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Epiploic foramen entrapment (EFE) is a common cause of small intestinal colic in horses and may lead to intestinal strangulation. Strangulating intestinal obstruction impairs the gastrointestinal outflow and can lead to secondary gastric rupture and endotoxemia. Clostridioides difficile can cause enterotyphlocolitis with colic in horses of all ages, and the process is commonly referred to as C. difficile–associated disease (CDAD). Here we report the results of the postmortem examination of a 7-y-old Thoroughbred racehorse with concurrent CDAD, EFE, and gastric rupture that was euthanized following a history of colic over several days. A segment of distal jejunum and proximal ileum had passed through the epiploic foramen, and the intestinal wall was thickened and dark-red. The remaining small intestinal loops were distended and filled with blood-tinged contents. Peritonitis had resulted from escape of gastric contents into the abdominal cavity through a tear in the major curvature of the stomach. Histologically, the incarcerated segment had acute transmural hemorrhage with congestion and mucosal necrosis; neutrophilic infiltrates with fibrin thrombi were in the mucosa of the non-incarcerated small intestinal segments. C. difficile toxins were detected in the small intestinal contents, and C. difficile was isolated from the small intestine, colon, and cecum.

Objectives: Mycetoma is a neglected tropical implantation disease caused by 70 different infectious agents. Identifying the causative organism to the species level is essential for appropriate patient management. Ultrasound, histopathology, culture and two species-specific PCRs are most the commonly used methods for species identification in endemic regions. The aim of this study was to compare the diagnostic performance of these commonly used assays using sequencing of barcoding genes as the gold standard. Methods: This descriptive cross-sectional study was conducted at the Mycetoma Research Centre, University of Khartoum, Sudan. It included 222 patients suspected of fungal mycetoma caused by Madurella mycetomatis. Results: 154 (69.3%) were correctly identified by ultrasound, histology, culture and both species-specific PCRs. In 60 patients, at least one of the diagnostic tests failed to identify M. mycetomatis. Five patients had no evidence of eumycetoma, and for three, only the ultrasound was indicative of mycetoma. The two species-specific PCRs were the most sensitive and specific methods, followed by culture and histology. Ultrasound was the least specific as it only allowed differentiation between actinomycetoma and eumycetoma. The time to result was 9.38 minutes for ultrasound, 3.76 hours for PCR, 8.5 days for histopathology and 21 days for grain culturing. Conclusion: Currently, PCR directly on DNA isolated from grains is the most rapid and reliable diagnostic tool to identify M. mycetomatis eumycetoma.

IntroductionSignificant differences in outcomes for mothers and babies following obstetric surgical interventions between low- and middle-income countries and high-income settings have demonstrated a need for improvements in quality of care and training of obstetric surgical and anaesthetic providers. To address this a five-day face-to-face training intervention was developed. When the COVID-19 pandemic interrupted its roll-out, the course was redesigned for delivery by blended learning.MethodsThis 3-part blended-learning course (part-1: 15 hours self-directed online learning, part-2: 13 hours facilitated virtual workshops and part-3: 10 hours face-to-face delivery), was conducted in Kenya. We assessed the completion rate of part-1 (21 assignments), participation rate in parts 2 and 3, participant satisfaction, change in knowledge and skills and compared the cost of the blended delivery compared to the 5-day face-to-face delivery, in GB Pounds.Results65 doctors took part in part 1, 53 completing at least 90% of the assignments. 60 doctors participated in part 2, and 53 participated in part 3. Participants completing an evaluation reported (n=53) attending the training was a good use of their time (each of parts-1 and 3: 98%, part-2: 94%) and would recommend this to other colleagues (part-1 and 3: 98%, part-2: 90%). Mean (SD) knowledge score improved from 64% (7%) to 80% (8%) and practical skills from 44% (14%) to 87% (7%). The blended course achieved a cost-saving of £207 per participant compared to the 5-day face-to-face delivery approach.ConclusionWe have demonstrated that a blended learning approach to clinical training in a low resource setting is feasible, acceptable and more cost effective. More studies are required to investigate the effectiveness of this approach on health outcomes.

Objectives This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis. Methods Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens. Results A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine. Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index Conclusions PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.

