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Positron emission tomography imaging using radiolabeled dolutegravir (DTG) is an interesting approach to understand the biodistribution of this antiretroviral drug at HIV-1 sanctuary sites. In the course of clinical translation, we depict herein an improved and pharmaceutically compliant radiosynthesis of [ 18 F]DTG from an original tin precursor. The radiosynthesis was achieved in two steps by copper-mediated radiofluorination, followed by enol ether deprotection using a kit-based AllInOne module. Ready-to-inject [ 18 F]DTG was obtained in 20 ± 5% ( n = 12) decay-corrected radiochemical yield within 90 min, representing a 4-fold increase compared to the previously published three-step radiosynthesis. Quality control was carried out with three consecutive [ 18 F]DTG productions according to the current European Pharmacopoeia guidelines, which include pH determination, identity and purity (chemical, radiochemical, and radionuclide) assessments, residual solvent quantification, dosage of lithium, copper, and tin traces, sterility and bacterial endotoxin tests. [ 18 F]DTG (∼2 GBq) was obtained with a molar activity of 59 ± 2 GBq/μmol at the time of injection and was suitable for human applications., Competing Interests: The authors declare the following competing financial interest(s): Thomas Bonasera is employed by GSK. Chris M. Parry is employed by ViiV Healthcare and has stock/shares in GSK., (© 2024 The Authors. Published by American Chemical Society.)

Background: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues., Objectives: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs)., Methods: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection., Results: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%., Conclusions: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Sepsis is a life-threatening condition arising from a dysregulated host immune response to infection, leading to a substantial global health burden. The accurate identification of bacterial pathogens in sepsis is essential for guiding effective antimicrobial therapy and optimising patient outcomes. Traditional culture-based bacterial typing methods present inherent limitations, necessitating the exploration of alternative diagnostic approaches. This study reports the successful application of Fourier-transform infrared (FT-IR) spectroscopy in combination with chemometrics as a potent tool for the classification and discrimination of microbial species and strains, primarily sourced from individuals with invasive infections. These samples were obtained from various children with suspected sepsis infections with bacteria and fungi originating at different sites. We conducted a comprehensive analysis utilising 212 isolates from 14 distinct genera, comprising 202 bacterial and 10 fungal isolates. With the spectral analysis taking several weeks, we present the incorporation of quality control samples to mitigate potential variations that may arise between different sample plates, especially when dealing with a large sample size. The results demonstrated a remarkable consistency in clustering patterns among 14 genera when subjected to principal component analysis (PCA). Particularly, Candida , a fungal genus, was distinctly recovered away from bacterial samples. Principal component discriminant function analysis (PC-DFA) allowed for distinct discrimination between different bacterial groups, particularly Gram-negative and Gram-positive bacteria. Clear differentiation was also observed between coagulase-negative staphylococci (CNS) and Staphylococcus aureus isolates, while methicillin-resistant S. aureus (MRSA) was also separated from methicillin-susceptible S. aureus (MSSA) isolates. Furthermore, highly accurate discrimination was achieved between Enterococcus and vancomycin-resistant enterococci isolates with 98.4% accuracy using partial least squares-discriminant analysis. The study also demonstrates the specificity of FT-IR, as it effectively discriminates between individual isolates of Streptococcus and Candida at their respective species levels. The findings of this study establish a strong groundwork for the broader implementation of FT-IR and chemometrics in clinical and microbiological applications. The potential of these techniques for enhanced microbial classification holds significant promise in the diagnosis and management of invasive bacterial infections, thereby contributing to improved patient outcomes.

The World Health Organization (WHO)'s list of neglected tropical diseases (NTDs) highlights conditions that are responsible for devastating health, social and economic consequences, and yet, they are overlooked and poorly resourced. The NTD list does not include conditions caused by Gram-negative bacilli (GNB). Infections due to GNB cause significant morbidity and mortality and are prevalent worldwide. Southeast Asia is a WHO region of low- and middle-income countries carrying the largest burden of NTDs. Two significant health threats in Southeast Asia are Burkholderia pseudomallei (causing melioidosis) and hypervirulent Klebsiella pneumoniae (HvKp). Both diseases have high mortality and increasing prevalence, yet both suffer from a lack of awareness, significant under-resourcing, incomplete epidemiological data, limited diagnostics, and a lack of evidence-based treatment. Emerging evidence shows that both melioidosis and HvKp are spreading globally, including in high-income countries, highlighting the potential future global threat they pose. In this article, we review both conditions, identifying current trends and challenges in Southeast Asia and areas for future research. We also argue that melioidosis and HvKp merit inclusion as NTDs, and that mandatory global surveillance and reporting systems should be established, and we make an urgent call for research to better understand, detect, and treat these neglected diseases.

Background: There is a lack of data on the characteristics of overlap between acquired antimicrobial resistance and virulence factors in Klebsiella pneumoniae in high-risk settings, especially with the inclusion of surveillance isolates along with the clinical. We investigated K. pneumoniae isolates, from a neonatal intensive care unit (NICU) in Nepal, for the presence of both accessory virulence factors and acquired antimicrobial resistance., Methods: Thirty-eight clinical and nineteen surveillance K. pneumoniae isolates obtained between January 2017 and August 2022 in the NICU of Siddhi Memorial Hospital, Bhaktapur, Nepal were investigated with antimicrobial susceptibility testing, PCR-based detection of β-lactamases and virulence factors, and genetic similarity by ERIC-PCR., Results: K. pneumoniae was found positive in 37/85 (43.5%) blood culture-positive neonatal bloodstream infections, 34/954 (3.6%) patient surveillance cultures, and 15/451 (3.3%) environmental surveillance samples. Among 57 isolates analyzed in this study, we detected multidrug resistance in 37/57 (64.9%), which was combined with at least one accessory virulence factor in 21/37 (56.8%). This overlap was mostly among β-lactamase producing isolates with accessory mechanisms of iron acquisition. These isolates displayed heterogenous ERIC-PCR patterns suggesting genetic diversity., Conclusions: The clinical significance of this overlap between acquired antimicrobial resistance and accessory virulence genes in K. pneumoniae needs further investigation. Better resource allocation is necessary to strengthen infection prevention and control interventions in resource-limited settings., (© 2024. The Author(s).)

Background: Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A, is a major public health problem in low- and middle-income countries. Moderate sensitivity and scalability of current methods likely underestimate enteric fever burden. Determining the serological responses to organism-specific antigens may improve incidence measures., Methods: Plasma samples were collected from blood culture-confirmed enteric fever patients, blood culture-negative febrile patients over the course of 3 months, and afebrile community controls. A panel of 17 Salmonella Typhi and Paratyphi A antigens was purified and used to determine antigen-specific antibody responses by indirect ELISAs., Results: The antigen-specific longitudinal antibody responses were comparable between enteric fever patients, patients with blood culture-negative febrile controls, and afebrile community controls for most antigens. However, we found that IgG responses against STY1479 (YncE), STY1886 (CdtB), STY1498 (HlyE), and the serovar-specific O2 and O9 antigens were greatly elevated over a 3-month follow up period in S. Typhi/S. Paratyphi A patients compared to controls, suggesting seroconversion., Conclusions: We identified a set of antigens as good candidates to demonstrate enteric fever exposure. These targets can be used in combination to develop more sensitive and scalable approaches to enteric fever surveillance and generate invaluable epidemiological data for informing vaccine policies., Clinical Trial Registration: ISRCTN63006567., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Data on antimicrobial resistance (AMR) among children in Nepal are limited. Here we have characterized the causes of bacterial bloodstream infections (BSIs), antimicrobial resistance patterns and the mechanisms of β-lactamase production in Enterobacterales among children attending outpatient and inpatient departments of a secondary care paediatric hospital in Nepal., Methods: We retrospectively collected demographic and clinical data of culture-proven bacterial BSIs between January 2017 and December 2022 among children <18 years attending a 50-bedded paediatric hospital. Stored isolates were subcultured for antimicrobial susceptibility testing against commonly used antimicrobials. Enterobacterales displaying non-susceptibility to β-lactams were phenotypically and genotypically investigated for ESBLs, plasmid-mediated AmpC (pAmpC) β-lactamases and carbapenemases., Results: A total of 377 significant bacteria were isolated from 27 366 blood cultures. Among 91 neonates with a BSI, Klebsiella pneumoniae ( n  = 39, 42.4 % ), Pseudomonas aeruginosa ( n  = 15, 16.3%) and Acinetobacter baumannii complex ( n  = 13, 14.1%) were most common. In the non-neonates, 275/285 (96.5%) infections were community-acquired including Staphylococcus aureus ( n  = 89, 32.4%), Salmonella Typhi ( n  = 54, 19.6%) and Streptococcus pneumoniae ( n  = 32, 11.6%). Among the 98 S. aureus , 29 (29.6%) were methicillin-resistant Staphylococcus aureus . K. pneumoniae and Escherichia coli demonstrated non-susceptibility to extended-spectrum cephalosporins and carbapenems in both community and hospital-acquired cases. For E. coli and K. pneumoniae , bla CTX-M (45/46), bla EBC (7/10) and bla OXA-48 (5/6) were common among their respective groups., Conclusions: We determined significant levels of AMR among children attending a secondary care paediatric hospital with BSI in Nepal. Nationwide surveillance and implementation of antimicrobial stewardship policies are needed to combat the challenge imposed by AMR., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: A 7.8 R scale earthquake hit Nepal in April 2015 and caused about 9000 deaths along with damage to infrastructure, including the water and sewage system. Bhaktapur was one of the highly affected districts. A typhoid vaccination campaign (pre-emptive) was carried out among children who were living in the temporary shelters in this district. The assessment of vaccine effectiveness after a pre-emptive typhoid vaccine campaign following an earthquake has previously not been attempted in Nepal., Objective: To describe the pre-emptive typhoid Vi capsular polysaccharide vaccination campaign and an evaluation of the vaccine effectiveness., Methods: We conducted a pre-emptive typhoid Vi capsular polysaccharide vaccination campaign among children between 2 and 15 years of age dwelling in 23 temporary shelters in Bhaktapur district after the earthquake. Surveillance of clinical typhoid was carried out from 2014 to 2017 in Siddhi Memorial Hospital, the only hospital for children in the district. We calculated vaccine effectiveness using a case-control study design (clinical typhoid as cases and chest x-ray confirmed pneumonia as controls)., Results: Three thousand nine hundred sixteen children of age 2-15 years residing in the 23 temporary shelters in Bhaktapur received the typhoid Vi capsular polysaccharide vaccine between July and December 2015. 2193 children of age 2-15 years were admitted to the hospital during the study period and 260 (11.9%) were diagnosed with clinical typhoid. The numbers of children admitted with clinical typhoid decreased over the study period (105 in 2014 and 47 in 2017; P = 0.001). Overall vaccine effectiveness was calculated at 52% (95% CI -46 to 85%), and it was 87% (95% CI -25 to 99) among children less than 5 years of age., Conclusions: We successfully conducted a pre-emptive vaccination campaign against typhoid after the 2015 Nepal earthquake. The pre-emptive vaccination campaign appeared to be more effective among children less than 5 years of age. Further studies are needed to assess the effectiveness of pre-emptive use of typhoid vaccines in the emergency situations. We highlight the challenges of calculating vaccine effectiveness of a typhoid vaccine in an emergency setting., (© 2024. The Author(s).)

