Antibiotic susceptibility patterns at the Médecins Sans Frontières (MSF) Acute Trauma Hospital in Aden, Yemen: a retrospective study from January 2018 to June 2021.

Background: Antimicrobial resistance (AMR) is an urgent global health concern, especially in countries facing instability or conflicts, with compromised healthcare systems. Médecins Sans Frontières (MSF) established an acute trauma hospital in Aden, Yemen, treating mainly war-wounded civilians, and implemented an antimicrobial stewardship (AMS) programme. This study aimed to describe clinical characteristics and identify antibiotic susceptibility patterns representative of patients treated with antibiotics. Methods: Retrospective cross-sectional study using routinely collected data from all patients treated with antibiotics in the MSF-Aden Acute Trauma hospital between January 2018 and June 2021. Routine clinical data from patients' files was entered into an AMS electronic database and microbiological data were entered into WHONET. Both databases were imported and merged in REDCap and analysed using RStudio. Results: Three hundred and sixty-three of 481 (75%) included patients were injured by violence-related trauma. Most were men aged 19-45 years (n = 331; 68.8%). In total, 598 infections were diagnosed and treated. MDR organisms were identified in 362 (60.5%) infections in 311 (65%) patients. Skin and soft-tissue infections (SSTIs) (n = 143; 24%) were the most common, followed by osteomyelitis (n = 125; 21%) and intra-abdominal-infections (IAIs) (n = 116; 19%), and 111 (19%) secondary bloodstream infections were identified. Escherichia coli was the most frequently identified pathogen, causing IAI (n = 87; 28%) and SSTI (n = 43; 16%), while Staphylococcus aureus caused mainly osteomyelitis (n = 84; 19%). Most Gram-negatives were ESBL producers, including E. coli (n = 193; 81.4%), Klebsiella pneumoniae (n = 72; 77.4%) and Enterobacter cloacae (n = 39; 50%) while most S. aureus were methicillin resistant (n = 93; 72.6%). Conclusions: High rates of MDR were found. This information will facilitate a comprehensive review of the empirical antibiotic treatment guidelines.

Antimicrobial stewardship in primary health care programs in humanitarian settings: the time to act is now.

Fragile and conflict-affected settings bear a disproportionate burden of antimicrobial resistance, due to the compounding effects of weak health policies, disrupted medical supply chains, and lack of knowledge and awareness about antibiotic stewardship both among health care providers and health service users. Until now, humanitarian organizations intervening in these contexts have confronted the threat of complex multidrug resistant infections mainly in their surgical projects at the secondary and tertiary levels of care, but there has been limited focus on ensuring the implementation of adequate antimicrobial stewardship in primary health care, which is known to be setting where the highest proportion of antibiotics are prescribed. In this paper, we present the experience of two humanitarian organizations, Médecins sans Frontières and the International Committee of the Red Cross, in responding to antimicrobial resistance in their medical interventions, and we draw from their experience to formulate practical recommendations to include antimicrobial stewardship among the standards of primary health care service delivery in conflict settings. We believe that expanding the focus of humanitarian interventions in unstable and fragile contexts to include antimicrobial stewardship in primary care will strengthen the global response to antimicrobial resistance and will decrease its burden where it is posing the highest toll in terms of mortality.

C-reactive protein and procalcitonin use in adults in low- and middle-income countries: a narrative review.