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S4.5 Mycetoma Clinical Trial on fosravuconazole treatment in eumycetoma– Top Line Results, September 22, 2022, 10:30 AM - 12:00 PM Objectives Eumycetoma is a neglected tropical disease characterized by large subcutaneous swellings and the formation of grains and most commonly caused by Madurella mycetomatis. The currently recommended therapy is a combination of antifungal therapy with an azole and surgery. Itraconazole is the current recommended drug and fosravuconazole, the pro-drug of ravuconzole, is currently clinically investigated. At the moment, there are no epidemiological cut-off values (ECV) for M. mycetomatis for either of these drugs or rapid diagnostic tests which can predict the therapeutic outcome of these treatments. Therefore, in this study, we determined the ECV for these drugs and determined whether there was a correlation between minimal inhibitory concentration (MIC) and the DNA sequence of the azole target gene CYP51A. We also assessed beta-glucan concentrations in the serum of mycetoma patients during treatment to establish whether any of these values were predictive for therapeutic outcomes. Methods In order to determine the ECV for M. mycetomatis, MIC distributions for itraconazole and ravuconazole were determined in genetically diverse clinical M. mycetomatis isolates using the ECOFFinder software. CYP51A sequences were sequenced and comparisons were made between the different CYP51A variants and the MIC distributions. Beta-glucan concentrations were measured in serum with the WAKO beta-glucan assay. Time points analyzed were 0, 22, 85, 176, 267, 358, and 455 days after the start of treatment. Results For M. mycetomatis the MICs ranged from 0.008 to 1 mg/l for itraconazole and from 0.002 to 0.125 mg/l for ravuconazole. The M. mycetomatis ECV for itraconazole was 1 mg/l and for ravuconazole 0.064 mg/l. In the wild-type population, two CYP51A variants were found for M. mycetomatis, which differed in one amino acid at position 499. The MIC distributions for itraconazole and ravuconazole were similar between the two variants. No mutations linked to decreased susceptibility were found. Before the start of treatment, beta-glucan concentrations ranged from below the detection limit to 217.9 pg/ml. Of these patients, 61.2% had a beta-glucan concentration above 7 pg/ml, the recommended cut-off value for positivity by the manufacturer, 72.8% had a beta-glucan concentration above 5.5 pg/ml, the recommended cut-off value for M. mycetomatis. During the first months of azole treatment, the beta-glucan concentrations remained relatively stable. After surgery, a sharp decrease in beta-glucan concentration in serum was noted. At the end of the observation period, only 13 patients had a beta-glucan concentration above 7 pg/ml and 14 above 5.5 pg/ml. Of these patients, for only 3, there was clinical evidence of a recurrence. For the remaining 4 patients with clinical evidence of a recurrence, the beta-glucan concentration was below the cut-off value for positivity. Conclusion In conclusion, so far there was no link established with the initial in vitro susceptibility and failure or success of the treatment therapy. Beta-glucan levels, in general, remained high during azole treatment, and a sharp drop in beta-glucan concentration in serum was only noted after surgery. A positive beta-glucan concentration at the end of the treatment was not indicative of a recurrence.

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM Objective Mycetoma is a neglected tropical skin disease, caused by 70 different causative agents. For most of the causative agents, molecular identification is the only reliable method to identify the species level. In practice, ultrasound, histopathology, culturing, and species-specific PCRs are most commonly used for species identification. However, the performance of these different tests was not validated using molecular identification by sequencing barcoding genes. Methods In this study, we validated the performance of the most commonly used diagnostic tools including culture, histopathology, Ultrasound and two species-specific PCR for Madurella mycetomatis on 222 patients suspected of fungal mycetoma by M. mycetomatis; the sensitivity, specificity, and accuracy of each method was calculated. Results From the 222 patients, 154 (69.3%) were correctly identified by ultrasound, histology, culture, and both species-specific PCRs. For five patients all tests were negative and for three only the ultrasound was indicative of mycetoma. For the other 60 patients, at least one of the assays was negative for M. mycetomatis. The two species-specific PCRs were the most sensitive and specific, followed by culture and histology. Ultrasound was the least specific as it only allows to differentiate between actinomycetoma and eumycetoma. However, with ultrasound, an identification could be obtained in 9.38 min. PCR took 3.76 h, histology 8.5 days, and culturing 21 days. Conclusion We concluded that PCR directly on DNA isolated from grains is the most rapid and reliable diagnostic tool to identify M. mycetomatis from eumycetoma grains to use species-specific PCRs. In order to shorten the time to identification of other causative agents, the focus should be on developing more molecular assays for those species.

