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Thundon Ngamprasertchai,1 Adhiratha Boonyasiri,2 Lantharita Charoenpong,3 Sireethorn Nimitvilai,4 Narisorn Lorchirachoonkul,5 Luksame Wattanamongkonsil,2 Visanu Thamlikitkul6 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; 2Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 3Division of Medicine, Chaophraya Yommarat Hospital, Suphanburi, Thailand; 4Division of Medicine, Nakhornpathom Hospital, Nakhornpathom, Thailand; 5Division of Medicine, Ratchaburi Hospital, Ratchaburi, Thailand; 6Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Background: Colistimethate sodium (colistin) has been used in the treatment of infections caused by extensively drug-resistant (XDR) Gram-negative bacteria in Thailand over the past decade, with a mortality rate of 50% and a nephrotoxicity rate of 40%. Polymyxin B has not been available in Thailand. We conducted a Phase II clinical study to determine the effectiveness and safety of polymyxin B, compared with colistin, for the treatment of XDR Gram-negative bacterial infections in Thai patients.Methods: A total of 73 adult patients hospitalized at four participating tertiary care hospitals from January 2015 to December 2015 who had infections caused by XDR Gram-negative bacteria and had to receive colistin were enrolled in the study. Polymyxin B (100 mg/day) was administered intravenously every 12 hours for 7–14 days.Results: Most of the patients were older males with comorbidities who had received antibiotics, particularly carbapenems, prior to receiving polymyxin B. More than half of the patients had pneumonia, and 51.5% of the infections were caused by XDR Acinetobacter baumannii, which was susceptible to colistin. Good clinical responses at the end of treatment were observed in 78.1% of cases, the overall 28-day mortality rate from all causes was 28.7%, the microbiological clearance of the targeted bacteria after therapy was 56.2% and nephrotoxicity occurred in 24.7% of cases. Neurotoxicity relating to reversible numbness was observed in two cases.Conclusion: Polymyxin B seems to be effective and safe for the treatment of XDR Gram-negative bacterial infections. Polymyxin B should be considered as an alternative to colistin for treatment of infections caused by XDR Gram-negative bacteria in Thai adult patients, especially those at risk of nephrotoxicity. Keywords: mortality, acute kidney injury, Acinetobacter baumannii

Abstract Background Colistin is one of the last resort therapeutic options for treating carbapenemase-producing Enterobacterales, which are resistant to a broad range of beta-lactam antibiotics. However, the increased use of colistin in clinical and livestock farming settings in Thailand and China, has led to the inevitable emergence of colistin resistance. To better understand the rise of colistin-resistant strains in each of these settings, we characterized colistin-resistant Enterobacterales isolated from farmers, swine, and hospitalized patients in Thailand. Methods Enterobacterales were isolated from 149 stool samples or rectal swabs collected from farmers, pigs, and hospitalized patients in Thailand between November 2014–December 2017. Confirmed colistin-resistant isolates were sequenced. Genomic analyses included species identification, multilocus sequence typing, and detection of antimicrobial resistance determinants and plasmids. Results The overall colistin-resistant Enterobacterales colonization rate was 26.2% (n = 39/149). The plasmid-mediated colistin-resistance gene (mcr) was detected in all 25 Escherichia coli isolates and 9 of 14 (64.3%) Klebsiella spp. isolates. Five novel mcr allelic variants were also identified: mcr-2.3, mcr-3.21, mcr-3.22, mcr-3.23, and mcr-3.24, that were only detected in E. coli and Klebsiella spp. isolates from farmed pigs. Conclusion Our data confirmed the presence of colistin-resistance genes in combination with extended spectrum beta-lactamase genes in bacterial isolates from farmers, swine, and patients in Thailand. Differences between the colistin-resistance mechanisms of Escherichia coli and Klebsiella pneumoniae in hospitalized patients were observed, as expected. Additionally, we identified mobile colistin-resistance mcr-1.1 genes from swine and patient isolates belonging to plasmids of the same incompatibility group. This supported the possibility that horizontal transmission of bacterial strains or plasmid-mediated colistin-resistance genes occurs between humans and swine.