Typhoid fever is an invasive bacterial disease associated with bloodstream infection that causes a high burden of disease in Africa and Asia. Typhoid primarily affects individuals ranging from infants through to young adults. The causative organism, Salmonella enterica subsp. enterica serovar Typhi is transmitted via the faecal-oral route, crossing the intestinal epithelium and disseminating to systemic and intracellular sites, causing an undifferentiated febrile illness. Blood culture remains the practical reference standard for diagnosis of typhoid fever, where culture testing is available, but novel diagnostic modalities are an important priority under investigation. Since 2017, remarkable progress has been made in defining the global burden of both typhoid fever and antimicrobial resistance; in understanding disease pathogenesis and immunological protection through the use of controlled human infection; and in advancing effective vaccination programmes through strategic multipartner collaboration and targeted clinical trials in multiple high-incidence priority settings. This Primer thus offers a timely update of progress and perspective on future priorities for the global scientific community., (© 2023. Springer Nature Limited.)

Longitudinal, community-based sampling is important for understanding prevalence and transmission of respiratory pathogens. Using a minimally invasive sampling method, the FAMILY Micro study monitored the oral, nasal and hand microbiota of families for 6 months. Here, we explore participant experiences and opinions. A mixed methods approach was utilised. A quantitative questionnaire was completed after every sampling timepoint to report levels of discomfort and pain, as well as time taken to collect samples. Participants were also invited to discuss their experiences in a qualitative structured exit interview. We received questionnaires from 36 families. Most adults and children >5y experienced no pain (94% and 70%) and little discomfort (73% and 47% no discomfort) regardless of sample type, whereas children ≤5y experienced variable levels of pain and discomfort (48% no pain but 14% hurts even more, whole lot or worst; 38% no discomfort but 33% moderate, severe, or extreme discomfort). The time taken for saliva and hand sampling decreased over the study. We conducted interviews with 24 families. Families found the sampling method straightforward, and adults and children >5y preferred nasal sampling using a synthetic absorptive matrix over nasopharyngeal swabs. It remained challenging for families to fit sampling into their busy schedules. Adequate fridge/freezer space and regular sample pick-ups were found to be important factors for feasibility. Messaging apps proved extremely effective for engaging with participants. Our findings provide key information to inform the design of future studies, specifically that self-sampling at home using minimally invasive procedures is feasible in a family context., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 German et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: To investigate the impact of the M184V/I mutation on virologic response to dolutegravir plus lamivudine (DTG + 3TC) in suppressed-switch populations, a meta-analysis was performed using virologic outcomes from people with human immunodeficiency virus type 1 (PWH) with and without M184V/I before DTG + 3TC switch in real-world studies identified via systematic literature review. Sensitivity analyses were performed using data from PWH with M184V/I in interventional studies identified via targeted literature review., Methods: Single-arm meta-analyses using common- and random-effects models were used to estimate proportions of PWH with virologic failure (VF) among real-world populations with and without M184V/I and interventional study participants with M184V/I at 24, 48, and 96 weeks., Results: Literature reviews identified 5 real-world studies from 3907 publications and 51 abstracts meeting inclusion criteria and 5 interventional studies from 1789 publications and 3 abstracts. All time points had low VF incidence in PWH with M184V/I (real-world: 1.43%-3.81%; interventional: 0.00%) and without (real-world: 0.73%-2.37%). Meta-analysis-estimated proportions (95% confidence interval) with VF were low at weeks 24, 48, and 96, respectively, for PWH with M184V/I (real-world: 0.01 [.00-.04], 0.03 [.01-.06], and 0.04 [.01-.07]; interventional: 0.00 [.00-.02], 0.00 [.00-.01], and 0.00 [.00-.03]) and without (real-world: 0.00 [.00-.02], 0.02 [.01-.04], and 0.02 [.00-.05]). One real-world study (n = 712) reported treatment-emergent M184V at VF in 1 of 652 (0.15%) PWH without prior M184V/I., Conclusions: Results suggest that prior M184V/I has minimal impact on virologic suppression after switching to DTG + 3TC and provide reassurance when considering switching regimens in virologically suppressed PWH with incomplete treatment history or limited treatment options., Competing Interests: Potential conflicts of interest. M. K. was a complimentary worker for ViiV Healthcare at the time of the analysis. G. V. is an employee of ViiV Healthcare. C. M. P., B. J., C. O., J. Pr., and E. L. are employees of ViiV Healthcare and own stock in GSK. T. J. B. has received grants from Gilead, MSD, Roche, and ViiV Healthcare; consulting fees and honoraria from Gilead, GSK, Janssen, MSD, Roche, Theratechnologies, and ViiV Healthcare; and travel support from Gilead and ViiV Healthcare. C. A. has received honoraria from Gilead, MSD, and ViiV Healthcare; has received travel support from Gilead and MSD; and is a member of the CPP Ouest IV Ethics Committee. A.-G. M. has received grants and honoraria from Gilead, MSD, and ViiV Healthcare; consulting fees from GSK; and travel support from Gilead. J. Pa. has received honoraria from Gilead, Janssen-Cilag, MSD, and ViiV Healthcare and travel support from Gilead and Janssen-Cilag. N. G. has received grants, honoraria, and travel support from Gilead, Janssen-Cilag, MSD, and ViiV Healthcare. J. M. L. has received grants from Gilead and ViiV Healthcare; has received speaker honoraria from Gilead, Janssen-Cilag, and ViiV Healthcare; and is a member of the Spanish Antiretroviral Treatment Guidelines panel. D. R.-C. has received honoraria from Gilead and ViiV Healthcare and travel support from Gilead. R. D. M.-B. has received speaker fees from Gilead and ViiV Healthcare and travel support from ViiV Healthcare. G. B. has received honoraria and travel support from ViiV Healthcare. M. T., C. H., and T. W. are employees of HEOR Ltd, which received funding from ViiV Healthcare to support this analysis. S. D. G. reports no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Monitoring the presence of commensal and pathogenic respiratory microorganisms is of critical global importance. However, community-based surveillance is difficult because nasopharyngeal swabs are uncomfortable and painful for a wide age range of participants. We designed a methodology for minimally invasive self-sampling at home and assessed its use for longitudinal monitoring of the oral, nasal and hand microbiota of adults and children within families. Healthy families with two adults and up to three children, living in and near Liverpool, United Kingdom, self-collected saliva, nasal lining fluid using synthetic absorptive matrices and hand swabs at home every two weeks for six months. Questionnaires were used to collect demographic and epidemiological data and assess feasibility and acceptability. Participants were invited to take part in an exit interview. Thirty-three families completed the study. Sampling using our approach was acceptable to 25/33 (76%) families, as sampling was fast (76%), easy (76%) and painless (60%). Saliva and hand sampling was acceptable to all participants of any age, whereas nasal sampling was accepted mostly by adults and children older than 5 years. Multi-niche self-sampling at home can be used by adults and children for longitudinal surveillance of respiratory microorganisms, providing key data for design of future studies., (© 2023. Springer Nature Limited.)