S4.5 Mycetoma Clinical Trial on fosravuconazole treatment in eumycetoma– Top Line Results, September 22, 2022, 10:30 AM - 12:00 PM Objectives Mycetoma is a neglected tropical implantation disease caused by 70 different infectious agents. Identifying the causative organism to the species level is essential for appropriate patient management. Ultrasound, histopathology, culture, and two species-specific PCRs are most the commonly used methods for species identification in endemic regions. The aim of this study was to compare the diagnostic performance of these commonly used assays using sequencing of barcoding genes as the gold standard. Methods This descriptive cross-sectional study was conducted at the Mycetoma Research Centre, University of Khartoum, Sudan. It included 222 patients suspected of fungal mycetoma caused by Madurella mycetomatis. Results In total 154 (69.3%) were correctly identified by ultrasound, histology, culture, and both species-specific PCRs. In 60 patients, at least one of the diagnostic tests failed to identify M. mycetomatis. A total of five patients had no evidence of eumycetoma, and for three, only the ultrasound was indicative of mycetoma. The two species-specific PCRs were the most sensitive and specific methods, followed by culture and histology. Ultrasound was the least specific as it only allowed differentiation between actinomycetoma and eumycetoma. The time to result was 9.38 minutes for ultrasound, 3.76 h for PCR, 8.5 days for histopathology, and 21 days for grain culturing. Conclusion Currently, PCR directly on DNA isolated from grains is the most rapid and reliable diagnostic tool to identify M. mycetomatis eumycetoma.

S4.5 Mycetoma Clinical Trial on fosravuconazole treatment in eumycetoma– Top Line Results, September 22, 2022, 10:30 AM - 12:00 PM Objective To evaluate the pharmacokinetics (PK) of fosravuconazole (measured as ravuconazole) and itraconazole in patients with mild to moderate eumycetoma caused by Madurella mycetomatis using a non-compartmental PK analysis. Methods Participants received either 200 mg or 300 mg ravuconazole once weekly or 400 mg itraconazole daily for a total duration of 12 months. Plasma concentrations of ravuconazole and itraconazole were measured on day 1 of week 1, and on weeks 2, 3, 4, and months 2, 3, 6, and 12 (at end of treatment) for analysis of population PK. The exact time of dosing on the days of sample collection, and the exact time of sample collection within the collection time window, were recorded. Plasma concentrations were quantified using Ultraperformance Liquid Chromatography with fluorescence detection (UPLC-UV). Ravuconazole and itraconazole plasma concentration-time data was performed using a standard two stage approach with non-compartmental analysis. Derived exposure parameters of ravuconazole and itraconazole, including, but not limited to, Cmax and AUC at steady state (AUCs), were calculated. The effect of covariates, such as baseline characteristics/demographics, on PK were explored. AUCs were determined when at least three subsequent samples within one dosing interval were available. Results A total of 766 samples of ravuconazole in 68 participants and 226 samples of itraconazole in 36 participants were analyzed. The average concentration of ravuconazole (range) was 3.1 mg/l (0.01-12.33 mg/l), and for itraconazole was 1.59 mg/l (0.01-5.53 mg/l). Detailed Pharmacokinetic results will be communicated and discussed in the oral presentation.

