoculated on the InTray COLOREX Screen and extended-spectrum beta-lactamase culture plates. Results A total of 216 neonates with suspected sepsis were recruited. Pathogens were isolated from blood cultures in 56 (25.9%) neonates of which 54 were Klebsiella pneumoniae. All K. pneumoniae were resistant to ceftriaxone and 53 (98%) were resistant to gentamicin. Sensitivity and specificity for ceftriaxone-resistant K. pneumoniae detection using InTrays were 100%. InTrays results were interpretable as early as 5-10 hours (median 7 hours, interquartile range 7-7) post blood culture positivity enabling rapid identification and notification of result and leading to a 60% reduction in time to result from blood culture collection. Conclusions This study shows that the implementation of a novel culture method was feasible and reduced turnaround times for results by 60% compared with standard microbiological techniques. An impact on patient outcomes and cost-effectiveness of this method needs to be demonstrated.

Background People living with HIV may be at increased risk for infections with resistant organisms. Infections with ESBL-producing organisms are of particular concern because they limit treatment options for severe Gram-negative infections in low-resource settings. Objectives To investigate the association between HIV status and urinary tract infections (UTIs) with ESBL-producing Escherichia coli. Patients and methods Cross-sectional study enrolling adults presenting with UTI symptoms to primary care clinics in Harare, Zimbabwe. Demographic and clinical data were collected during interviews and a urine sample was collected for culture from each participant. Antimicrobial susceptibility testing was performed according to EUCAST recommendations. Results Of the 1164 who were enrolled into the study, 783 (64%) were female and 387 (33%) were HIV infected. The median age was 35.8 years. Urine cultures were positive in 338 (29.0%) participants, and the majority of bacterial isolates were E. coli (n = 254, 75.2%). The presence of ESBL was confirmed in 49/254 (19.3%) E. coli. Participants with HIV had a 2.13 (95% CI 1.05–4.32) higher odds of infection with ESBL-producing E. coli than individuals without HIV. Also, the prevalence of resistance to most antimicrobials was higher among participants with HIV. Conclusions This study found an association between HIV and ESBL-producing E. coli in patients presenting with symptoms suggestive of UTI to primary care in Harare. HIV status should be considered when prescribing empirical antimicrobial treatment.

Background People living with HIV may be at increased risk for infections with resistant organisms. Infections with ESBL-producing organisms are of particular concern because they limit treatment options for severe Gram-negative infections in low-resource settings. Objectives To investigate the association between HIV status and urinary tract infections (UTIs) with ESBL-producing Escherichia coli. Patients and methods Cross-sectional study enrolling adults presenting with UTI symptoms to primary care clinics in Harare, Zimbabwe. Demographic and clinical data were collected during interviews and a urine sample was collected for culture from each participant. Antimicrobial susceptibility testing was performed according to EUCAST recommendations. Results Of the 1164 who were enrolled into the study, 783 (64%) were female and 387 (33%) were HIV infected. The median age was 35.8 years. Urine cultures were positive in 338 (29.0%) participants, and the majority of bacterial isolates were E. coli (n = 254, 75.2%). The presence of ESBL was confirmed in 49/254 (19.3%) E. coli. Participants with HIV had a 2.13 (95% CI 1.05–4.32) higher odds of infection with ESBL-producing E. coli than individuals without HIV. Also, the prevalence of resistance to most antimicrobials was higher among participants with HIV. Conclusions This study found an association between HIV and ESBL-producing E. coli in patients presenting with symptoms suggestive of UTI to primary care in Harare. HIV status should be considered when prescribing empirical antimicrobial treatment.