Abstract Background Stroke is a major cause of morbidity and mortality worldwide. Urinary tract infection (UTI) is a common post-acute ischemic stroke (AIS) complication. We assessed the incidence, determinant factors, infection characteristics, post-stroke complications, and outcomes of hospitalized AIS patients with UTI. Methods This retrospective cohort study included AIS patients admitted within 7 days of stroke onset. The patients were divided into the UTI group and the non-UTI (control) group. Clinical data were collected and compared between the groups. Results There were 342 AIS patients (31 with UTIs and 311 controls). The multivariate analysis showed that an initial National Institutes of Health Stroke Scale (NIHSS) score of ≥ 15 (odds ratio [OR] 5.00, 95% confidence interval [CI] 1.33–18.72) and Foley catheter retention (OR 14.10, 95% CI 3.25–61.28) were risk factors for UTI, whereas smoking (OR 0.08, 95% CI 0.01–0.50), an initial systolic blood pressure (SBP) of > 120 mmHg (OR 0.06, 95% CI 0.01–0.31), and statin use (OR 0.02, 95% CI 0.0006–0.42) were protective factors. Twenty cases (64.5%) were community-acquired and 11 cases (35.3%) were hospital-acquired. Ten patients (32.3%) had catheter-associated UTIs. The most common pathogen was Escherichia coli (13 patients, 41.9%). Post-stroke complications were significantly more common in the UTI group, including pneumonia, respiratory failure, sepsis, brain edema, seizure, symptomatic hemorrhagic transformation, congestive heart failure, atrial fibrillation with a rapid ventricular response, acute kidney injury, and hyponatremia. The median length of stay (LOS) in the UTI group was 12 days versus 3 days in the control group (p 120 mmHg and statin use were protective factors. The UTI group had significantly worse post-stroke complications, a longer LOS, and worse 3-month outcomes. Smoking was protective, which requires further investigation.

Stroke-associated pneumonia (SAP) is a common complication of acute ischemic stroke (AIS). This single-center retrospective observational study aimed to identify factors associated with SAP and predictors of poor outcomes in hospitalized patients with AIS. The study included patients admitted to Chumphon Khet Udomsakdi Hospital in Thailand within 7 days of the onset of AIS between July 2019 and July 2020. The patients were divided according to whether they were diagnosed with SAP during hospitalization into a pneumonia group and a non-pneumonia (control) group. Factors associated with SAP were identified. After 3 months, the patients with AIS were divided into those with a poor outcome (modified Rankin scale [mRS] score ≥4) and those with a non-poor outcome (mRS score

Abstract Background Neurosyphilis (NS) can lead to acute ischemic stroke (AIS) or transient ischemic attack (TIA). We compared the clinical characteristics and laboratory features among AIS and TIA patients who were syphilis-seronegative (control group) or had latent syphilis (LS) or NS to evaluate their stroke outcome. Methods This prospective cohort study was conducted on patients who had recently suffered AIS or TIA. After serological syphilis screening, clinical and laboratory data were collected, and brain imaging and spinal tap (serologically syphilis-positive patients only) were performed. Stroke outcome was re-evaluated approximately three months later. Results The 344 enrolled patients were divided into three groups: control group (83.7%), LS (13.1%), and NS (3.2%). A multivariate analysis revealed: 1) age of ≥ 70 years, generalized brain atrophy via imaging, and alopecia (adjusted odds ratio [AOR] = 2.635, 2.415, and 13.264, respectively) were significantly associated with LS vs controls; 2) age of ≥ 70 years (AOR = 14.633) was significantly associated with NS vs controls; and 3) the proportion of patients with dysarthria was significantly lower (AOR = 0.154) in the NS group than in the LS group. Regarding the NS patient cerebrospinal fluid (CSF) profile, only 2/11 cases had positive CSF-Venereal Disease Research Laboratory (VDRL) test results; the other nine cases were diagnosed from elevated white blood cell counts or protein levels combined with positive CSF fluorescent treponemal antibody absorption (FTA-ABS) test results. Regarding disability, the initial modified Rankin scale (mRS) score was lower in the control group than in the NS group (p = 0.022). At 3 months post-stroke, the mRS score had significantly decreased in the control (p

Background Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of imipenemase (IMP)–encoding CPE among diverse Enterobacterales species between 2016 and 2019 across a London regional network. Methods We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE–positive patients. Genomes of IMP-encoding CPE isolates were overlaid with patient contacts to imply potential transmission events. Results Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, and Escherichia coli); 86% (72 of 84) harbored an IncHI2 plasmid carrying bla IMP and colistin resistance gene mcr-9 (68 of 72). Phylogenetic analysis of IncHI2 plasmids identified 3 lineages showing significant association with patient contacts and movements between 4 hospital sites and across medical specialties, which was missed in initial investigations. Conclusions Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of bla IMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multimodal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks. Summary This was an investigation, using integrated pathway networks and genomics methods, of the emergence of imipenemase-encoding carbapenemase-producing Enterobacterales among diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network, which was missed on routine investigations. [ABSTRACT FROM AUTHOR]