Background: Transferrable mechanisms of quinolone resistance (TMQR) can lead to fluoroquinolone non-susceptibility in addition to chromosomal mechanisms. Some evidence suggests that fluoroquinolone resistance is increasing among the pediatric population. We sought to determine the occurrence of TMQR genes among quinolone-resistant E. coli and K. pneumoniae causing urinary tract infections among Nepalese outpatient children (< 18 years) and identify molecular characteristics of TMQR-harboring isolates., Methods: We performed antimicrobial susceptibility testing, phenotypic extended-spectrum β-lactamase (ESBL) and modified carbapenem inactivation method tests, and investigated the presence of six TMQR genes (qnrA, qnrB, qnrS, aac(6')-Ib-cr, oqxAB, qepA), three ESBL genes (bla CTX-M , bla TEM , bla SHV ), and five carbapenemase genes (bla NDM , bla OXA-48 , bla KPC , bla IMP , bla VIM ). The quinolone resistance-determining region (QRDR) of gyrA and parC were sequenced for 35 TMQR-positive isolates., Results: A total of 74/147 (50.3%) isolates were TMQR positive by multiplex PCR [aac(6')-Ib-cr in 48 (32.7%), qnrB in 23 (15.7%), qnrS in 18 (12.3%), qnrA in 1 (0.7%), and oqxAB in 1 (0.7%) isolate]. The median ciprofloxacin minimum inhibitory concentration of TMQR-positive isolates (64 µg/mL) was two-fold higher than those without TMQR (32 µg/mL) (p = 0.004). Ser-83→Leu and Asp-87→Asn in GyrA and Ser-80→Ile in ParC were the most common QRDR mutations (23 of 35). In addition, there was a statistically significant association between TMQR and two β-lactamase genes; bla CTX-M (p = 0.037) and bla TEM (p = 0.000)., Conclusion: This study suggests a high prevalence of TMQR among the quinolone-resistant E. coli and K. pneumoniae isolates causing urinary tract infection in children in this area of Nepal and an association with the carriage of ESBL gene. This is a challenge for the management of urinary infections in children. Comprehensive prospective surveillance of antimicrobial resistance in these common pathogens will be necessary to devise strategies to mitigate the emergence of further resistance., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000)., Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch., Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes., Conclusions: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies., Funding: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210])., Competing Interests: MC, ZD, DI, AA, MA, MC, KC, JC, BH, KK, MM, CP, SV, HW, AA, AA, SA, JA, PA, BB, AB, JC, Kd, AD, Jd, PD, CD, SD, ME, LF, DG, GG, MG, AG, CG, MG, RH, RH, YH, JH, OI, JI, JJ, CJ, DJ, JJ, GK, AK, AK, AK, SK, RK, RK, AL, ML, RL, SL, GM, TM, CM, AM, GN, SN, SN, TN, SN, EN, IO, SP, AP, FQ, FQ, SR, SR, DR, PR, RR, TR, JR, SS, SS, KS, MS, JS, JS, VS, JS, RS, SS, MS, AS, AS, KT, DT, AT, MT, MT, RT, NT, ST, KV, MV, BV, FW, JW, GD, SA, JK, DA, SB, KH No competing interests declared, NF NAF chairs the Wellcome Surveillance and Epidemiology of Drug Resistant Infections (SEDRIC) group, which has a focus on antimicrobial resistance. This could be perceived as relevant although not a direct conflict, IB IB has consulted to BlueDot and the NHL Players' Association, AP AJP is chair of the UK Department of Health and Social Care's (DHSC) Joint Committee on Vaccination and Immunisation (JCVI) but does not take part in the JCVI COVID-19 committee. He was a member of WHO SAGE until 2022. AJPs employer, Oxford University has entered into a partnership with AstraZeneca for development of a COVID-19 vaccine. AJP has provided advice to Shionogi & Co., Ltd on development of a COVID19 vaccine, (© 2023, Carey et al.)

Continual antibiotic prophylaxis (CAP) can reduce the risk of recurrent UTI (rUTI). However, antimicrobial resistance in subsequent UTIs is a concern. This study aimed to explore antimicrobial resistance in young children prescribed CAP for rUTIs. A retrospective review of patient records/microbiology results was undertaken for children < 2 years of age, on CAP, with 2-3 clean catch/mid-stream/supra-pubic aspirate urine cultures with a pure growth of bacteria, between January 2017 and December 2019. One hundred twenty-four urine specimens from 54 patients (26 (48%) males, median age 6 months) were analysed. CAP prescribed was trimethoprim in 37 (69%), cefalexin in 11 (29%), and nitrofurantoin in 6 (11%). Based on antimicrobial susceptibility of the index UTI within the study period, 41 patients (76%) grew organisms on urine culture classified as sensitive and 13 (24%) resistant. Thirty-five (65%) children had congenital anomaly of the kidneys and urinary tract (CAKUT); they were more likely to be in the resistant group (P = 0.032). Escherichia coli (37/54, 69%) was the commonest index uropathogen. The resistant group had a higher proportion of non-E. coli index UTI pathogens (P = 0.098). Breakthrough UTI with a CAP-resistant organism was more likely in the resistant group (P = 0.010). Age, sex, and kidney scarring on DMSA (dimercaptosuccinic acid) scan were not significantly different between groups.  Conclusion: Over a 3-year period, the proportion of children on CAP with resistant organism UTI doubled and resistant infections were more likely in children with CAKUT. Development of non-antimicrobial prophylaxis options is required. What is Known: • Recurrent urinary tract infections are common in children, particularly in those with underlying anatomical abnormalities of the kidneys and urinary tract. • Continuous antibiotic prophylaxis is used frequently in these children, however there is a lack of consensus on whether the potential benefits of CAP outweigh the harms. What is New: • This study adds further evidence towards the consequences of using continuous antibiotic prophylaxis in recurrent UTI; specifically, a 2-fold increase in antimicrobial resistance was seen in subsequent UTIs following long-term use of CAP, providing further vigour for the need for non-antibiotic alternatives., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society-USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (<1%), and thymidine analogue mutations (2%) were infrequent. Through week 144, >99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL <50 copies/mL) regardless of the presence of major RAMs. Results from the sensitivity analysis by Snapshot were consistent with the last available on-treatment VL. In TANGO, archived, pre-existing major RAMs did not impact virologic outcomes through week 144.

Patients with suspected enteric (typhoid and paratyphoid) fever are predominantly managed as outpatients in endemic regions. Nonspecific clinical presentation, lack of accurate diagnostic tools, and widespread antimicrobial resistance makes management challenging. Resistance has been described for all antimicrobials including chloramphenicol, amoxycillin, trimethoprim-sulfamethoxazole, ciprofloxacin, ceftriaxone, and azithromycin. No significant differences have been demonstrated between these antimicrobials in their ability to treat enteric fever in systematic reviews of randomized controlled trials (RCTs). Antimicrobial choice should be guided by local resistance patterns and national guidance. Extensively drug-resistant typhoid isolates require treatment with azithromycin and/or meropenem. Combining antimicrobials that target intracellular and extracellular typhoid bacteria is a strategy being explored in the Azithromycin and Cefixime in Typhoid Fever (ACT-SA) RCT, in progress in South Asia. Alternative antimicrobials, such as the oral carbapenem, tebipenem, need clinical evaluation. There is a paucity of evidence to guide the antimicrobial management of chronic fecal carriers., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Adrenal suppression is a clinically concerning side effect of inhaled corticosteroid (ICS) treatment in patients with asthma. Increased susceptibility to ICS-induced adrenal suppression has previously been identified in those with the rs591118 polymorphism in platelet-derived growth factor D (PDGFD). The mechanism underpinning this relationship is not known., Methods: H295R cells were genotyped for rs591118 using a validated Taqman PCR allelic discrimination assay. H295R cell viability was determined after treatment with beclometasone and fluticasone (range 0-330 μM). Cortisol was measured in cell culture medium using competitive enzyme immunoassay., Results: PDGFD protein expression in H295R cells was confirmed using Western blotting. When ACTH and forskolin were added to H295R cells, a reduction in PDGFD expression was seen, which was then restored by incubation with prochloraz, a known inhibitor of steroidogenesis. A dose-dependent, decrease in PDGFD expression was observed with beclometasone (over a 24 h incubation period) but not with beclometasone incubations beyond 24 h nor with fluticasone (at 24 or 48 h)., Conclusions: H295R cells express PDGFD protein, which can be modulated by incubation with steroidogenesis agonists and antagonists and additionally with exogenous beclometasone., Impact: PDGFD is expressed in the human adrenal cell line, H295R, and expression can be modulated by beclometasone as well as agonists/antagonists of steroidogenesis. This builds on previous research that identified a SNP in PDGFD (rs591118) as an independent risk factor for adrenal suppression in adults and children with obstructive airway disease treated with inhaled corticosteroids. First in vitro experiments to support a link between the PDGF and cortisol production pathways, supporting the hypothesis that PDGFD variants can affect an individual's sensitivity to corticosteroid-induced adrenal suppression., (© 2022. The Author(s).)