Before the coronavirus 2019 (COVID-19) pandemic began, antimicrobial resistance (AMR) was among the top priorities for global public health. Already a complex challenge, AMR now needs to be addressed in a changing healthcare landscape. Here, we analyse how changes due to COVID-19 in terms of antimicrobial usage, infection prevention, and health systems affect the emergence, transmission, and burden of AMR. Increased hand hygiene, decreased international travel, and decreased elective hospital procedures may reduce AMR pathogen selection and spread in the short term. However, the opposite effects may be seen if antibiotics are more widely used as standard healthcare pathways break down. Over 6 months into the COVID-19 pandemic, the dynamics of AMR remain uncertain. We call for the AMR community to keep a global perspective while designing finely tuned surveillance and research to continue to improve our preparedness and response to these intersecting public health challenges.

Antimicrobial resistance surveillance data is lacking from many resource-limited settings mainly due to limited laboratory testing. Novel culture systems may address some of the limitations of conventional culture media and expand the availability of microbiology services. The aims of this study were to evaluate the performance of InTray COLOREX Screen/ESBL and Compact Dry for the detection of uropathogens and of extended-spectrum beta-lactamase (ESBL)-producing organisms from urine samples. Urines samples were collected from patients presenting with symptoms of urinary tract infection to primary care clinics in Harare. Performance of the InTray COLOREX Screen, ESBL and Compact Dry chromogenic media were compared to the reference of culture using Brilliance UTI agar and conventional antimicrobial susceptibility testing. A total of 414 samples were included in the analysis. Of the included samples, 98 were positive on Brilliance UTI agar and 83 grew Enterobacterales. The sensitivities and specificities for Enterobacterales were 89.2% (95% CI 80.4–94.9) and 98.2% (95% CI 96.1–99.3) for InTray Screen and 95.2% (95% CI 88.1–98.7) and 99.7% (95% CI 98.3–100) for Compact Dry. Extended-spectrum beta-lactamases were present in 22 isolates from the Brilliance UTI agar. The sensitivity of the InTray COLOREX ESBL culture plates for the detection of ESBL-producing organisms was 95.5% (95% CI 77.2–99.9) and specificity was 99.5% (95% CI 98.2–99.9%). Our findings show good performance of the novel culture systems for the detection of uropathogens and ESBL-producing organisms. Both systems have several advantages over conventional media and have the potential to expand and decentralize laboratory testing. Supplementary Information The online version contains supplementary material available at 10.1007/s10096-021-04312-4.

Background: Increasing antimicrobial resistance (AMR) is threatening our ability to effectively treat infections. People living with HIV (PLWH) may be at increased risk of infections with resistant organisms due to more frequent healthcare utilisation and antimicrobial prescriptions. This systematic review investigated the association between HIV and AMR. Methods: 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 antimicrobial tested were included. Pooled odds ratios were used to evaluate the association between HIV and resistance. The completeness of reporting was evaluated using the STROBE checklist. Findings: A total of 92 studies from 23 countries 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. Overall, there was a high heterogeneity between studies. Interpretation: This review shows an increased risk of AMR in PLWH across a range of bacterial pathogens and multiple drug classes, which has important clinical implications for treatment. 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. This knowledge should translate into treatment guideline changes especially in settings where diagnostics are limited. Funding: IDO received funding though the Wellcome Trust Clinical PhD Programme awarded to the London School of Hygiene & Tropical Medicine (grant number 203905/Z/16/Z). Declaration of Interests: None of the authors have any competing interests.