Objectives: C-reactive protein (CRP) and procalcitonin (PCT) are widely used biomarkers in high-income countries. However, evidence for their use in low- and middle-income countries (LMICs) is scant. Because many factors, including rates of endemic disease, comorbidities and genetics, may influence biomarkers' behaviour, we aimed to review available evidence generated in LMICs. Methods: We searched the PubMed database for relevant studies within the last 20 years that originated in regions of interest (Africa, Latin America, Middle East, South Asia or South East Asia), and full-text articles involving diagnosis, prognostication and evaluation of therapeutic response with CRP and/or PCT in adults (n = 88) were reviewed and categorized in 12 predefined focus areas. Results: Overall, results were highly heterogeneous, at times conflicting, and often lacking clinically useful cut-off values. However, most studies demonstrated higher levels of CRP/PCT in patients with bacterial versus other infections. HIV and TB patients had consistently higher levels of CRP/PCT versus controls. In addition, higher CRP/PCT levels at baseline and follow-up in HIV, TB, sepsis and respiratory tract infections were associated with poorer prognosis. Conclusions: Evidence generated from LMIC cohorts suggests that CRP and PCT may have potential to become effective clinical guiding tools particularly in respiratory tract infections, sepsis and HIV/TB. However, more studies are needed to define potential scenarios for use and cost-effectiveness. Consensus across stakeholders regarding target conditions, laboratory standards and cut-off values would support the quality and applicability of future evidence.

AMR in low-resource settings: Médecins Sans Frontières bridges surveillance gaps by developing a turnkey solution, the Mini-Lab.

BACKGROUND: In low- and middle-income countries (LMICs), data related to antimicrobial resistance (AMR) are often inconsistently collected. Humanitarian, private and non-governmental medical organizations (NGOs), working with or in parallel to public medical systems, are sometimes present in these contexts. Yet, what is the role of NGOs in the fight against AMR, and how can they contribute to AMR data collection in contexts where reporting is scarce? How can context-adapted, high-quality clinical bacteriology be implemented in remote, challenging and underserved areas of the world? OBJECTIVES: The aim was to provide an overview of AMR data collection challenges in LMICs and describe one initiative, the Mini-Lab project developed by Médecins Sans Frontières (MSF), that attempts to partially address them. SOURCES: We conducted a literature review using PubMed and Google scholar databases to identify peer-reviewed research and grey literature from publicly available reports and websites. CONTENT: We address the necessity of and difficulties related to obtaining AMR data in LMICs, as well as the role that actors outside of public medical systems can play in the collection of this information. We then describe how the Mini-Lab can provide simplified bacteriological diagnosis and AMR surveillance in challenging settings. IMPLICATIONS: NGOs are responsible for a large amount of healthcare provision in some very low-resourced contexts. As a result, they also have a role in AMR control, including bacteriological diagnosis and the collection of AMR-related data. Actors outside the public medical system can actively contribute to implementing and adapting clinical bacteriology in LMICs and can help improve AMR surveillance and data collection.

COVID-19 in Australia: our national response to the first cases of SARS-CoV-2 infection during the early biocontainment phase.

BACKGROUND: On 31 December 2019, the World Health Organization recognised clusters of pneumonia-like cases due to a novel coronavirus disease (COVID-19). COVID-19 became a pandemic 71 days later. AIM: To report the clinical and epidemiological features, laboratory data and outcomes of the first group of 11 returned travellers with COVID-19 in Australia. METHODS: This is a retrospective, multi-centre case series. All patients with confirmed COVID-19 infection were admitted to tertiary referral hospitals in New South Wales, Queensland, Victoria and South Australia. RESULTS: The median age of the patient cohort was 42 years (interquartile range (IQR), 24-53 years) with six men and five women. Eight (72.7%) patients had returned from Wuhan, one from Shenzhen, one from Japan and one from Europe. Possible human-to-human transmission from close family contacts in gatherings overseas occurred in two cases. Symptoms on admission were fever, cough and sore throat (n = 9, 81.8%). Co-morbidities included hypertension (n = 3, 27.3%) and hypercholesterolaemia (n = 2, 18.2%). No patients developed severe acute respiratory distress nor required intensive care unit admission or mechanical ventilation. After a median hospital stay of 14.5 days (IQR, 6.75-21), all patients were discharged. CONCLUSIONS: This is a historical record of the first COVID-19 cases in Australia during the early biocontainment phase of the national response. These findings were invaluable for establishing early inpatient and outpatient COVID-19 models of care and informing the management of COVID-19 over time as the outbreak evolved. Future research should extend this Australian case series to examine global epidemiological variation of this novel infection.

Tocilizumab for severe COVID-19 pneumonia: Case series of 5 Australian patients.