Objectives To determine whether, in addition to surgery, fosravuconazole (Fos) monotherapy of either 200 mg or 300 mg weekly was more effective [defined as complete cure at the End of Treatment (EOT; 52-week) visit] than the standard-of-care 12-month regimen of itraconazole (Itra) monotherapy, in patients with small to moderate eumycetoma lesions caused by Madurella mycetomatis. Methods This was a single-center (Mycetoma Research Center, Khartoum, Sudan), comparative, randomized, double-blind, parallel-group, active-controlled, clinical superiority trial in participants with eumycetoma requiring surgery. Participants were randomized in a 1:1:1 ratio. In Arm 1 participants took a loading dose of Fos 300 mg on Day 1, Day 2, and Day 3, followed by a weekly dose of 300 mg for a total duration of 12 months. In Arm 2 participants took Fos 200 mg on Day 1, Day 2, and Day 3, followed by a weekly dose of 200 mg for a total duration of 12 months. In Arm 3 participants took Itra 400 mg daily for 12 months. All patients underwent surgery after 6 months of treatment in which the remaining lesion was removed. Mycetoma lesions were between 2 to ≤16 cm in diameter. The age cut-off was ≥15 years. The diagnosis of M. mycetomatis was confirmed by PCR. Safety monitoring included, among other, severe, and serious treatment-related events. Results A total of 122 participants were screened and 104 participants were enrolled (34 in Fos 300 mg, 34 in Fos 200 mg weekly, and 36 in Itra 400 mg). Complete cure after 12 months (EOT) of treatment was demonstrated in terms of an absence of eumycetoma mass, sinuses, and discharge; normal ultrasound of the lesion site or normal MRI; and a negative fungal culture from a surgical biopsy if a mycetoma mass was present. The complete cure rate was assessed in the mITT population. Secondary efficacy analyses were performed in the Per Protocol population. In addition, the influence of age, changes in clinical symptoms and signs, size, and duration of the lesion on outcome was examined. Safety was satisfactory and compliance was good. Conclusion This is the first randomized controlled trial in eumycetoma, comparing two azoles, fosravuconazole (two dosage regimens) and itraconazole, in combination with surgery. Detailed efficacy and safety results will be communicated and discussed in the oral presentation.

OBJECTIVE: To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis. DESIGN: A single-centre open-label randomised controlled trial. SETTING: Kilifi County Hospital, Kenya. PATIENTS: 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019. INTERVENTION: We randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days. MAIN OUTCOMES AND MEASURES: Serum sodium, AEs and fosfomycin pharmacokinetics. RESULTS: 61 and 59 infants aged 0-23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference -0.95 events/100 infant-days (95% CI -2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged

Background Eumycetoma is a neglected tropical disease. It is a chronic inflammatory subcutaneous infection characterised by painless swellings which produce grains. It is currently treated with a combination of itraconazole and surgery. In an ongoing clinical study, the efficacy of fosravuconazole, the prodrug of ravuconazole, is being investigated. For both itraconazole and ravuconazole, no clinical breakpoints or epidemiological cut-off values (ECV) to guide treatment are currently available. Objective To determine tentative ECVs for itraconazole and ravuconazole in Madurella mycetomatis, the main causative agent of eumycetoma. Materials and Methods Minimal inhibitory concentrations (MICs) for itraconazole and ravuconazole were determined in 131 genetically diverse clinical M. mycetomatis isolates with the modified CLSI M38 broth microdilution method. The MIC distributions were established and used to determine ECVs with the ECOFFinder software. CYP51A sequences were sequenced to determine whether mutations occurred in this azole target gene, and comparisons were made between the different CYP51A variants and the MIC distributions. Results The MICs ranged from 0.008 to 1 mg/L for itraconazole and from 0.002 to 0.125 mg/L for ravuconazole. The M. mycetomatis ECV for itraconazole was 1 mg/L and for ravuconazole 0.064 mg/L. In the wild-type population, two CYP51A variants were found for M. mycetomatis, which differed in one amino acid at position 499 (S499G). The MIC distributions for itraconazole and ravuconazole were similar between the two variants. No mutations linked to decreased susceptibility were found. Conclusion The proposed M. mycetomatis ECV for itraconazole is 1 mg/L and for ravuconazole 0.064 mg/L.