BackgroundClinically suspected and laboratory-confirmed bloodstream infections are frequent causes of morbidity and mortality during neonatal care. The most effective infection prevention and control (IPC) interventions for neonates in low-and-middle-income countries (LMIC) are unknown.AimTo identify effective interventions in the prevention of hospital-acquired bloodstream infections in LMIC neonatal units.MethodsMedline, PUBMED, The Cochrane Database of Systematic Reviews, EMBASE, and PsychInfo (January 2003 – October 2020) were searched to identify studies reporting single or bundled interventions for prevention of bloodstream infections in LMIC neonatal units.ResultsOur initial search identified 5206 articles; following application of filters, 27 publications met the inclusion and ICROMS assessment criteria and were summarised in the final analysis. No studies were carried out in low-income countries, only one in sub-Saharan Africa and just two in multiple countries. Of the 18 single intervention studies, most targeted skin (n=4) and gastrointestinal mucosal integrity (n=5). Whereas emollient therapy and lactoferrin achieved significant reductions in proven neonatal infection, glutamine and mixed probiotics showed no benefit. Chlorhexidine gluconate for cord care and kangaroo mother care reduced infection in individual single-centre studies. Of the nine studies evaluating bundles, most focused on prevention of device-associated infections and achieved significant reductions in catheter- and ventilator-associated infections.ConclusionThere is a limited evidence-base for the effectiveness of IPC interventions in LMIC neonatal units; bundled interventions targeting device-associated infections were most effective. More multi-site studies with robust study designs are needed to inform IPC intervention strategies in low-resource neonatal units.Sources of SupportFF is supported by the Academy of Medical Sciences, the funders of the Starter Grant for Clinical Lecturers scheme and UCL Great Ormond Street NIHR Biomedical Research Centre. AD is supported by the Fogarty International Center of the National Institutes of Health, Emerging Global Leader Award Number K43-TW010682.

Emerging multidrug-resistant tuberculosis is a major global health challenge. The World Health Organization currently recommends treatment durations of 9–18 months or more for patients with multidrug-resistant tuberculosis. We identified and validated a host-RNA signature to serve as a biomarker for individualized therapy durations for patients with multidrug-resistant tuberculosis. Adult patients with pulmonary tuberculosis were prospectively enrolled into 5 independent cohorts in Germany and Romania. Clinical and microbiological data, and whole-blood for RNA transcriptomic analysis were collected at pre-defined timepoints throughout therapy. Treatment outcomes were ascertained one year after end-of-therapy. A whole-blood RNA therapy end model was developed in a multi-step process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment timepoints. Fifty patients with drug-susceptible tuberculosis and 30 patients with multidrug-resistant tuberculosis were recruited in the German identification cohorts (DS- and MDR-GIC), 28 patients with drug-susceptible tuberculosis and 32 patients with multidrug-resistant tuberculosis in the German validation cohorts (DS- and MDR-GVC), and 52 patients with multidrug-resistant tuberculosis in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model that defined cure-associated end-of-therapy timepoints was derived from the DS- and MDR-GIC data. The model accurately predicted clinical outcomes for patients in the DS-GVC (AUC=0.937 [95%CI:0.899–0.976]) and suggested that cure may be achieved with shorter treatment durations for tuberculosis patients in the MDR-GIC (mean reduction 218.0 days, 34.2%, pOne Sentence SummaryWe identified and validated a transcriptome model based on a 22-gene signature to predict individual treatment durations for patients with multidrug-resistant tuberculosis.