Background: Typhoid and paratyphoid (enteric fever) are febrile bacterial illnesses common in many low- and middle-income countries. The World Health Organization (WHO) currently recommends treatment with azithromycin, ciprofloxacin, or ceftriaxone due to widespread resistance to older, first-line antimicrobials. Resistance patterns vary in different locations and are changing over time. Fluoroquinolone resistance in South Asia often precludes the use of ciprofloxacin. Extensively drug-resistant strains of enteric fever have emerged in Pakistan. In some areas of the world, susceptibility to old first-line antimicrobials, such as chloramphenicol, has re-appeared. A Cochrane Review of the use of fluoroquinolones and azithromycin in the treatment of enteric fever has previously been undertaken, but the use of cephalosporins has not been systematically investigated and the optimal choice of drug and duration of treatment are uncertain., Objectives: To evaluate the effectiveness of cephalosporins for treating enteric fever in children and adults compared to other antimicrobials., Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, the WHO ICTRP and ClinicalTrials.gov up to 24 November 2021. We also searched reference lists of included trials, contacted researchers working in the field, and contacted relevant organizations., Selection Criteria: We included randomized controlled trials (RCTs) in adults and children with enteric fever that compared a cephalosporin to another antimicrobial, a different cephalosporin, or a different treatment duration of the intervention cephalosporin. Enteric fever was diagnosed on the basis of blood culture, bone marrow culture, or molecular tests., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcomes were clinical failure, microbiological failure and relapse. Our secondary outcomes were time to defervescence, duration of hospital admission, convalescent faecal carriage, and adverse effects. We used the GRADE approach to assess certainty of evidence for each outcome., Main Results: We included 27 RCTs with 2231 total participants published between 1986 and 2016 across Africa, Asia, Europe, the Middle East and the Caribbean, with comparisons between cephalosporins and other antimicrobials used for the treatment of enteric fever in children and adults. The main comparisons are between antimicrobials in most common clinical use, namely cephalosporins compared to a fluoroquinolone and cephalosporins compared to azithromycin. Cephalosporin (cefixime) versus fluoroquinolones Clinical failure, microbiological failure and relapse may be increased in patients treated with cefixime compared to fluoroquinolones in three small trials published over 14 years ago: clinical failure (risk ratio (RR) 13.39, 95% confidence interval (CI) 3.24 to 55.39; 2 trials, 240 participants; low-certainty evidence); microbiological failure (RR 4.07, 95% CI 0.46 to 36.41; 2 trials, 240 participants; low-certainty evidence); relapse (RR 4.45, 95% CI 1.11 to 17.84; 2 trials, 220 participants; low-certainty evidence). Time to defervescence in participants treated with cefixime may be longer compared to participants treated with fluoroquinolones (mean difference (MD) 1.74 days, 95% CI 0.50 to 2.98, 3 trials, 425 participants; low-certainty evidence). Cephalosporin (ceftriaxone) versus azithromycin Ceftriaxone may result in a decrease in clinical failure compared to azithromycin, and it is unclear whether ceftriaxone has an effect on microbiological failure compared to azithromycin in two small trials published over 18 years ago and in one more recent trial, all conducted in participants under 18 years of age: clinical failure (RR 0.42, 95% CI 0.11 to 1.57; 3 trials, 196 participants; low-certainty evidence); microbiological failure (RR 1.95, 95% CI 0.36 to 10.64, 3 trials, 196 participants; very low-certainty evidence). It is unclear whether ceftriaxone increases or decreases relapse compared to azithromycin (RR 10.05, 95% CI 1.93 to 52.38; 3 trials, 185 participants; very low-certainty evidence). Time to defervescence in participants treated with ceftriaxone may be shorter compared to participants treated with azithromycin (mean difference of -0.52 days, 95% CI -0.91 to -0.12; 3 trials, 196 participants; low-certainty evidence). Cephalosporin (ceftriaxone) versus fluoroquinolones It is unclear whether ceftriaxone has an effect on clinical failure, microbiological failure, relapse, and time to defervescence compared to fluoroquinolones in three trials published over 28 years ago and two more recent trials: clinical failure (RR 3.77, 95% CI 0.72 to 19.81; 4 trials, 359 participants; very low-certainty evidence); microbiological failure (RR 1.65, 95% CI 0.40 to 6.83; 3 trials, 316 participants; very low-certainty evidence); relapse (RR 0.95, 95% CI 0.31 to 2.92; 3 trials, 297 participants; very low-certainty evidence) and time to defervescence (MD 2.73 days, 95% CI -0.37 to 5.84; 3 trials, 285 participants; very low-certainty evidence). It is unclear whether ceftriaxone decreases convalescent faecal carriage compared to the fluoroquinolone gatifloxacin (RR 0.18, 95% CI 0.01 to 3.72; 1 trial, 73 participants; very low-certainty evidence) and length of hospital stay may be longer in participants treated with ceftriaxone compared to participants treated with the fluoroquinolone ofloxacin (mean of 12 days (range 7 to 23 days) in the ceftriaxone group compared to a mean of 9 days (range 6 to 13 days) in the ofloxacin group; 1 trial, 47 participants; low-certainty evidence)., Authors' Conclusions: Based on very low- to low-certainty evidence, ceftriaxone is an effective treatment for adults and children with enteric fever, with few adverse effects. Trials suggest that there may be no difference in the performance of ceftriaxone compared with azithromycin, fluoroquinolones, or chloramphenicol. Cefixime can also be used for treatment of enteric fever but may not perform as well as fluoroquinolones.  We are unable to draw firm general conclusions on comparative contemporary effectiveness given that most trials were small and conducted over 20 years previously. Clinicians need to take into account current, local resistance patterns in addition to route of administration when choosing an antimicrobial., (Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Diphtheria is a potentially fatal respiratory disease caused by toxigenic forms of the Gram-positive bacterium Corynebacterium diphtheriae . Despite the availability of treatments (antitoxin and antimicrobials) and effective vaccines, the disease still occurs sporadically in low-income countries and in higher income where use of diphtheria vaccine is inconsistent. Diphtheria was highly endemic in Vietnam in the 1990s; here, we aimed to provide some historical context to the circulation of erythromycin resistant organisms in Vietnam during this period. After recovering 54 C . diphtheriae isolated from clinical cases of diphtheria in Ho Chi Minh City between 1992 and 1998 we conducted whole genome sequencing and analysis. Our data outlined substantial genetic diversity among the isolates, illustrated by seven distinct Sequence Types (STs), but punctuated by the sustained circulation of ST67 and ST209. With the exception of one isolate, all sequences contained the tox gene, which was classically located on a corynebacteriophage. All erythromycin resistant isolates, accounting for 13 % of organisms in this study, harboured a novel 18 kb erm(X )-carrying plasmid, which exhibited limited sequence homology to previously described resistance plasmids in C. diphtheriae . Our study provides historic context for the circulation of antimicrobial resistant C. diphtheriae in Vietnam; these data provide a framework for the current trajectory in global antimicrobial resistance trends.

Background: Malnutrition has various adverse effects in children. This study aimed to determine risk factors for malnutrition among hospitalised children, changes in nutritional status at admission and discharge and effects of use of systematic anthropometric measurement in identification of malnutrition., Methods: We enrolled 426 children, aged between 6 months and 15 years, admitted to Siddhi Memorial Hospital, Bhaktapur, Nepal, from November 2016 to June 2017. Anthropometric measurements were performed at the time of admission and discharge. Risk factors were assessed by multivariable logistic regression models., Results: Median age of children was 26 months (IQR: 13-49), and males were 58.7%. The prevalence of wasting was 9.2% (39/426) at admission and 8.5% (36/426) at discharge. Risk factors associated with wasting at admission were ethnic minority (aOR: 3.6, 95% CI 1.2-10.8), diarrhoeal diseases (aOR = 4.0; 95% CI 1.3-11.8), respiratory diseases (aOR: 3.4, 95% CI 1.4-8.1) and earthquake damage to house (aOR = 2.6; 95% CI 1.1-6.3). Clinical observation by care providers identified only 2 out of 112 malnutrition cases at admission and 4 out of 119 cases at discharge that were detected by the systematic anthropometric measurement., Conclusions: Ethnic minority, diarrhoeal diseases, respiratory infections and house damage due to the earthquake were risk factors associated with wasting. Systematic anthropometric examination can identify significantly more malnourished children than simple observation of care providers., (© 2022. The Author(s).)