BackgroundSepsis severity scores are used in clinical practice and trials to define risk groups. There are limited data to derive hospital-based sepsis severity scores for neonates and young infants in high-burden low- and middle-income country (LMIC) settings where trials are urgently required. We aimed to create linked sepsis severity and recovery scores applicable to hospitalized neonates and young infants in LMIC which could be used to inform antibiotic trials.Methods & FindingsA prospective observational cohort study was conducted across 19 hospitals in 11 countries in sub-Saharan Africa, Asia, Latin America and Europe. Infants aged 3204 infants were enrolled between 2018-2020. Median age was 5 days (IQR 2-15), 90.4% (n=2,895) were A related NeoSep Recovery Score based on evolving post-baseline clinical signs and supportive care discriminated well between infants who died or survived the following day or subsequent few days. The area under the ROC curve for score on day 2 and death in the following 5 days was 0.82 (95%CI 0.78-0.85) and 0.85 (95%CI 0.78-0.93) in the derivation and validation data, respectively.ConclusionThe baseline NeoSep Severity Score predicted 28-day mortality and could identify infants with high risk of mortality for inclusion in hospital-based sepsis trials. The NeoSep Recovery Score predicts day-by-day inpatient mortality and could, with further validation, help to identify poor response to antibiotics.Author SummaryWhy was this study done?➣Evidence to guide hospital-based antibiotic treatment of sepsis in neonates and young infants is scarce, and clinical trials are particularly urgent in low- and middle-income (LMIC) settings where antimicrobial resistance threatens to undermine existing guidelines➣There is limited data to inform the design of antibiotic trials in LMIC settings, particularly to define risk stratification and inclusion and escalation criteria in hospitalised neonates and young infantsWhat did the researchers do and find?➣To our knowledge this is the first global, prospective, hospital-based observational study of clinically diagnosed neonatal sepsis across 4 continents including LMIC settings, with extensive daily data collection on clinical status, antibiotic use and outcomes.➣There was a high mortality among infants with sepsis in LMIC hospital settings. 4 non-modifiable and 6 modifiable factors predicted mortality and were included in a NeoSep Severity score which defines patterns of mortality risk at baseline➣A NeoSep Recovery Score including the same modifiable factors (with the addition of cyanosis) predicted mortality on the following day during the course of treatment.What do these findings mean?➣The NeoSep Severity Score and NeoSep Recovery score are now informing inclusion and escalation criteria in the NeoSep1 antibiotic trial (ISRCTN48721236) which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis➣The NeoSep Severity Score could be used to predict mortality at baseline in future studies of targeting resources in routine care. With further validation, the NeoSep Recovery Score could potentially be used to identify poor response to empiric antibiotic treatment

BackgroundNeonatal sepsis is a leading cause of child mortality, and increasing antimicrobial resistance threatens progress towards the Sustainable Development Goals. Evidence to guide antibiotic treatment for sepsis in neonates and young infants from randomized controlled trials or observational studies in low- and middle-income countries (LMICs) is scarce. We aimed to describe patterns of antibiotic use, pathogens and outcomes in LMIC hospital settings globally to inform future clinical trials on the management of neonatal sepsis.Methods & FindingsHospitalised infants aged 206 different empiric antibiotic combinations were used, which were structured into 5 groups that were developed from the World Health Organisation (WHO) AWaRe classification. 25.9% (n=814) of infants started a WHO first line regimen (Group 1 -Access, penicillin-based regimen) and 13.8% (n=432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2- ‘Low’ Watch). The largest group (34.0%, n=1068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3 – ‘Medium’ Watch), 18.0% (n=566) started a carbapenem (Group 4 – ‘High’ Watch), and 1.8% (n=57) started a Reserve antibiotic (Group 5, largely colistin-based). Predictors of starting non-WHO recommended regimens included lower birth weight, longer in-hospital stay, central vascular catheter use, previous culture positive sepsis or antibiotic exposure, previous surgery and greater sepsis severity. 728/2880 (25.3%) of initial regimens in Group 1-4 were escalated, mainly to carbapenems, and usually for clinical indications (n=480; 65.9%).564 infants (17.6%) isolated a pathogen from their baseline blood culture, of which 62.9% (n=355) had a Gram-negative organism, predominantlyKlebsiella pneumoniae(n=132) andAcinetobacterspp. (n=72). These leading Gram-negatives were both mostly resistant to WHO-recommended regimens, and also resistant to carbapenems in 32.6% and 71.4% of cases respectively. MRSA accounted for 61.1% ofStaphylococcus aureus(n=54) isolates.Overall, 350/3204 infants died (11.3%; 95%CI 10.2-12.5%), with 17.7% case fatality rate among infants with a pathogen in baseline culture (95%CI 14.7-20.1%, n=99/564). Gram-negative infections accounted for 75/99 (75.8%) of pathogen-positive deaths, especiallyKlebsiella pneumoniae(n=28; 28.3%), andAcinetobacterspp. (n=24; 24.2%).ConclusionA very wide range of antibiotic regimens are now used to treat neonatal sepsis globally. There is common use of higher-level Watch antibiotics, frequent early switching and very infrequent de-escalation of therapy. Future hospital based neonatal sepsis trials will ideally need to account for the multiple regimens used as standard of care globally and include both empiric first line regimens and subsequent switching in the trial design.Author SummaryWhy was this study done?➢Increasing trends in antimicrobial resistance (AMR) disproportionately affect neonates and young infants with sepsis in LMIC settings and undermine the effectiveness of WHO-recommended antibiotics.➢Despite this, longitudinal data on antibiotic management strategies and outcomes of affected hospitalised neonates and young infants in LMIC settings are extremely limited, impeding the design of robust antibiotic trials.What did the researchers do and find?➢To our knowledge this is the first global, prospective, hospital-based observational study of clinically diagnosed neonatal sepsis across 4 continents including LMIC settings, with daily data on clinical status, antibiotic use and outcomes.➢There was a high mortality among infants with culture positive sepsis (almost 1 in 5), and a significant burden of antibiotic resistance.➢This study highlights wide variations in standard of care for sepsis in neonates and young infants with more than 200 different antibiotic combinations, significant divergence from WHO-recommended regimens, and frequent switching of antibiotics.What do these findings mean?➢These data demonstrate that patterns of routine antibiotic use are now markedly divergent from global guidance➢There is an urgent need for randomised controlled trials to address optimal empiric first and second line antibiotic treatment strategies in LMIC hospital settings with a significant AMR burden.➢Data from this study can inform the design of multicentre hospital-based neonatal antibiotic trials in LMIC settings.➢The wide range of multiple antibiotic regimens routinely used as Standard of Care (SOC) suggests the need for novel trial designs.