Summary Background The prevalence of sexually transmitted infections (STIs) among youth is high in sub-Saharan Africa. We investigated the uptake of testing for and prevalence of Chlamydia trachomatis (chlamydia) and Neisseria gonorrhoeae (gonorrhoea) infections among youth in community-based settings in Zimbabwe, and explored the facilitators and barriers to testing. Methods This study was nested within a cluster randomised trial of community-based delivery of integrated HIV and sexual and reproductive health services for youth aged 16–24 years. Chlamydia and gonorrhoea testing via urine samples using the Xpert CT/NG test was offered in the four intervention clusters in Harare, Zimbabwe. Factors associated with testing uptake were investigated in a subset of participants (n=257) using hierarchical multivariate logistic regression. In-depth interviews with a separate purposively selected sample (n=26) explored facilitators and barriers to STI testing and partner notification and were analysed using thematic analysis. Findings Between June 1, 2019, and Jan 31, 2020, there were 6200 attendances by 4440 participants (78·2% women, 21·8% men) median age 20·3 (IQR 17·9–22·8) years. 1478 participants had 1501 tests done, and 248 tests were positive and 1253 tests were negative for chlamydia or gonorrhoea, or both. STI test uptake was 33·3% (95% CI 31·9–34·7), increasing from 11·7% in June, 2019, to 37·1% in January, 2020. The prevalence of chlamydia or gonorrhoea, or both, was 16·5% (95% CI 14·7–18·5; 248 of 1501), with only seven participants (3%) showing symptoms. The overall yield of testing was 4·0% (95% CI 3·5–4·5; 248 of 6200). Uptake was associated with having symptoms (adjusted odds ratio [OR] 14·8, 95% CI 1·66–132·07) and negatively associated with being single (adjusted OR 0·33, 95% CI 0·13–0·84) or having a boyfriend or girlfriend (adjusted OR 0·19, 95% CI 0·087–0·43) compared with being married, and being a student compared with being employed (adjusted OR 0·26, 95% CI 0·10–0·68). Perceived risk and symptoms of STIs were motivators for testing whereas misinformation, anticipated stigma, and concern about confidentiality were barriers. Interpretation The prevalence of chlamydia or gonorrhoea, or both, was high among youth but only a minority were symptomatic. Therefore most infections would remain untreated without access to STI testing. Provision of education, counselling, and confidentiality are essential to improve uptake and acceptability of STI testing. Funding Wellcome Trust.

Antimicrobial resistance (AMR) is compromising our ability to successfully treat infections. There are few data on gram-negative AMR prevalence in sub-Saharan Africa especially from the outpatient setting. This study aims to investigate the prevalence of and underlying molecular mechanisms for AMR in gram-negative bacilli causing urinary tract infections (UTIs) in Zimbabwe. Risk factors for AMR and how AMR impacts on clinical outcomes will also be investigated.Adults presenting with UTI symptoms at primary health clinics in Harare will be included. A questionnaire will be administered, and urine samples will be collected for culture. Participants with positive urine cultures will be followed up at 7-14 days post-enrolment. All participants will also be followed by telephone at 28 days to determine clinical outcomes.Bacterial identification and antibiotic susceptibility testing will be performed on positive cultures.The results from this study will be used to inform policy and development of treatment recommendations. Whole genome sequencing results will provide a better understanding of the prevalent resistance genes in Zimbabwe, of the spread of successful clones, and potentially will contribute to developing strategies to tackle AMR.

Young people living with HIV (YPLHIV) in sub-Saharan Africa (SSA) are at high risk of having a poor quality of life. Addressing wellbeing explicitly within HIV/AIDS policies could assist mitigation efforts. However, guidance on wellbeing measures to evaluate policies for YPLHIV is scarce. The aims of this mixed-methods review were to identify: i) key dimensions of wellbeing and ii) wellbeing measures that align to these dimensions among YPLHIV (15–24 years) in SSA. We searched six social science and medical databases, including grey literature. We included studies that examined correlates and lived experiences of wellbeing, among YPLHIV in SSA, from January 2000 to May 2019. Two reviewers independently screened abstracts and full texts and assessed methodological quality of included articles. We analysed quantitative and qualitative data using descriptive and meta-ethnographic approaches, respectively. Thereafter, we integrated findings using a framework approach. We identified 6527 citations. Of these, 10 quantitative and 30 qualitative studies were included. Being male, higher educational status, less stigma and more social support were likely correlates of wellbeing. Themes that shaped experiences suggestive of wellbeing were: 1) acceptance and belonging— stigma, social support; 2) coping; 3) standard of living. Our final synthesis found that the following dimensions potentially characterise wellbeing: self-acceptance, belonging, autonomy; positive relations, environmental mastery, purpose in life. Wellbeing for YPLHIV is multi-dimensional and relational. Relevant measures include the Personal Wellbeing Index, Ryff’s Psychological Wellbeing Scale and Mental Health Continuum Short Form. However, psychometric evaluations of these scales among YPLHIV in SSA are needed.