AIM: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. METHODS: Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 µg/L) were administered variable-dose tocilizumab. RESULTS: At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. CONCLUSIONS: Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.

Inclusion of Real-Time Hand Hygiene Observation and Feedback in a Multimodal Hand Hygiene Improvement Strategy in Low-Resource Settings.

Importance: Hand hygiene adherence monitoring and feedback can reduce health care-acquired infections in hospitals. Few low-cost hand hygiene adherence monitoring tools exist in low-resource settings. Objective: To pilot an open-source application for mobile devices and an interactive analytical dashboard for the collection and visualization of health care workers' hand hygiene adherence data. Design, Setting, and Participants: This prospective multicenter quality improvement study evaluated preintervention and postintervention adherence with the 5 Moments for Hand Hygiene, as suggested by the World Health Organization, among health care workers from April 23 to May 25, 2018. A novel data collection form, the Hand Hygiene Observation Tool, was developed in open-source software and used to measure adherence with hand hygiene guidelines among health care workers in the inpatient therapeutic feeding center and pediatric ward of Anka General Hospital, Anka, Nigeria, and the postoperative ward of Noma Children's Hospital, Sokoto, Nigeria. Qualitative data were analyzed throughout data collection and used for immediate feedback to staff. A more formal analysis of the data was conducted during October 2018. Exposures: Multimodal hand hygiene improvement strategy with increased availability and accessibility of alcohol-based hand sanitizer, staff training and education, and evaluation and feedback in near real-time. Main Outcomes and Measures: Hand hygiene adherence before and after the intervention in 3 hospital wards, stratified by health care worker role, ward, and moment of hand hygiene. Results: A total of 686 preintervention adherence observations and 673 postintervention adherence observations were conducted. After the intervention, overall hand hygiene adherence increased from 32.4% to 57.4%. Adherence increased in both wards in Anka General Hospital (inpatient therapeutic feeding center, 24.3% [54 of 222 moments] to 63.7% [163 of 256 moments]; P < .001; pediatric ward, 50.9% [132 of 259 moments] to 68.8% [135 of 196 moments]; P < .001). Adherence among nurses in Anka General Hospital also increased in both wards (inpatient therapeutic feeding center, 17.7% [28 of 158 moments] to 71.2% [79 of 111 moments]; P < .001; pediatric ward, 45.9% [68 of 148 moments] to 68.4% [78 of 114 moments]; P < .001). In Noma Children's Hospital, the overall adherence increased from 17.6% (36 of 205 moments) to 39.8% (88 of 221 moments) (P < .001). Adherence among nurses in Noma Children's Hospital increased from 11.5% (14 of 122 moments) to 61.4% (78 of 126 moments) (P < .001). Adherence among Noma Children's Hospital physicians decreased from 34.2% (13 of 38 moments) to 8.6% (7 of 81 moments). Lowest overall adherence after the intervention occurred before patient contact (53.1% [85 of 160 moments]), before aseptic procedure (58.3% [21 of 36 moments]), and after touching a patient's surroundings (47.1% [124 of 263 moments]). Conclusions and Relevance: This study suggests that tools for the collection and rapid visualization of hand hygiene adherence data are feasible in low-resource settings. The novel tool used in this study may contribute to comprehensive infection prevention and control strategies and strengthening of hand hygiene behavior among all health care workers in health care facilities in humanitarian and low-resource settings.

Post-traumatic osteomyelitis in Middle East war-wounded civilians: resistance to first-line antibiotics in selected bacteria over the decade 2006-2016.