The paper determined the initial impact of COVID-19 pandemic on reproductive, maternal, newborn, child and adolescent health (RMNCAH) services in Kenya. Hospital data for the first four months (March-June 2020) of the pandemic and the equivalent period in 2019 were compared using two-sample test of proportions. Despite the global projections for worse indicators, there were no differences in monthly mean (±SD) attendance between March-June 2019 vs 2020 for antenatal care (400,191.2±12,700.0 vs 384,697.3±20,838.6), hospital births (98,713.0±4,117.0 vs 99,634.5±3,215.5), family planning attendance (431,930.5±19,059.9 vs 448,168.3±31,559.8), post-abortion care (3,206.5±111.7 vs 448,168.3±31,559.8) and pentavalent 1 immunisation (114,701.0±3,701.1 vs 110,915.8±7,209.4), p>0.05. However, there were significant increases in FP utilisation among young people (25.7% to 27.0%), injectable (short-term) FP method uptake (58.2% to 62.3%), caesarean section rate (14.6% to 15.8%), adolescent maternal deaths (6.2% to 10.9%) and fresh stillbirths (0.9% to 1.0%) with a reduction in implants (long-term) uptake (16.5% to 13.0%) (p

ObjectiveTo assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.DesignA single-centre open-label randomised controlled trial.SettingKilifi County Hospital, Kenya.Patients120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019.InterventionWe randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days.Main outcome(s) and measure(s)Serum sodium, AEs and fosfomycin pharmacokinetics.Results61 and 59 infants aged 0–23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference −0.95 events/100 infant-days (95% CI −2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged Conclusion and relevanceFosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial.Trial registration numberNCT03453177.

The paper determined the initial impact of COVID-19 pandemic on reproductive, maternal, newborn, child and adolescent health (RMNCAH) services in Kenya. Hospital data for the first four months (March-June 2020) of the pandemic and the equivalent period in 2019 were compared using two-sample test of proportions. Despite the global projections for worse indicators, there were no differences in monthly mean (±SD) attendance between March-June 2019 vs 2020 for antenatal care (400,191.2±12,700.0 vs 384,697.3±20,838.6), hospital births (98,713.0±4,117.0 vs 99,634.5±3,215.5), family planning attendance (431,930.5±19,059.9 vs 448,168.3±31,559.8), post-abortion care (3,206.5±111.7 vs 448,168.3±31,559.8) and pentavalent 1 immunisation (114,701.0±3,701.1 vs 110,915.8±7,209.4), p>0.05. However, there were significant increases in FP utilisation among young people (25.7% to 27.0%), injectable (short-term) FP method uptake (58.2% to 62.3%), caesarean section rate (14.6% to 15.8%), adolescent maternal deaths (6.2% to 10.9%) and fresh stillbirths (0.9% to 1.0%) with a reduction in implants (long-term) uptake (16.5% to 13.0%) (p