Background: Bone marrow culture (BMC) is the reference standard for typhoid fever diagnosis. We studied the additional yield of BMC over blood culture (BC) and the relationship between quantitative BMC counts and severe disease., Methods: Hospitalised Vietnamese patients with suspected typhoid fever were prospectively investigated with a BC, BMC, faecal culture and quantitative BMC counts., Results: Salmonella typhi was isolated in 195 of 231 patients: from BC and BMC in 144 (73.8%), from BMC alone in 33 (16.9%), from BC alone in 12 (6.2%) and from faeces alone in 6 (3.1%). In 167 patients the median extracellular count of S. typhi was 2.5 cfu/mL (interquartile range [IQR] 0-10) and the intracellular count was 10.5 cfu/mL (IQR 2-42) with a ratio of 1.3 bacteria/cell (IQR 0.6-2.5). The median count of intracellular bacteria in 24 patients with severe disease was 46 bacteria/cell (IQR 9-105) compared with 6.5 bacteria/cell (IQR 2-34) in 143 with non-severe disease (p=0.005). The intracellular BMC count was negatively correlated with the peripheral white cell count and positively correlated with hepatomegaly, splenomegaly, aspartate transaminase, a positive BC and the fever clearance time following treatment with azithromycin, ofloxacin or a combination of the two., Conclusions: BMC gave a moderate additional yield over BC. Intracellular BMC counts may reflect the bacterial load in typhoid fever., (© The Author(s) 2022. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Chronic carriage of S. Typhi or S. Paratyphi is an important source of enteric fever transmission. Existing guidance and treatment options for this condition are limited. This systematic review aims to assess the evidence concerning the efficacy of different antimicrobials in treating enteric fever chronic carriage., Methods: We searched major bibliographic databases using relevant keywords between 1946 and September 2021. We included all interventional studies that included patients with confirmed enteric fever chronic carriage and deployed an antimicrobial that remains in clinical practice today. Case reports and case series of under 10 patients were excluded. Two reviewers screened abstracts, selected articles for final inclusion and quality-assessed the included studies for risk of bias. Extracted data was analysed, with pooling of data and eradication rates for each antimicrobial calculated. As only one randomised controlled trial was identified, no meta-analysis was performed., Results: Of the 593 papers identified by the initial search, a total of eight studies met the inclusion criteria and were included in the systematic review. Evidence was identified for the use of fluoroquinolones and amoxicillin/ampicillin in the treatment for enteric fever chronic carriage. Fluoroquinolones were superior to amoxicillin/ampicillin with 92% of patients achieving eradication after one antimicrobial course compared to 68% (p = 0.02). The quality of included studies was poor, and all were carried out before 1990., Conclusion: This review identified fluoroquinolones and amoxicillin/ampicillin as treatment options for enteric fever chronic carriage, with fluoroquinolones the more effective option. However, this evidence pre-dates rises in antimicrobial resistance in enteric fever and therefore the significance of these findings to today's practice is unclear. Further research is needed to investigate whether these antimicrobials remain appropriate treatment options or whether alternative interventions are more effective., Competing Interests: The authors have declared that no competing interests exist.

Rabies remains a public health problem in the Philippines despite the widespread provision of rabies vaccines and rabies immunoglobulin (RIG) as post-exposure prophylaxis (PEP). Detailed descriptions of recent human rabies cases in the Philippines are scarce. This study aimed to describe the clinical, epidemiological, and spatial features of human rabies cases between January 1, 2006, and December 31, 2015. We conducted a retrospective hospital-based case record review of all patients admitted to one referral hospital in Manila who received a clinical diagnosis of rabies. During the 10-year study period there were 575 patients (average 57.5 cases per year, range 57 to 119) with a final diagnosis of rabies. Most patients were male (n = 404, 70.3%) and aged ≥ 20 years (n = 433, 75.3%). Patients mostly came from the National Capital Region (n = 160, 28.0%) and the adjacent Regions III (n = 197, 34.4%) and IV-A (n = 168, 29.4%). Case mapping and heatmaps showed that human rabies cases were continuously observed in similar areas throughout the study period. Most patients had hydrophobia (n = 444, 95.5%) and/or aerophobia (n = 432, 93.3%). The leading causative animals were dogs (n = 421, 96.3%) and cats (n = 16, 3.7%). Among 437 patients with animal exposure history, only 42 (9.6%) had been administered at least one rabies vaccine. Two patients (0.5%), young children bitten on their face, had received and a full course of rabies vaccine. Human rabies patients were continuously admitted to the hospital, with no notable decline over the study period. The geographical area in which human rabies cases commonly occurred also did not change. Few patients received PEP and there were two suspected cases of PEP failure. The retrospective design of this study was a limitation; thus, prospective studies are required., Competing Interests: The authors have declared that no competing interests exist.

Community-acquired bacterial bloodstream infections are caused by diverse pathogens with changing antimicrobial-resistance patterns. In low-middle income countries in Southeast Asia, where dengue fever is endemic and a leading cause of fever, limited information is available about bacterial bloodstream infections due to challenges of implementing a blood culture service. This study describes bacterial bloodstream pathogens and antimicrobial-resistance patterns in Metro Manila, the Philippines. We aimed to identify the proportion of patients with a positive blood culture, the bacteria isolated and their antimicrobial resistance patterns, and the clinical characteristics of these patients, in this dengue endemic area. We conducted a prospective observational study in a single hospital enrolling febrile patients clinically suspected of having a community-acquired bacterial bloodstream infection between 1st July 2015 and 30th June 2019. Each patient had a blood culture and additional diagnostic tests according to their clinical presentation. We enrolled 1315 patients and a significant positive blood culture was found in 77 (5.9%) including Staphylococcus aureus (n = 20), Salmonella enterica Typhi (n = 18), Escherichia coli (n = 16), Streptococcus pneumoniae (n = 3) and Burkholderia pseudomallei (n = 2). Thirty-four patients had meningococcal disease diagnosed by culture (n = 8) or blood PCR (n = 26). Additional confirmed diagnoses included leptospirosis (n = 177), dengue virus infection (n = 159) and respiratory diphtheria (n = 50). There were 79 (6.0%, 95%CI 4.8%-7.4%) patients who died within 28 days of enrollment. Patients with a positive blood culture were significantly more likely to die than patients with negative culture (15.2% vs 4.4%, P<0.01). Among S. aureus isolates, 11/20 (55%) were methicillin-resistant (MRSA) and ST30: USA1100 was dominant sequence type (88.9%). Antimicrobial-susceptibility was well preserved in S. enterica Typhi. Among hospitalized patients with clinically suspected community-acquired bacterial bloodstream infection in Metro Manila, the Philippines, 5.9% had a blood culture confirmed infection of whom 15.6% died. S. aureus, including a significant number of MRSA (USA1100 clones), S. enterica Typhi, E.coli and Neisseria meningitidis were frequently identified pathogens., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: An automated hematology analyzer, Sysmex XN-1000, and the related reagents were supplied to this study by Sysmex corporation. The Rapidchip PCT kit was provided by Sekisui Medical to this study. KA has received research funds from Sysmex Corporation for unrelated research. The other authors have no conflict of interest in the conduct of this study.

Deciphering the drug/virus/host interactions at infected cell reservoirs is a key leading to HIV-1 remission for which positron emission tomography (PET) imaging using radiolabeled antiretroviral (ARV) drugs is a powerful asset. Dolutegravir (DTG) is one of the preferred therapeutic options to treat HIV and can be isotopically labeled with fluorine-18. [18F]DTG was synthesized via a three-step approach of radiofluorination/nitrile reduction/peptide coupling with optimization for each step. Radiofluorination was performed on 2-fluoro-4-nitrobenzonitrile in 90% conversion followed by nitrile reduction using sodium borohydride and aqueous nickel(II) chloride with 72% conversion. Final peptide coupling reaction followed by HPLC purification and formulation afforded ready-to-inject [18F]DTG in 5.1 ± 0.8% (n = 10) decay-corrected radiochemical yield within 95 min. The whole process was automatized using a TRACERlab® FX NPro module, and quality control performed by analytical HPLC showed that [18F]DTG was suitable for in vivo injection with >99% chemical and radiochemical purity and a molar activity of 83 ± 18 GBq/µmol (n = 10). Whole-body distribution of [18F]DTG was performed by PET imaging on a healthy macaque and highlighted the elimination routes of the tracer. This study demonstrated the feasibility of in vivo [18F]DTG PET imaging and paved the way to explore drug/virus/tissues interactions in animals and humans.

Background: Acute interstitial nephritis (AIN) is an important cause of kidney injury accounting for up to 27% of unexplained renal impairment. In up to 70% of cases, drugs, including aminosalicylates, are reported as the underlying cause. Following two recent paediatric cases of suspected mesalazine induced AIN within our own department, we performed a systematic review of the literature to address the following question: In patients with inflammatory bowel disease (IBD), is interstitial nephritis associated with 5-aminosalicylate (5-ASA) treatment? Our primary objective was to identify the number of cases reported in the literature of biopsy-proven 5-ASA induced interstitial nephritis, in children and adults with IBD. We also aimed to identify which variables influence the onset, severity and recovery of 5-ASA interstitial nephritis., Methods: Embase and PubMed databases were searched from inception to 07/10/20. Search terms had three main themes: "inflammatory bowel disease", "interstitial nephritis" and "aminosalicylates". Studies were included if they reported an outcome of AIN, confirmed on biopsy, suspected to be secondary to a 5-ASA drug in those with IBD. A narrative synthesis was performed., Results: Forty-one case reports were identified. Mesalazine was the most frequently reported aminosalicylate associated with AIN (95%). The median duration of treatment before AIN was diagnosed was 2.3 years (Interquartile Range (IQR) 12-48 months). The median rise in creatinine was 3.3 times the baseline measurement (IQR 2.5-5.5). Aminosalicylate withdrawal and steroids were the most frequently used treatments. Despite treatment, 15% of patients developed end-stage renal failure., Conclusions: AIN is a serious adverse drug reaction associated with aminosalicylates, with mesalazine accounting for most reports. The current guidance of annual monitoring of renal function may not be sufficient to identify cases early. Given the severity of AIN and reports in the literature that early treatment with steroids may be beneficial, we would recommend at least 6 monthly monitoring of renal function. PROSPERO registration number CRD42020205387., (© 2022. The Author(s).)

