Search

Background:The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. Methods:In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. Findings:156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30–44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3(IQR 349–828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2–9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. Interpretation:Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital.

BackgroundEnvironmental water samples are increasingly recognised as an important reservoir of antimicrobial resistance (AMR) genes. Polymerase chain reaction (PCR) and next generation sequencing (NGS) offer a potentially inclusive surveillance platform for a wide range of AMR genes. However, molecular methods are dependent upon the extraction of DNA of high yield and quality. Current options for DNA extraction from complex environmental matrices for downstream molecular applications are either expensive or low yielding. We present here a novel magnetic bead-based DNA extraction method, for the detection of antimicrobial resistance genes (ARGs) from river water in Malawi, named MagnaExtract. MethodsMagnaExtract involves initial filtration of 250ml freshwater, followed by an overnight incubation of the filter in 15ml buffered peptone water (BPW), common procedure in microbiology laboratories. 200{micro}l is then taken for a boil (95{degrees}C) and spin step and mixed with magnetic beads to bind DNA. Following washes with ethanol, the DNA is eluted in nuclease-free water. To determine the effectiveness of this method, 98 freshwater samples were collected from two rivers in Southern Malawi, and DNA was isolated using the MagnaExtract method, two commercial Qiagen (Germany) kits; PowerWater and DNeasy Blood and tissue, alongside a boil and spin of BPW, and a boil and spin from bacterial isolate grown on agar media. All samples were screened with a high-resolution melt (HRM) PCR panel previously validated for the detection of third generation cephalosporin and carbapenem ARGs. We compared the DNA yield obtained using all extraction methods, as well as the identification of each ARG. ResultsDNA yield using MagnaExtract was statistically greater than both boil and spin methods and DNeasy Blood & Tissue (Qiagen, Germany). DNA yield was slightly lower than using PowerWater (Qiagen) but the difference was not statistically significant. MagnaExtract was the only method to identify ARGs in all 98 water samples compared with PowerWater (n=82), DNeasy (n=95) boilate of BPW (n=75) and boilate of bacterial isolate (n=87). The most commonly detected ARG was OXA-48 (n=93). In addition, we found overnight incubation in non-selective enrichment broth (BPW) to promote the growth of bacteria harbouring extended spectrum beta lactamase (ESBL) genes and reduction in the detection of carbapenemase genes. ConclusionThe MagnaExtract approach offers a simple, affordable, high yielding DNA extraction method for the detection of ARGs isolated from river water samples.

BackgroundSub-Saharan Africa has the highest estimated death rate attributable to antimicrobial resistance, especially from extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E). However, the dynamics of human colonization in the community with ESBL-E are not well described. Inadequate water, sanitation, and hygiene infrastructure and associated behaviors are believed to play an important role in transmission of ESBL-E, and an improved understanding of the temporal dynamics of within-household transmission could help inform the design of future policies.MethodsIn this 18-month study, using microbiological data and household surveys, we built a multivariable hierarchical harmonic logistic regression model to identify risk factors for colonization with ESBL-producing Escherichia coli and Klebsiella pneumoniae, reflecting household structure and temporal correlation of colonization status.ResultsBeing male was associated with a lower risk of colonization with ESBL-producing E. coli (odds ratio [OR], 0.786; credible interval [CrI], .678–.910), whereas the use of a tube well or a borehole was associated with an increased risk (OR, 1.550; CrI, 1.003–2.394). For ESBL-producing K. pneumoniae, recent antibiotic exposure increased risk of colonization (OR, 1.281; CrI, 1.049–1.565), whereas sharing plates decreased that risk (OR, 0.672; CrI, .460–.980). Finally, the temporal correlation range of 8 to 11 weeks provided evidence that within-household transmission occurs within this time frame.ConclusionsWe describe different risks for colonization with different enteric bacterial species. Our findings suggest interventions to reduce transmission targeted at the household level need to focus on improving water, sanitation, and hygiene infrastructure and associated behaviors, whereas at the community level, they should focus on both environmental hygiene and antibiotic stewardship.