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 non-infectious 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 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 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 is being addressed.

National Mycobacterium Reference Laboratory, Borstel, Germany. : To evaluate the effectiveness of OMNIgene®•SPUTUM (OM-S) reagent in comparison with a method using N-acetyl-L-cysteine-sodium hydroxide (NALC-NaOH) with regard to mycobacterial recovery and contamination of broth and solid cultures. : Sputum samples from patients with tuberculosis and other respiratory diseases underwent decontamination with NALC-NaOH-based (MycoDDR™) or OM-S reagent. The decontamination procedure was assigned by block randomisation. Samples were inoculated on Lowenstein-Jensen, Stonebrink and MGIT™ (Mycobacterial Growth Indicator Tubes). Mycobacterial recovery from samples spiked with Mycobacterium tuberculosis following decontamination was determined. : Eighty-five samples were randomised to NALC-NaOH and 84 to OM-S reagent. Mycobacterial recovery was significantly lower for samples processed with OM-S reagent compared with the NALC-NaOH method across all media types. Culture contamination was lower with NALC-NaOH reagent on solid media (9.4-12.9% vs. 28.6-29.8%). Growth was not observed in MGIT among samples spiked with 10 600-16 800 colony-forming units of M. tuberculosis following decontamination with OM-S reagent. : Low mycobacterial recovery, especially in MGIT, observed in the present study suggests that OM-S reagent might not be compatible with the MGIT system. More extensive field evaluations of the OM-S reagent are warranted to demonstrate a significant benefit over currently used methods.

Günther Fink and colleagues are to be congratulated for their analysis of antibiotic exposure among children younger than 5 years in low-income and middle-income countries (LMICs) with a range of common illnesses, including cough, fever, diarrhoea, and malaria.1 The authors explain that their study1 is the first to use a robust method to comprehensively quantify cumulative antibiotic exposure among children in LMICs by obtaining nationally representative data from surveys of households and formal-sector health-care facilities. Quantifying exposure is important, as previous surveys have only had limited coverage in low-income settings, particularly in sub-Saharan African countries, which have the highest incidence of infectious diseases globally.2,3 However, quantifying true antibiotic use in LMICs might be difficult if antibiotics are frequently purchased without a prescription due to issues with affordability and access. Obtaining antibiotics in this way accounts for up to 93% of all antibiotics dispensed in some LMICs.4,5 The remaining 7% or more include antibiotics obtained from ambulatory care and inpatient hospital care.2 Antimicrobial resistance is a growing public

Background Overuse of antibiotics is one of the main drivers for antimicrobial resistance (AMR). Globally, most antibiotics are prescribed in the outpatient setting. This survey aimed to explore attitudes and practices with regards to microbiology tests, AMR and antibiotic prescribing among healthcare providers at public primary health clinics in Harare, Zimbabwe. Methods This cross-sectional survey was conducted in nine primary health clinics located in low-income suburbs of Harare between October and December 2020. In Zimbabwe, primary health clinics provide nurse-led outpatient care for acute and chronic illnesses. Healthcare providers who independently prescribe antibiotics and order diagnostic tests were invited to participate. The survey used self-administered questionnaires. A five-point Likert scale was used to determined attitudes and beliefs. Results A total of 91 healthcare providers agreed to participate in the survey. The majority of participants (62/91, 68%) had more than 10 years of work experience. Most participants reported that they consider AMR as a global (75/91, 82%) and/or national (81/91, 89%) problem, while 52/91 (57%) considered AMR to be a problem in their healthcare facilities. A fifth of participants (20/91, 22%) were unsure if AMR was a problem in their clinics. Participants felt that availability of national guidelines (89/89, 100%), training sessions on antibiotic prescribing (89/89, 100%) and regular audit and feedback on prescribing (82/88, 93%) were helpful interventions to improve prescribing. Conclusions These findings support the need for increased availability of data on AMR and antibiotic use in primary care. Educational interventions, regular audit and feedback, and access to practice guidelines may be useful to limit overuse of antibiotics.