Background: Evidence supporting personalised treatment for asthma based on an individual's genetics is mounting. The views of children and young people (CYP), parents and healthcare professionals (HCPs) about this evolution of clinical care are not known., Methods: A pilot prospective questionnaire-based study was undertaken of CYP with asthma, their parents and HCPs at a secondary/tertiary children's hospital in the UK., Results: Fifty-nine questionnaires were distributed and 50 returned (response rate 84.7%), comprising 26 CYP (10 were 5-11 years, 11 were 12-15 years and 5 were 16-18 years old), 13 parents and 11 HCPs. For all types of data, personal information was ranked as the 'most important' (n=19, 47.5%) and 'most private' (n=16, 40%), but with considerable variation across groups. Within health data, allergies were rated as 'most important' (n=12, 30.8%), and mental health records the 'most private' (n=21, 53.8%), again with variation across groups. A 'personalised genetic asthma plan' was acceptable to the majority overall (n=40, 80.0%). With regard to sharing CYP's genetic data, 23 (46%) of participants were happy for unconditional sharing between HCPs, and 23 (46%) agreed to sharing solely in relation to the CYP's asthma management. Forty-two (84.0%) of participants felt CYP should be informed about genetic data being shared, and the majority felt this should commence by 12 years of age., Conclusion: The use of genetic information to guide management of asthma in CYP is largely acceptable to CYP, parents/guardians and HCPs. However, there are key differences between the opinions of CYP, parents and HCPs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Resistance to piperacillin/tazobactam (TZP) in Escherichia coli has predominantly been associated with mechanisms that confer resistance to third-generation cephalosporins. Recent reports have identified E. coli strains with phenotypic resistance to piperacillin/tazobactam but susceptibility to third-generation cephalosporins (TZP-R/3GC-S). In this study we sought to determine the genetic diversity of this phenotype in E. coli ( n =58) isolated between 2014-2017 at a single tertiary hospital in Liverpool, UK, as well as the associated resistance mechanisms. We compare our findings to a UK-wide collection of invasive E. coli isolates ( n =1509) with publicly available phenotypic and genotypic data. These data sets included the TZP-R/3GC-S phenotype ( n =68), and piperacillin/tazobactam and third-generation cephalosporin-susceptible (TZP-S/3GC-S, n =1271) phenotypes. The TZP-R/3GC-S phenotype was displayed in a broad range of sequence types, which was mirrored in the same phenotype from the UK-wide collection, and the overall diversity of invasive E. coli isolates. The TZP-R/3GC-S isolates contained a diverse range of plasmids, indicating multiple acquisition events of TZP resistance mechanisms rather than clonal expansion of a particular plasmid or sequence type. The putative resistance mechanisms were equally diverse, including hyperproduction of TEM-1, either via strong promoters or gene amplification, carriage of inhibitor-resistant β-lactamases, and an S133G bla CTX-M-15 mutation detected for the first time in clinical isolates. Several of these mechanisms were present at a lower abundance in the TZP-S/3GC-S isolates from the UK-wide collection, but without the associated phenotypic resistance to TZP. Eleven (19%) of the isolates had no putative mechanism identified from the genomic data. Our findings highlight the complexity of this cryptic phenotype and the need for continued phenotypic monitoring, as well as further investigation to improve detection and prediction of the TZP-R/3GC-S phenotype from genomic data.

Enteric fever (EF) is an infection caused by the bacteria called Salmonella Typhi or Paratyphi. Infection is acquired through swallowing contaminated food or water. Most EF in England occurs in people returning from South Asia and other places where EF is common; catching EF in England is rare. The main symptom is fever, but stomach pain, diarrhoea, muscle aches, rash and other symptoms may occur. EF is diagnosed by culturing the bacteria from blood and/or stool in a microbiology laboratory. EF usually responds well to antibiotic treatment. Depending on how unwell the individual is, antibiotics may be administered by mouth or by injection. Over the past several years, there has been an overall increase in resistance to antibiotics used to treat enteric fever, in all endemic areas. Additionally, since 2016, there has been an ongoing outbreak of drug-resistant EF in Pakistan. This infection is called extensively drug-resistant, or XDR, EF and only responds to a limited number of antibiotics. Occasionally individuals develop complications of EF including confusion, bleeding, a hole in the gut or an infection of the bones or elsewhere. Some people may continue to carry the bacteria in their stool for a longtime following treatment for the initial illness. These people may need treatment with a longer course of antibiotics to eradicate infection. Travellers can reduce their risk of acquiring EF by following safe food and water practices and by receiving the vaccine at least a few weeks before travel. These guidelines aim to help doctors do the correct tests and treat patients for enteric fever in England but may also be useful to doctors and public health professionals in other similar countries., (Copyright © 2022. Published by Elsevier Ltd.)

Typhoid is an endemic in Fiji with increases observed since the early 2000s and frequent outbreaks reported. We assessed the diagnostic accuracy of currently available typhoid rapid diagnostic tests (RDTs) (TUBEX, Typhidot Rapid, and Test-It assay) to establish their performance against blood culture in Fiji and to examine their suitability for rapid typhoid outbreak identification. The performance of RDTs was assessed in the public health reference laboratory in Suva, Fiji, according to the manufacturers' instructions. A simulation was used to examine the potential use of RDTs for attribution of a febrile illness outbreak to typhoid. For the diagnostic evaluation, 179 patients were included; 49 had blood culture-confirmed typhoid, 76 had fever as a result of non-typhoid etiologies, and 54 were age-matched community controls. The median (interquartile range) age was 29 (20-46) years. Of the participants, 92 (51.4%) were male and 131 (73.2%) were indigenous Fijians. The sensitivities of the tests were 77.6% for TUBEX, 75.5% for Typhidot Rapid, and 57.1% for Test-It assay. The Test-It assay had the highest specificity of 93.4%, followed by Typhidot Rapid 85.5% and TUBEX 60.5%. Typhidot Rapid had the best performance in the simulation for attribution of a febrile illness outbreak to typhoid. Typhoid RDTs performed suboptimally for individual patient diagnosis due to low sensitivity and variable specificity. We demonstrate that RDTs could be useful in the field for rapid attribution of febrile illness outbreaks to typhoid. Typhidot Rapid had the best combination of sensitivity, specificity, positive and negative predictive values, cost, and ease of use for this purpose.

Background: Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia.  A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime, or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of clinically suspected and culture-confirmed typhoid fever in South Asia. Methods: This is a phase IV, international multi-center, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and cefixime 20mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg/kg/day oral dose once daily (max 1gm/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal, and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up. Discussion: Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas. Clinicaltrials.gov registration: NCT04349826 (16/04/2020)., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Giri A et al.)

Background: The clinical response to ceftriaxone in patients with typhoid fever is significantly slower than with ofloxacin, despite infection with Salmonella enterica serovar Typhi (S. Typhi) isolates with similar susceptibilities (MIC 0.03-0.12 mg/L). The response to ofloxacin is slower if the isolate has intermediate susceptibility (MIC 0.25-1.0 mg/L)., Objectives: To determine the bactericidal activity and post-antibiotic effect (PAE) of ceftriaxone and ofloxacin against S. Typhi., Methods: The mean time to reach a 99.9% reduction in log10 count (bactericidal activity) and PAE of ceftriaxone and ofloxacin were determined for 18 clinical isolates of S. Typhi in time-kill experiments (MIC range for ofloxacin 0.06-1.0 mg/L and for ceftriaxone 0.03-0.12 mg/L)., Results: The mean (SD) bactericidal activity of ofloxacin was 33.1 (15.2) min and 384.4 (60) min for ceftriaxone. After a 30 min exposure to ofloxacin, the mean (SD) duration of PAE was 154.7 (52.6) min. There was no detectable PAE after 1 h of exposure to ceftriaxone. For ofloxacin, bactericidal activity and PAE did not significantly differ between isolates with full or intermediate susceptibility provided ofloxacin concentrations were maintained at 4×MIC., Conclusions: Infections with S. Typhi with intermediate ofloxacin susceptibility may respond to doses that maintain ofloxacin concentrations at 4×MIC at the site of infection. The slow bactericidal activity of ceftriaxone and absent PAE may explain the slow clinical response in typhoid., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background: Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia.  A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of typhoid fever in South Asia. Methods: This is a phase IV, international multi-centre, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomised to one of the two interventions: Arm A: azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and cefixime 20mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg/kg/day oral dose once daily (max 1gm/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up. Discussion: Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial's activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas. Clinicaltrials.gov registration: NCT04349826 (16/04/2020)., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Giri A et al.)

Identification of the causative pathogen in infectious diseases is important for surveillance and to guide treatment. In low- and middle-income countries (LMIC), conventional culture and identification methods, including biochemical methods, are reference-standard. Biochemical methods can lack sensitivity and specificity and have slow turnaround times, causing delays in definitive therapy. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) is a rapid and accurate diagnostic method. Most studies comparing MALDI-TOF MS and biochemical methods are from high-income countries, with few reports from LMIC with tropical climates. The aim of this study was to assess the performance of MALDI-TOF MS compared to conventional methods in the Philippines. Clinical bacterial or fungal isolates were identified by both MALDI-TOF MS and automated (VITEK2) or manual biochemical methods in the San Lazaro Hospital, Metro Manila, the Philippines. The concordance between MALDI-TOF MS and automated (VITEK2) or manual biochemical methods was analyzed at the species and genus levels. In total, 3530 bacterial or fungal isolates were analyzed. The concordance rate between MALDI-TOF MS and biochemical methods was 96.2% at the species level and 99.9% at the genus level. Twenty-three isolates could not be identified by MALDI-TOF MS. In this setting, MALDI-TOF MS was accurate compared with biochemical methods, at both the genus and the species level. Additionally, MALDI-TOF MS improved the turnaround time for results. These advantages could lead to improved infection management and infection control in low- and middle-income countries, even though the initial cost is high.