Background: Bloodstream infections caused by Enterobacterales show high frequency of antimicrobial resistance (AMR) in many Low- and Middle-Income Countries. We aimed to describe the variation in circumstances for management of such resistant infections in a group of African public-sector hospitals participating in a major research study. Methods: We gathered data from eight hospitals across sub-Saharan Africa to describe hospital services, infection prevention and antibiotic stewardship activities, using two WHO-generated tools. We collected monthly cross-sectional data on availability of antibiotics in the hospital pharmacies for bloodstream infections caused by Enterobacterales.We compared the availability of these antibiotics to actual patient-level use of antibiotics in confirmed Enterobacterales bloodstream infections (BSI). Results: Hospital circumstances for institutional management of resistant BSI varied markedly. This included self-evaluated infection prevention level (WHO-IPCAF score: median 428, range 155 to 687.5) and antibiotic stewardship activities (WHO stewardship toolkit questions: median 14.5, range 2 to 23). These results did not correlate with national income levels. Across all sites, ceftriaxone and ciprofloxacin were the most consistently available antibiotic agents, followed by amoxicillin, co-amoxiclav, gentamicin and co-trimoxazole. There was substantial variation in the availability of some antibiotics, especially carbapenems, amikacin and piperacillin-tazobactam with degree of access linked to national income level. Investigators described out-of-pocket payments for access to additional antibiotics at 7/8 sites. The in-pharmacy availability of antibiotics correlated well with actual use of antibiotics for treating BSI patients. Conclusion: There was wide variation between these African hospitals for a range of important circumstances relating to treatment and control of severe bacterial infections, though these did not all correspond to national income level. For the majority of antibiotics and hospitals, patient-level use reflected local in-hospital drug availability, suggesting external sourcing of antibiotics was relatively infrequent. Antimicrobial resistant bacterial infections could plausibly show different clinical impacts across sub-Saharan Africa due to this contextual variation. More estimates of the impact of AMR are needed from countries of different income levels to account for these differences.

BackgroundLow- and middle-income countries (LMICs) have high morbidity and mortality from drug-resistant infections, especially from enteric bacteria such as Escherichia coli. LMICs have varying infrastructure and services in the community to separate people from human and animal waste, creating risks for ESBL-Enterobacterales (ESBL-E) transmission. Limited data exist from Southern Africa on the prevalence of ESBL-E the community.Methods and findingsIn this longitudinal cohort study we took a one-health approach to investigating prevalence and distribution of ESBL-E in urban, peri-urban and rural Malawian households between May 2018 and October 2020. We described human health, antibiotic usage (ABU), health seeking behaviour, structural and behavioural environmental health practices, and animal husbandry at these households. In parallel, human and animal stool and diverse environmental samples were collected and cultured to identify presence of ESBL E. coli and ESBL K. pneumoniae. Univariable and multivariable analysis was performed to determine associations with human ESBL-E colonisation.We recruited 300 households, totalling 841 visits, and a paucity of environmental health infrastructure and materials for safe sanitation was noted across all sites. In total, 11,975 samples were cultured and ESBL-E were isolated from 41.8% (n=1190) of human stool and 29.8% (n=290) of animal stool samples. Animal species with particularly high rates of ESBL-E colonisation included pigs (56.8%, n=21) poultry (32.5%, n=148) and dogs (58.8% n= 30). ESBL-E were isolated from 66.2% (n=339) of river water samples and 46.0% (n=138) of drain samples. Urban areas had greater ESBL-E contamination of food, household surfaces, floors and the external environment, alongside the highest rates of ESBL-E colonisation in humans (47.1%, n=384) and animals (55.1%, n=65). Multivariable models illustrated that human ESBL E. coli colonisation was associated with the wet season (aOR = 1.66, 95%CrI: 1.38-2.00), living in urban areas (aOR = 2.01, 95%CrI: 1.26-3.24), advanced age (aOR = 1.14, 95%CrI: 1.05-1.24) and in households where animals were observed interacting with food (aOR = 1.62, 95%CrI: 1.17-2.28) or kept inside (aOR = 1.58, 95%CrI: 1.00-2.43). Human ESBL K. pneumoniae colonisation was also associated with the wet season (aOR = 2.23, 95%CrI: 1.63-2.76.ConclusionWe identified extremely high levels of ESBL-E colonisation in humans and animals and contamination of the environment in Southern Malawi. Urbanisation and season are key risks for ESBL-E colonisation, perhaps reflecting environmental contamination as toilets overflow in high population density areas in heavy rains in the wet season. Without adequate efforts to improve environmental health, ESBL transmission is likely to persist in this setting.