BACKGROUND: War-wounded civilians in Middle East countries are at risk of post-traumatic osteomyelitis (PTO). We aimed to describe and compare the bacterial etiology and proportion of first-line antibiotics resistant bacteria (FLAR) among PTO cases in civilians from Syria, Iraq and Yemen admitted to the reconstructive surgical program of Médecins Sans Frontières (MSF) in Amman, Jordan, and to identify risk factors for developing PTO with FLAR bacteria. METHODS: We retrospectively analyzed the laboratory database of the MSF program. Inclusion criteria were: patients from Iraq, Yemen or Syria, admitted to the Amman MSF program between October 2006 and December 2016, with at least one bone biopsy sample culture result. Only bone samples taken during first orthopedic surgery were included in the analysis. To assess factors associated with FLAR infection, logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CI). RESULTS: 558 (76.7%) among 727 patients included had ≥1 positive culture results. 318 were from Iraq, 140 from Syria and 100 from Yemen. Median time since injury was 19 months [IQR 8-40]. Among the 732 different bacterial isolates, we identified 228 Enterobacteriaceae (31.5%), 193 Staphylococcus aureus (26.3%), 99 Pseudomonas aeruginosa (13.5%), and 21 Acinetobacter baumanii (2.8%). Three hundred and sixty four isolates were FLAR: 86.2% of Enterobacteriaceae, 53.4% of Pseudomonas aeruginosa, 60.5% of S. aureus and 45% of Acinetobacter baumannii. There was no difference in bacterial etiology or proportion of FLAR according to the country of origin. In multivariate analysis, a FLAR infection was associated with an infection of the lower extremity, with a time since the injury ≤12 months compared with time > 30 months and with more than 3 previous surgeries. CONCLUSIONS: Enterobacteriaceae were frequently involved in PTO in war wounded civilians from Iraq, Yemen and Syria between 2006 and 2016. Proportion of FLAR was high, particularly among Enterobacteriaceae, regardless of country of origin.

Experimental Treatment of Ebola Virus Disease with Brincidofovir.

BACKGROUND: The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic. METHODS AND FINDINGS: In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD. CONCLUSIONS: Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201411000939962.

The significance of HIV 'blips' in resource-limited settings: is it the same? analysis of the treat Asia HIV Observational Database (TAHOD) and the Australian HIV Observational Database (AHOD).

INTRODUCTION: Magnitude and frequency of HIV viral load blips in resource-limited settings, has not previously been assessed. This study was undertaken in a cohort from a high income country (Australia) known as AHOD (Australian HIV Observational Database) and another cohort from a mixture of Asian countries of varying national income per capita, TAHOD (TREAT Asia HIV Observational Database). METHODS: Blips were defined as detectable VL (≥ 50 copies/mL) preceded and followed by undetectable VL (<50 copies/mL). Virological failure (VF) was defined as two consecutive VL ≥50 copies/ml. Cox proportional hazard models of time to first VF after entry, were developed. RESULTS: 5040 patients (AHOD n = 2597 and TAHOD n = 2521) were included; 910 (18%) of patients experienced blips. 744 (21%) and 166 (11%) of high- and middle/low-income participants, respectively, experienced blips ever. 711 (14%) experienced blips prior to virological failure. 559 (16%) and 152 (10%) of high- and middle/low-income participants, respectively, experienced blips prior to virological failure. VL testing occurred at a median frequency of 175 and 91 days in middle/low- and high-income sites, respectively. Longer time to VF occurred in middle/low income sites, compared with high-income sites (adjusted hazards ratio (AHR) 0.41; p<0.001), adjusted for year of first cART, Hepatitis C co-infection, cART regimen, and prior blips. Prior blips were not a significant predictor of VF in univariate analysis (AHR 0.97, p = 0.82). Differing magnitudes of blips were not significant in univariate analyses as predictors of virological failure (p = 0.360 for blip 50-≤1000, p = 0.309 for blip 50-≤400 and p = 0.300 for blip 50-≤200). 209 of 866 (24%) patients were switched to an alternate regimen in the setting of a blip. CONCLUSION: Despite a lower proportion of blips occurring in low/middle-income settings, no significant difference was found between settings. Nonetheless, a substantial number of participants were switched to alternative regimens in the setting of blips.

Human immunodeficiency virus and menopause.