We report the complete genome sequencing and annotation of four Salmonella enterica serovar Enteritidis isolates, two that are representative of the Central/Eastern African clade (CP255 and D7795) and two of the Global Epidemic clade (A1636 and P125109)., (Copyright © 2021 Perez-Sepulveda et al.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Background: Diphtheria is a vaccine-preventable disease that persists as a global health problem. An understanding of the pattern of disease is lacking in low- and middle-income countries such as the Philippines., Methods: We conducted a retrospective review of the clinical, microbiological, and epidemiological features of patients admitted with a clinical diagnosis of diphtheria to an infectious disease referral hospital in Metro Manila, the Philippines, between 2006 and 2017. Cases were mapped and the distribution was compared with population density. Corynebacterium diphtheriae isolates from between 2015 and 2017 were examined by multilocus sequence typing (MLST)., Results: We studied 267 patients (range:12-54 cases/year) admitted between 2006 and 2017. The case fatality rate (CFR) was 43.8% (95% confidence interval, 37.8-50.0%). A higher number of cases and CFR was observed among children <10 years. Mortality was associated with a delayed admission to hospital and a lack of diphtheria antitoxin. Between 2015 and 2017 there were 42 laboratory-confirmed cases. We identified 6 multilocus sequence types (STs). ST-302 was the most common (17/34, 48.6%), followed by ST67 (7/34, 20%) and ST458 (5/34, 14%). Case mapping showed a wide distribution of diphtheria patients in Metro Manila. Higher case numbers were found in densely populated areas but with no apparent clustering of ST types., Conclusions: Our analysis indicates that diphtheria remains endemic in Metro Manila and that the infection is frequently fatal in young children. Improved vaccine coverage and a sustainable supply of diphtheria antitoxin should be prioritized., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Approximately 6% of children hospitalized with severe falciparum malaria in Africa are also bacteremic. It is therefore recommended that all children with severe malaria should receive broad-spectrum antibiotics in addition to parenteral artesunate. Empirical antibiotics are not recommended currently for adults with severe malaria., Methods: Blood cultures were performed on sequential prospectively studied adult patients with strictly defined severe falciparum malaria admitted to a single referral center in Vietnam between 1991 and 2003., Results: In 845 Vietnamese adults with severe falciparum malaria admission blood cultures were positive in 9 (1.07%: 95% confidence interval [CI], .37-1.76%); Staphylococcus aureus in 2, Streptococcus pyogenes in 1, Salmonella Typhi in 3, Non-typhoid Salmonella in 1, Klebsiella pneumoniae in 1, and Haemophilus influenzae type b in 1. Bacteremic patients presented usually with a combination of jaundice, acute renal failure, and high malaria parasitemia. Four bacteremic patients died compared with 108 (12.9%) of 836 nonbacteremic severe malaria patients (risk ratio, 3.44; 95% CI, 1.62-7.29). In patients with >20% parasitemia the prevalence of concomitant bacteremia was 5.2% (4/76; 95% CI, .2-10.3%) compared with 0.65% (5/769; 0.08-1.2%) in patients with <20% parasitemia, a risk ratio of 8.1 (2.2-29.5)., Conclusions: In contrast to children, the prevalence of concomitant bacteremia in adults with severe malaria is low. Administration of empirical antibiotics, in addition to artesunate, is warranted in the small subgroup of patients with very high parasitemias, emphasizing the importance of quantitative blood smear microscopy assessment, but it is not indicated in most adults with severe falciparum malaria., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background and Objectives: Treatment guidelines do not recommend antibiotic use for acute respiratory infections (ARI), except for streptococcal pharyngitis/tonsillitis and pneumonia. However, antibiotics are prescribed frequently for children with ARI, often in absence of evidence for bacterial infection. The objectives of this study were 1) to assess the appropriateness of antibiotic prescriptions for mild ARI in paediatric outpatients in relation to available guidelines and detected pathogens, 2) to assess antibiotic use on presentation using questionnaires and detection in urine 3) to assess the carriage rates and proportions of resistant intestinal Enterobacteriaceae before, during and after consultation., Materials and Methods: Patients were prospectively enrolled in Children's Hospital 1, Ho Chi Minh City, Vietnam and diagnoses, prescribed therapy and outcome were recorded on first visit and on follow-up after 7 days. Respiratory bacterial and viral pathogens were detected using molecular assays. Antibiotic use before presentation was assessed using questionnaires and urine HPLC. The impact of antibiotic usage on intestinal Enterobacteriaceae was assessed with semi-quantitative culture on agar with and without antibiotics on presentation and after 7 and 28 days., Results: A total of 563 patients were enrolled between February 2009 and February 2010. Antibiotics were prescribed for all except 2 of 563 patients. The majority were 2nd and 3rd generation oral cephalosporins and amoxicillin with or without clavulanic acid. Respiratory viruses were detected in respiratory specimens of 72.5% of patients. Antibiotic use was considered inappropriate in 90.1% and 67.5%, based on guidelines and detected pathogens, respectively. On presentation parents reported antibiotic use for 22% of patients, 41% of parents did not know and 37% denied antibiotic use. Among these three groups, six commonly used antibiotics were detected with HPLC in patients' urine in 49%, 40% and 14%, respectively. Temporary selection of 3rd generation cephalosporin resistant intestinal Enterobacteriaceae during antibiotic use was observed, with co-selection of resistance to aminoglycosides and fluoroquinolones., Conclusions: We report overuse and overprescription of antibiotics for uncomplicated ARI with selection of resistant intestinal Enterobacteriaceae, posing a risk for community transmission and persistence in a setting of a highly granular healthcare system and unrestricted access to antibiotics through private pharmacies., Registration: This study was registered at the International Standard Randomised Controlled Trials Number registry under number ISRCTN32862422: http://www.isrctn.com/ISRCTN32862422., Competing Interests: The authors have declared that no competing interests exist.

A phenotype of Escherichia coli and Klebsiella pneumoniae, resistant to piperacillin/tazobactam (TZP) but susceptible to carbapenems and 3rd generation cephalosporins, has emerged. The resistance mechanism associated with this phenotype has been identified as hyperproduction of the β-lactamase TEM. However, the mechanism of hyperproduction due to gene amplification is not well understood. Here, we report a mechanism of gene amplification due to a translocatable unit (TU) excising from an IS26-flanked pseudo-compound transposon, PTn6762, which harbours bla TEM-1B . The TU re-inserts into the chromosome adjacent to IS26 and forms a tandem array of TUs, which increases the copy number of bla TEM-1B, leading to TEM-1B hyperproduction and TZP resistance. Despite a significant increase in bla TEM-1B copy number, the TZP-resistant isolate does not incur a fitness cost compared to the TZP-susceptible ancestor. This mechanism of amplification of bla TEM-1B is an important consideration when using genomic data to predict susceptibility to TZP.