Objective: The aim of our study was to retrospectively validate a previously described rapid clinical score (RCS) in distinguishing tuberculous meningitis (TBM) from viral meningitis (VM) in people who are at increased risk of tuberculosis, as well as from cryptococcal meningitis (CM) in HIV-infected patients. Methods: We performed a retrospective study of patients admitted with a diagnosis of aseptic meningitis between January 2012 and December 2015, to a referral hospital for infectious diseases. The variables included in RCS were duration of symptoms before admission, neurological stage, cerebrospinal fluid (CSF) to blood glucose ratio, and CSF protein. We included in this retrospective study 31 patients with definite or probable TBM including 14 HIV-infected patients, 62 HIV-noninfected patients with VM, and 18 HIV-infected patients with CM. Results: The sensitivity of RCS to distinguish TBM from VM was 96.7%, with a specificity of 81.1% and the area under the receiver operating characteristic (ROC) curve was 0.949 (0.90–0.99). When all four criteria from the RCS were present, the specificity increased at 100%. In HIV-infected patients, the sensitivity and specificity of RCS in differentiating TBM from CM were 86.6% and 27.7%, respectively, and the area under the ROC curve was 0.669 (0.48–0.85). Conclusion: This easy-to-use RCS was found to be helpful in differentiating TBM from VM, with a better sensitivity than molecular amplification techniques and a relatively good specificity. However, the RCS was not useful to differentiate between TBM and CM in HIV-infected patients.

RATIONALE: We evaluated whether treatment outcomes for patients with multidrug-resistant and extensively drug-resistant tuberculosis can be substantially improved when sufficient resources for personalizing medical care are available. OBJECTIVES: To describe the characteristics and outcomes of patients with pulmonary multidrug-resistant tuberculosis at the Otto Wagner Hospital in Vienna, Austria. METHODS: We conducted a retrospective single-center study of patients initiated on treatment for multi-drug resistant tuberculosis between January 2003 and December 2012 at the Otto Wagner Hospital, Vienna, Austria. The records of patients with multidrug-resistant tuberculosis were reviewed for epidemiological, clinical, laboratory, treatment, and outcome data. MEASUREMENTS AND MAIN RESULTS: Ninety patients with pulmonary multidrug-resistant tuberculosis were identified. The median age was 30 years (interquartile range, 26-37). All patients were of non-Austrian origin, and 70 (78%) came from former states of the Soviet Union. Thirty-nine (43%) patients had multidrug-resistant tuberculosis; 28 (31%) had additional bacillary resistance to at least one second-line injectable drug and 9 (10%) to a fluoroquinolone. Fourteen (16%) patients had extensively drug-resistant tuberculosis. Eighty-eight different drug combinations were used for the treatment of the 90 patients. Surgery was performed on 10 (11.1%) of the patients. Sixty-five (72.2%) patients had a successful treatment outcome, 8 (8.9%) defaulted, 3 (3.3%) died, 8 (8.9%) continued treatment in another country and their outcome was unknown, and 6 (6.7%) were still on therapy. None of the patients experienced treatment failure. Treatment outcomes for patients with extensively drug-resistant tuberculosis were similar to those of patients with multidrug-resistant tuberculosis. CONCLUSIONS: High rates of treatment success can be achieved in patients with multidrug-resistant and extensively drug-resistant tuberculosis when individually tailored treatment regimens can be provided in a high-resource setting.