OBJECTIVE: This article aims to review currently available evidence for women infected with human immunodeficiency virus (HIV) and menopause and to propose clinical management algorithms. METHODS: Key studies addressing HIV and menopause have been reviewed, specifically age of menopause onset in HIV-infected women, frequency of menopausal symptoms, comorbidities associated with HIV and aging (including cardiovascular disease and bone disease), treatment of menopausal symptoms, and prevention of comorbidities in HIV-infected women. RESULTS: Studies suggest an earlier onset of menopause in HIV-infected women, with increased frequency of symptoms. Cardiovascular disease risk may be increased in this population, with combination antiretroviral therapy (cART) and chronic inflammation associated with HIV, contributing to increased risk. Chronic inflammation and cART have been independently implicated in bone disease. No published data have assessed the safety and efficacy of hormone therapy in relation to symptoms of menopause, cardiovascular risk, and bone disease among HIV-infected women. CONCLUSIONS: Few studies on menopause have been conducted in HIV-infected women compared with HIV-uninfected women. Many questions regarding age of menopause onset, frequency of menopausal symptoms and associated complications such as bone disease and cardiovascular disease, and efficacy of treatment among HIV-infected women remain. The incidence and severity of some of these factors may be increased in the setting of HIV and cART.

Treatment initiation, program attrition and patient treatment outcomes associated with scale-up and decentralization of HIV care in rural Malawi.

OBJECTIVE: To describe patient antiretroviral therapy (cART) outcomes associated with intensive decentralization of services in a rural HIV program in Malawi. METHODS: Longitudinal analysis of data from HIV-infected patients starting cART between August 2001 and December 2008 and of a cross-sectional immunovirological assessment conducted 12 (±2) months after therapy start. One-year mortality, lost to follow-up, and attrition (deaths and lost to follow-up) rates were estimated with exact Poisson 95% confidence intervals (CI) by type of care delivery and year of initiation. Association of virological suppression (<50 copies/mL) and immunological success (CD4 gain ≥100 cells/µL), with type of care was investigated using multiple logistic regression. RESULTS: During the study period, 4322 cART patients received centralized care and 11,090 decentralized care. At therapy start, patients treated in decentralized health facilities had higher median CD4 count levels (167 vs. 130 cell/µL, P<0.0001) than other patients. Two years after cART start, program attrition was lower in decentralized than centralized facilities (9.9 per 100 person-years, 95% CI: 9.5-10.4 vs. 20.8 per 100 person-years, 95% CI: 19.7-22.0). One year after treatment start, differences in immunological success (adjusted OR=1.23, 95% CI: 0.83-1.83), and viral suppression (adjusted OR=0.80, 95% CI: 0.56-1.14) between patients followed at centralized and decentralized facilities were not statistically significant. CONCLUSIONS: In rural Malawi, 1- and 2-year program attrition was lower in decentralized than in centralized health facilities and no statistically significant differences in one-year immunovirological outcomes were observed between the two health care levels. Longer follow-up is needed to confirm these results.

Benefit of viral load testing for confirmation of immunological failure in HIV patients treated in rural Malawi.

OBJECTIVE: Viral load testing is used in the HIV programme of Chiradzulu, Malawi, to confirm the diagnosis of immunological failure to prevent unnecessary switching to second-line therapy. Our objective was to quantify the benefit of this strategy for management of treatment failure in a large decentralized HIV programme in Africa. METHODS: Retrospective analysis of monitoring data from adults treated with first-line antiretroviral regimens for >1 year and meeting the WHO immunological failure criteria in an HIV programme in rural Malawi. The positive predictive value of using immunological failure criteria to diagnose virological failure (viral load >5000 copies/ml) was estimated. RESULTS: Of the 227 patients with immunological failure (185 confirmed with a repeat CD4 measurement), 155 (68.2%) had confirmatory viral load testing. Forty-four (28.4%) had viral load >5000 copies/ml and 57 (36.8%) >1000 copies/ml. Positive predictive value was 28.4% (95% CI 21.4-36.2%). Repeat CD4 count testing showed that 41% of patients initially diagnosed with immunological failure did no longer meet failure criteria. CONCLUSIONS: Our results support the need for confirming all cases of immunological failure with viral load testing before switching to second-line ART to optimize the use of resources in developing countries.