BackgroundAntimicrobial resistance (AMR) represents an important threat to achieving the sustainable development goals in Sub-Saharan Africa (sSA). sSA is reported to have the highest estimated death rate attributable to AMR, with Extended-Spectrum Beta-Lactamase-producing Enterobacterales, such as Klebsiella pneumoniae and Escherichia coli, representing the greatest challenge. However, the dynamics of human colonisation with such bacteria in the sSA community setting are not well known. Inadequate water, sanitation and hygiene (WASH) infrastructure and associated behaviours are thought to play an important role in transmission of AMR-bacteria, and an improved understanding of the temporal dynamics of within-household transmission could help inform the design of public health policies that interrupt transmission of AMR-bacteria.Methods and FindingsIn this 18-month study, individuals from households in diverse areas of Southern Malawi were recruited and human stool samples were longitudinally collected. Using microbiological data and household surveys, we built a multivariable hierarchical harmonic logistic regression model to identify risk factors for colonisation with ESBL-producing E. coli and K. pneumoniae, reflecting household structure and temporal correlation of colonisation status between timepoints.Important risk factors were identified, with men having a lower risk of becoming colonised with ESBL-producing E. coli (OR 0.786 CrI[0.678-0.910]) and the use of a tube well or a borehole as a water drinking source highly increasing the risk of becoming colonised (OR 1.550 CrI[1.003-2.394]). Coming into contact with standing water also appeared to be negatively associated with colonisation status (OR 0.749 CrI[0.574-0.978]). For ESBL-producing K. pneumoniae, having recently taken a course of antibiotics increased the risk of being colonised (OR 1.281 CrI[1.049-1.565]). We also found a negative association between eating from shared plates and colonisation with ESBL-producing K. pneumoniae (OR 0.672 CrI[0.460-0.980]). Finally, we detected a temporal correlation range of eight to eleven weeks, providing evidence that within-household transmission occurs within this time frame.ConclusionsWe suggest that interventions aimed at preventing transmission might have the best impact when targeted at the household-level and focused on a combination of improving WASH infrastructure and modifying associated behaviours. Additionally, we showed that antibiotic use is important when looking at colonisation with ESBL-producing K. pneumoniae and therefore infection prevention and control measures and antibiotic use and stewardship training could help in reducing transmission.

Background: Bloodstream infections caused by Enterobacterales show high frequency of antimicrobial resistance (AMR) in many Low- and Middle-Income Countries. We aimed to describe the variation in circumstances for management of such resistant infections in public-sector hospitals across sub-Saharan Africa. Methods: We gathered data from eight hospitals across sub-Saharan Africa to describe hospital services, infection prevention and antibiotic stewardship activities, using two WHO-generated tools. We collected monthly cross-sectional data on availability of antibiotics in the hospital pharmacies for bloodstream infections caused by Enterobacterales. Results: Hospital circumstances for institutional management of resistant BSI varied markedly. This included self-evaluated infection prevention level (WHO-IPCAF score: median 428, range 155 to 687.5) and antibiotic stewardship activities (WHO stewardship toolkit questions: median 14.5, range 2 to 23). These results did not correlate with national income levels. Across all sites, ceftriaxone and ciprofloxacin were the most consistently available antibiotic agents, followed by amoxicillin, co-amoxiclav, gentamicin and co-trimoxazole. There was substantial variation in the availability of some antibiotics, especially carbapenems, amikacin and piperacillin-tazobactam with degree of access linked to national income level. Investigators described out-of-pocket payments for access to additional antibiotics at 7/8 sites. Conclusion: There was wide variation between these African hospitals for a range of important circumstances relating to treatment and control of severe bacterial infections, though these did not all correspond to national income level. Antimicrobial resistant bacterial infections could plausibly show different clinical impacts across sub-Saharan Africa due to this contextual variation. More estimates of the impact of AMR are needed from countries of different income levels to account for these differences.