Background: The Philippines is a high TB and multidrug-resistant TB burden country. Although the scale-up of GeneXpert testing is occurring, the benefits of universal Xpert-Mycobacterium tuberculosis/ rifampicin (MTB/RIF) testing in inpatients have not been documented., Methods: Routine GeneXpert testing irrespective of priority criteria for testing was conducted within a prospective cohort of all adults with known or presumptive TB admitted to a tertiary infectious diseases hospital in Manila. Study-specific TB diagnosis was decided upon bacteriological results, chest x-ray assessment, if already on anti-TB treatment (ATT) at admission and a cough duration of ≥2 wk., Results: Of submitted sputum samples, 87.1% (277/318) had valid acid-fast bacilli (AFB) microscopy and Xpert® MTB/RIF results. Xpert® MTB/RIF was positive in 97.7% (n = 87/89) of AFB-positive patients and 25.5% (n = 48/188) of AFB-negative patients. Bacteriological confirmation in smear negative cases not on ATT prior to admission was 25.2% (34/135). Rifampicin resistance was detected in 26/135 Xpert positive cases (19.3%), including nine who might not otherwise have been detected, representing a 53% increase in yield., Conclusion: Universal GeneXpert testing in this setting enhanced the yield of bacterial confirmation, revealing a high incidence of rifampicin resistance and suggesting a need for further investigations in Xpert-negative/smear-positive patients who may not have mycobacterial TB., (© The Author(s) 2020. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: The emergence of multidrug-resistant (MDR) and extended-spectrum beta-lactamase (ESBL)-producing uropathogens has complicated the treatment of urinary tract infections (UTI). Paediatric UTI is a common illness, which if not treated properly, may lead to acute and long-term complications, such as renal abscess, septicaemia, and renal scarring. This study aimed to determine the prevalence of MDR and ESBL-producing uropathogens among children., Methods: During the study period (April 2017-April 2018), midstream urine samples were collected following aseptic procedures from children < 16 years in Siddhi Memorial Hospital. Standard culture and biochemical tests were performed to identify uropathogens and antimicrobial susceptibility test was done by modified Kirby-Bauer disc diffusion method following Clinical and Laboratory Standard Institute (CLSI) guidelines. ESBL-producing uropathogens were screened by ceftazidime (30 μg) and cefotaxime (30 μg) discs, and confirmed by the combination disc tests: ceftazidime + clavulanic acid (30/10 μg) or cefotaxime + clavulanic acid (30/10 μg) as recommended by CLSI., Results: We processed 5545 non-repeated urine samples from the children with symptoms of UTI. A significant growth of uropathogens was observed in 203 samples (3.7%). The median age of the children was 24 months (interquartile range (IQR), 12-53 months). Escherichia coli ( n = 158, 77.8%) and Klebsiella pneumoniae ( n = 30, 14.8%) were common among the uropathogens. Among them, 80.3% were resistant to amoxycillin and 51.2% were resistant to cotrimoxazole. Most of them were susceptible to amikacin, nitrofurantoin, and ofloxacin. MDR was detected in 34.5% ( n = 70/203) and ESBL producers in 24.6% ( n = 50/203) of them. The proportion of MDR isolates was higher in children < 5 years ( n = 59/153, 38.6%) than children ≥ 5 years ( n = 11/50, 22%) ( P = 0.03)., Conclusions: Nitrofurantoin, ofloxacin, and amikacin can be used for the empirical treatment for UTI in children in Bhaktapur, Nepal. MDR and ESBL-producing uropathogens are prevalent; this warrants a continuous surveillance of antimicrobial resistance., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: The nutritional status of children may deteriorate after natural disasters such as earthquakes. A 7.8 Richter scale earthquake struck Nepal in 2015 that affected 1.1 million children. Children whose homes were destroyed and had to live in temporary shelters were at risk of malnutrition. With the support of Nagasaki University School of Tropical Medicine and Global Health (TMGH) and Siddhi Memorial Hospital (SMH), we conducted a nutritional survey of under-5 children living in temporary shelters in Bhaktapur Municipality in 2015 immediately after the earthquake and a follow-up survey in 2017., Results: We found 591 under-5 children living in 22 temporary shelters in 2015. A total of 285 children were followed up and re-assessed in 2017. In a paired analysis ( n = 285), the prevalence of underweight children increased from 10.9% in 2015 to 14.0% in 2017 ( P < 0.001), stunting increased from 26.7 to 31.9% ( P = 0.07), and wasting decreased from 4.2 to 2.5% ( P = 0.19)., Conclusions: Children who lived in temporary shelters after the 2015 Nepal earthquake might be at increased risk of a deterioration in nutritional status., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Experimental murine models and human challenge studies of Salmonella Typhi infection have suggested that the gut microbiome plays an important protective role against the development of typhoid fever. Anaerobic bacterial communities have been hypothesized to mediate colonization resistance against Salmonella species by producing short-chain fatty acids, yet the composition and function of the intestinal microbiota in human patients with typhoid fever remain ill defined., Methods: We prospectively collected fecal samples from 60 febrile patients admitted to Chittagong Medical College Hospital, Bangladesh, with typhoid fever or nontyphoidal febrile illness and from 36 healthy age-matched controls. The collected fecal samples were subjected to 16s rRNA sequencing followed by targeted metabolomics analysis., Results: Patients with typhoid fever displayed compositional and functional disruption of the gut microbiota compared with patients with nontyphoidal febrile illness and healthy controls. Specifically, typhoid fever patients had lower microbiota richness and alpha diversity and a higher prevalence of potentially pathogenic bacterial taxa. In addition, a lower abundance of short-chain fatty acid-producing taxa was seen in typhoid fever patients. The differences between typhoid fever and nontyphoidal febrile illness could not be explained by a loss of colonization resistance after antibiotic treatment, as antibiotic exposure in both groups was similar., Conclusions: his first report on the composition and function of the gut microbiota in patients with typhoid fever suggests that the restoration of these intestinal commensal microorganisms could be targeted using adjunctive, preventive, or therapeutic strategies., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI., Methods: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022., Findings: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84)., Interpretation: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients., Funding: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The ultimate goal of pharmacogenomics is to understand how the effects of interindividual genetic variation impact on the response of patients to treatments and in turn optimise those treatments while minimising potential side effects. This review article provides a brief overview of pharmacogenomics, focusing on the methods used to understand how genes of interest are identified, how pharmacogenomics is currently used within paediatric clinical practice within the UK, potential areas for future use and some of the caveats specific to paediatric medicine., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The treatment of enteric fever is complicated by the emergence of antimicrobial resistant Salmonella Typhi. Azithromycin is commonly used for first-line treatment of uncomplicated enteric fever, but the response to treatment may be sub-optimal in some patient groups when compared with fluoroquinolones., Methods: We performed an analysis of responses to treatment with azithromycin (500mg once-daily, 14 days) or ciprofloxacin (500mg twice-daily, 14 days) in healthy UK volunteers (18-60 years) enrolled into two Salmonella controlled human infection studies. Study A was a single-centre, open-label, randomised trial. Participants were randomised 1:1 to receive open-label oral ciprofloxacin or azithromycin, stratified by vaccine group (Vi-polysaccharide, Vi-conjugate or control Men-ACWY vaccine). Study B was an observational challenge/re-challenge study, where participants were randomised to challenge with Salmonella Typhi or Salmonella Paratyphi A. Outcome measures included fever clearance time, blood-culture clearance time and a composite measure of prolonged treatment response (persistent fever ≥38.0°C for ≥72 hours, persistently positive S. Typhi blood cultures for ≥72 hours, or change in antibiotic treatment). Both trials are registered with ClinicalTrials.gov (NCT02324751 and NCT02192008)., Findings: In 81 participants diagnosed with S. Typhi in two studies, treatment with azithromycin was associated with prolonged bacteraemia (median 90.8 hours [95% CI: 65.9-93.8] vs. 20.1 hours [95% CI: 7.8-24.3], p<0.001) and prolonged fever clearance times <37.5°C (hazard ratio 2.4 [95%CI: 1.2-5.0]; p = 0.02). Results were consistent when studies were analysed independently and in a sub-group of participants with no history of vaccination or previous challenge. A prolonged treatment response was observed significantly more frequently in the azithromycin group (28/52 [54.9%]) compared with the ciprofloxacin group (1/29 [3.5%]; p<0.001). In participants treated with azithromycin, observed systemic plasma concentrations of azithromycin did not exceed the minimum inhibitory concentration (MIC), whilst predicted intracellular concentrations did exceed the MIC. In participants treated with ciprofloxacin, the observed systemic plasma concentrations and predicted intracellular concentrations of ciprofloxacin exceeded the MIC., Interpretation: Azithromycin at a dose of 500mg daily is an effective treatment for fully sensitive strains of S. Typhi but is associated with delayed treatment response and prolonged bacteraemia when compared with ciprofloxacin within the context of a human challenge model. Whilst the cellular accumulation of azithromycin is predicted to be sufficient to treat intracellular S. Typhi, systemic exposure may be sub-optimal for the elimination of extracellular circulating S. Typhi. In an era of increasing antimicrobial resistance, further studies are required to define appropriate azithromycin dosing regimens for enteric fever and to assess novel treatment strategies, including combination therapies., Trial Registration: ClinicalTrials.gov (NCT02324751 and NCT02192008)., Competing Interests: AJP chairs the UK Department of Health’s (DH) Joint Committee on Vaccination and Immunisation (JCVI) and the European Medicines Agency Scientific Advisory Group on Vaccines, and is a member of the World Health Organization’s (WHO) Strategic Advisory Group of Experts. The views expressed in this manuscript are those of the authors and do not necessarily reflect the views of the JCVI, the DH, or the WHO. All other authors declare no conflicts of interest.

Background: Typhoid fever is endemic in Fiji. We sought to describe the epidemiology, clinical features and case fatality risk of blood culture-confirmed typhoid fever from January 2014 through December 2015., Methods: Blood culture-positive patients were identified from a typhoid surveillance line list. A standardised case investigation form was used to record data from patients' medical records., Results: Of 542 patients, 518 (95.6%) were indigenous Fijians (iTaukei) and 285 (52.6%) were male. The median (IQR) age was 25 (16-38) y. Mean (SD) time from the onset of illness to admission was 11.1 (6.9) d. Of 365 patients with clinical information, 346 (96.9%) had fever, 239 (66.9%) diarrhoea, 113 (33.5%) vomiting, and 72 (30.2%) abdominal pain. There were 40 (11.0%) patients with complications, including 17 (4.7%) with shock, and 11 (3.0%) with hepatitis. Nine patients died for a case fatality risk of 1.7%. Of the 544 Salmonella Typhi isolates tested, none were resistant to first line antimicrobials; 3(0.8%) were resistant to ciprofloxacin and 5(1.4%) to nalidixic acid., Conclusions: In Fiji, most blood culture-confirmed typhoid fever cases were in young adults. Common clinical manifestations were fever and gastrointestinal symptoms. Further studies are required to elucidate the factors associated with complications and death., (© The Author(s) 2019. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)