We would like to thank Dr. Navisha Dookie and colleagues for their comment and for sharing their view on genotypic drug-susceptibility testing (DST) to predict phenotypic drug-susceptibility for the management of patients with drug-resistant tuberculosis (1, 2). We agree that DST should ideally be conducted for all drugs in a regimen, particularly given the severe adverse effects of second-line anti-tuberculosis drugs. Yet, even whole-genome sequencing in not a one-size-fits-all solution. Instead, the goal has to be to optimally combine genotypic and phenotypic assays in a diagnostic algorithm that capitalises on the strengths of both approaches whilst including appropriate reflex and confirmatory testing to minimize the impact of their respective limitations, including systematic errors (3).

BACKGROUND: Excellent treatment outcomes have recently been reported for patients with multi/extensively drug-resistant tuberculosis (M/XDR-TB) in settings where optimal resources for individualised therapy are available. OBJECTIVE: To ascertain whether differences remain in treatment responses between patients with M/XDR-TB and those with non-M/XDR-TB. METHOD: Patients with TB were prospectively enrolled between March 2013 and March 2016 at five hospitals in Germany. Treatment was conducted following current guidelines and individualised on the basis of drug susceptibility testing. Two-month and 6-month sputum smear and sputum culture conversion rates were assessed. A clinical and radiological score were used to assess response to anti-tuberculosis treatment. RESULTS: Non-M/XDR-TB (n = 29) and M/XDR-TB (n = 46) patients showed similar rates of microbiological conversion: 2-month smear conversion rate, 90% vs. 78%; culture conversion rate, 67% vs. 61%; time to smear conversion, 19 days (IQR 10-32) vs. 31 days (IQR 14-56) (P = 0.066); time to culture conversion, 39 days (IQR 17-67) vs. 39 days (IQR 6-85) (P = 0.191). Both clinical and radiological scores decreased after the introduction of anti-tuberculosis treatment. CONCLUSION: There were no significant differences in scores between the two groups until 6 months of treatment. Under optimal clinical conditions, with the availability of novel diagnostics and a wide range of therapeutic options for individualised treatment, patients with M/XDR-TB achieved 6-month culture conversion rates that were compatible with those in patients with non-M/XDR-TB.

Multidrug-resistant (MDR) tuberculosis (TB), defined by bacillary resistance against rifampicin and isoniazid, has been identified as a global threat to mankind [1]. According to the latest report by the European Centres for Disease Prevention and Control, and World Health Organization (WHO) regional office for Europe, only approximately 50% of MDR-TB patients in Europe reach favourable treatment outcomes [2]. Successful treatment outcomes are achieved for less than 25% of patients with extensively drug-resistant (XDR)-TB (MDR plus resistance against a least one fluoroquinolone and one second-line injectable drug) in the European Union/European Economic Area Countries [2].

The emergence of MDR-TB is a cause of great concern due to difficulties in patient management and poor treatment outcomes. Currently the duration of treatment and the choice of drugs for patients with MDR-TB are standardized in many countries. This might not be the best approach since the optimal therapy may depend on different pathogen- and host-related features. Combining the introduction of technological innovations such as whole bacillary genome sequencing for the identification of drug-resistance-associated mutations, therapeutic drug monitoring and host-directed therapies with an individualized approach to MDR-TB management will likely lead to more tolerable, shorter and more efficient treatment regimens and an increase in the quality of life of those affected by MDR-TB.

We evaluated the relationship between the degree of immunodeficiency indicated by the number of circulating CD4+ T-cells and Mycobacterium tuberculosis lineages identified by spoligotyping and mycobacterial interspersed repetitive units-variable number of tandem repeats genotyping in human immunodeficiency virus (HIV) infected individuals with pulmonary tuberculosis from Mbeya, Tanzania. Of M. tuberculosis strains from 129 patients, respectively 55 (42.6%) and 37 (28.7%) belonged to Latin American Mediterranean and Delhi/Central-Asian lineages, while 37 (28.7%) patients were infected with other strains. There was no difference in the distribution of M. tuberculosis lineages among patients with early or advanced stages of HIV infection (P = 0.785), indicating that the virulence of strains from these lineages may not be substantially different in vivo.