Background Linezolid was recently re‐classified as a Group A drug by the World Health Organization (WHO) for treatment of multi‐drug resistant tuberculosis (MDR‐TB) and extensively drug‐resistant tuberculosis (XDR‐TB), suggesting that it should be included in the regimen for all patients unless contraindicated. Linezolid use carries a considerable risk of toxicity, with the optimal dose and duration remaining unclear. Current guidelines are mainly based on evidence from observational non‐comparative studies. Objectives To assess the efficacy of linezolid when used as part of a second‐line regimen for treating people with MDR and XDR pulmonary tuberculosis, and to assess the prevalence and severity of adverse events associated with linezolid use in this patient group. Search methods We searched the following databases: the Cochrane Infectious Diseases Specialized Register; CENTRAL; MEDLINE; Embase; and LILACS up to 13 July 2018. We also checked article reference lists and contacted researchers in the field. Selection criteria We included studies in which some participants received linezolid, and others did not. We included randomized controlled trials (RCTs) of linezolid for MDR and XDR pulmonary tuberculosis to evaluate efficacy outcomes. We added non‐randomized cohort studies to evaluate adverse events. Primary outcomes were all‐cause and tuberculosis‐associated death, treatment failure, and cure. Secondary outcomes were treatment interrupted, treatment completed, and time to sputum culture conversion. We recorded frequency of all and serious adverse events, adverse events leading to drug discontinuation or dose reduction, and adverse events attributed to linezolid, particularly neuropathy, anaemia, and thrombocytopenia. Data collection and analysis Two review authors (BS and DC) independently assessed the search results for eligibility and extracted data from included studies. All review authors assessed risk of bias using the Cochrane ‘Risk of bias' tool for RCTs and the ROBINS‐I tool for non‐randomized studies. We contacted study authors for clarification and additional data when necessary. We were unable to perform a meta‐analysis as one of the RCTs adopted a study design where participants in the study group received linezolid immediately and participants in the control group received linezolid after two months, and therefore there were no comparable data from this trial. We deemed meta‐analysis of non‐randomized study data inappropriate. Main results We identified three RCTs for inclusion. One of these studies had serious problems with allocation of the study drug and placebo, so we could not analyse data for intervention effect from it. The remaining two RCTs recruited 104 participants. One randomized 65 participants to receive linezolid or not, in addition to a background regimen; the other randomized 39 participants to addition of linezolid to a background regimen immediately, or after a delay of two months. We included 14 non‐randomized cohort studies (two prospective, 12 retrospective), with a total of 1678 participants. Settings varied in terms of income and tuberculosis burden. One RCT and 7 out of 14 non‐randomized studies commenced recruitment in or after 2009. All RCT participants and 38.7% of non‐randomized participants were reported to have XDR‐TB. Dosing and duration of linezolid in studies were variable and reported inconsistently. Daily doses ranged from 300 mg to 1200 mg; some studies had planned dose reduction for all participants after a set time, others had incompletely reported dose reductions for some participants, and most did not report numbers of participants receiving each dose. Mean or median duration of linezolid therapy was longer than 90 days in eight of the 14 non‐randomized cohorts that reported this information. Duration of participant follow‐up varied between RCTs. Only five out of 14 non‐randomized studies reported follow‐up duration. Both RCTs were at low risk of reporting bias and unclear risk of selection bias. One RCT was at high risk of performance and detection bias, and low risk for attrition bias, for all outcomes. The other RCT was at low risk of detection and attrition bias for the primary outcome, with unclear risk of detection and attrition bias for non‐primary outcomes, and unclear risk of performance bias for all outcomes. Overall risk of bias for the non‐randomized studies was critical for three studies, and serious for the remaining 11. One RCT reported higher cure (risk ratio (RR) 2.36, 95% confidence interval (CI) 1.13 to 4.90, very low‐certainty evidence), lower failure (RR 0.26, 95% CI 0.10 to 0.70, very low‐certainty evidence), and higher sputum culture conversion at 24 months (RR 2.10, 95% CI 1.30 to 3.40, very low‐certainty evidence), amongst the linezolid‐treated group than controls, with no differences in other primary and secondary outcomes. This study also found more anaemia (17/33 versus 2/32), nausea and vomiting, and neuropathy (14/33 versus 1/32) events amongst linezolid‐receiving participants. Linezolid was discontinued early and permanently in two of 33 (6.1%) participants who received it. The other RCT reported higher sputum culture conversion four months after randomization (RR 2.26, 95% CI 1.19 to 4.28), amongst the group who received linezolid immediately compared to the group who had linezolid initiation delayed by two months. Linezolid was discontinued early and permanently in seven of 39 (17.9%) participants who received it. Linezolid discontinuation occurred in 22.6% (141/624; 11 studies), of participants in the non‐randomized studies. Total, serious, and linezolid‐attributed adverse events could not be summarized quantitatively or comparatively, due to incompleteness of data on duration of follow‐up and numbers of participants experiencing events. Authors' conclusions We found some evidence of efficacy of linezolid for drug‐resistant pulmonary tuberculosis from RCTs in participants with XDR‐TB but adverse events and discontinuation of linezolid were common. Overall, there is a lack of comparative data on efficacy and safety. Serious risk of bias and heterogeneity in conducting and reporting non‐randomized studies makes the existing, mostly retrospective, data difficult to interpret. Further prospective cohort studies or RCTs in high tuberculosis burden low‐income and lower‐middle‐income countries would be useful to inform policymakers and clinicians of the efficacy and safety of linezolid as a component of drug‐resistant TB treatment regimens., Linezolid for managing people with drug‐resistant tuberculosis What is drug‐resistant tuberculosis, and how might linezolid work? Tuberculosis is caused by infection with Mycobacterium tuberculosis bacteria. When there are symptoms or signs of illness, this is called active tuberculosis. An estimated one‐third of the world's population are infected with tuberculosis, and around 1.4 million people died from active tuberculosis in 2015. Bacteria that cause tuberculosis can develop resistance to the drugs most commonly used to treat tuberculosis, also called first‐line antibiotics. This is an increasing problem that makes treatment more difficult, because second‐line tuberculosis treatment drugs are less powerful against the bacteria, and more likely to cause harmful effects. Standard treatment for drug‐resistant tuberculosis requires patients to take multiple antibiotics for nearly two years. Linezolid is a second‐line drug that laboratory studies have found to be good at killing bacteria that cause tuberculosis, but that can also cause frequent, serious harmful effects. The review question Recent international guidelines recommend trying to include linezolid in the treatment of all patients with multi‐drug resistant tuberculosis, but there is concern about whether enough good evidence exists to tell us how well it works, what dose is best, and how safe it is for people who take it. Study characteristics We searched for evidence up to 13 July 2018. We analysed data from two trials, one of which randomly allocated 65 people with drug‐resistant tuberculosis to either a linezolid‐containing or linezolid‐free drug combination, and another that randomly allocated 39 participants to receive linezolid as part of their treatment from the start or have it added after a delay of two months. We also included 14 studies, including 1678 people, in which some participants received linezolid but others did not, but this was not determined at random. What are the main results of the review? One trial showed a higher likelihood of cure and lower risk of treatment failure in participants receiving linezolid compared to those who did not. The second trial showed that participants who received linezolid immediately had a higher chance of tuberculosis being cleared from their sputum four months after the start of the study than those who added linezolid after a two‐month delay. When they examined safety, the first trial found a higher risk of developing low red blood cell counts, nausea and vomiting, and nerve damage in people receiving linezolid. From 11 of the non‐randomized studies that reported this, 22.6% of people had to stop linezolid due to adverse effects (side effects), though further comparisons of harmful effects were not possible due to incomplete reporting in the non‐randomized studies. Overall, although there is some evidence of benefit, we have very low certainty in its accuracy. More high‐quality studies are required before we can be certain how effective and safe linezolid is for drug‐resistant tuberculosis. How up‐to‐date is this review? This review is current up to 13 July 2018.

Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism, which leads to an accumulation of homogentisic acid (HGA) and is associated with a progressive arthropathy. Fatal complications are unusual and usually result from cardiac disease or progressive renal impairment; rapidly fatal haematological complications are exceptionally rare and described in only a handful of case reports. This case involves a 63-year-old male with AKU and modest chronic kidney disease who developed rapidly fatal haemolysis and methaemoglobinuria following an episode of acute kidney injury triggered by an obstructing ureteric calculus and urosepsis. The patient succumbed despite aggressive antioxidant therapy with ascorbic acid and n-acetyl cysteine. A rapid build-up of HGA due to reduced renal clearance, triggering oxidative haemolysis and methaemoglobinuria is proposed as the mechanism. Alternative strategies to consider when conventional antioxidants fail are discussed including the potent inhibitor of HGA production, nitisonone.

Key Clinical Message While rare, Fahr's disease should be considered as a differential diagnosis for seizures, movement disorders, or cognitive impairment in tropical settings. Classically, bilateral calcification of the basal ganglia is seen on CT. Endemic infections, metabolic, and toxic causes should be excluded. Treatment using Levodopa is often beneficial.

Letters not directly related to articles published in Clinical Medicine and presenting unpublished original data should be submitted for publication in this section. Clinical and scientific letters should not exceed 500 words and may include one table and up to five references. Introduction Attention to detail in the prescription of intravenous (IV) fluids for medical and surgical inpatients is often less rigorous than for other drugs, with errors in fluid volume, composition and rate being commonplace.1–2 As part of a review of fluid prescribing and fluid balance we introduced a weight-based fluid prescribing policy, in a large adult teaching hospital. Including algorithms, this largely mirrors the recent NICE guidance (2014).1 Medical inpatients were prospectively assessed for adherence to local and subsequent national guidance, over four consecutive time points (May 2010, Spetember 2010, February 2013 and August 2014). Tailored education and campaigns were introduced. We report our findings, highlighting the ongoing problems in fluid prescribing.

Two novel indolizidine analogues, (7a) and (7b), of the substance P antagonist CP 99,994 have been prepared. Possible conformational factors for their low biological activity are discussed.

Clinical Medicine 2015;15;503–4 Derek Sloan’s name was submitted with incorrect spelling. The correct spelling is printed above