Abstract Background Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) have continually grown as a global public health threat, with significant mortality rates observed across the world. We examined the clinical data from patients with CPE infections and their outcomes, concentrating on Klebsiella pneumoniae isolates. We analysed the clinical information, performed antimicrobial susceptibility testing, and conducted molecular epidemiological and genomic analyses on the isolates to identify patterns in the data. Methods The clinical characteristics of 33 hospitalised patients with confirmed CPE, including patient-related factors associated with the development of CPE infections, were examined. Patients were divided according to whether they were “colonised” or “infected” with CPE and by the timing and frequency of their rectal swab collections, from which 45 swabs were randomly selected for analysis. CPE isolates were purified, and antimicrobial susceptibility tests performed. Whole genome sequences of these isolates were determined and analysed to compute bacterial multilocus sequence types and plasmid replicon types, infer phylogenetic relationships, and identify antimicrobial resistance and virulence genes. Results Altogether, 88.9% (40/45) of the CPE isolates were K. pneumoniae. The most abundant carbapenemase gene family in the K. pneumoniae isolates (33/39) was bla OXA-232, with bla NDM-1 additionally identified in 19 of them. All CPE isolates carrying either bla OXA-232 or bla NDM-1 were resistant to meropenem, but only 40 from 45 were susceptible to colistin. Among the CPE-infected patients (n = 18) and CPE-colonised patients who developed CPE infections during the study (n = 3), all but one received standard colistin-based combination therapy. Phylogenetic analysis revealed the polyclonal spread of carbapenemase-producing K. pneumoniae (CPKP) within the patient population, with the following two major subclades identified: ST16 (n = 15) and ST231 (n = 14). CPKP-ST231 had the highest virulence score of 4 and was associated with primary bacteraemia. The siderophores yersiniabactin and aerobactin, considered to be important virulence factors, were only identified in the CPKP-ST231 genomes. Conclusions This study has revealed the genomic features of colonising CPE isolates, focusing on antimicrobial resistance and virulence determinants. This type of multi-layered analysis can be further exploited in Thailand and elsewhere to modify the regimes used for empirical antibiotic treatment and improve the management strategies for CPE infections in hospitalised patients.

Objectives: In this data collation study, we aimed to provide a comprehensive database describing the epidemic trends and responses during the first wave of coronavirus disease 2019 (COVID-19) throughout the main provinces in China. Methods: From mid-January to March 2020, we extracted publicly available data regarding the spread and control of COVID-19 from 31 provincial health authorities and major media outlets in mainland China. Based on these data, we conducted descriptive analyses of the epidemic in the six most-affected provinces. Results: School closures, travel restrictions, community-level lockdown, and contact tracing were introduced concurrently around late January but subsequent epidemic trends differed among provinces. Compared with Hubei, the other five most-affected provinces reported a lower crude case fatality ratio and proportion of critical and severe hospitalised cases. From March 2020, as the local transmission of COVID-19 declined, switching the focus of measures to the testing and quarantine of inbound travellers may have helped to sustain the control of the epidemic. Conclusions: Aggregated indicators of case notifications and severity distributions are essential for monitoring an epidemic. A publicly available database containing these indicators and information regarding control measures is a useful resource for further research and policy planning in response to the COVID-19 epidemic.

Background: As of August 2021, every region of the world has been affected by the COVID-19 pandemic, with more than 196,000,000 cases worldwide. Methods: We analysed COVID-19 cases among travellers from mainland China to different regions and countries, comparing the region- and country-specific rates of detected and confirmed cases per flight volume to estimate the relative sensitivity of surveillance in different regions and countries. Results: Although travel restrictions from Wuhan City and other cities across China may have reduced the absolute number of travellers to and from China, we estimated that up to 70% (95% CI: 54% - 80%) of imported cases could remain undetected relative to the sensitivity of surveillance in Singapore. The percentage of undetected imported cases rises to 75% (95% CI 66% - 82%) when comparing to the surveillance sensitivity in multiple countries. Conclusions: Our analysis shows that a large number of COVID-19 cases remain undetected across the world. These undetected cases potentially resulted in multiple chains of human-to-human transmission outside mainland China.

Summary: Background: COVID-19 has the potential to cause substantial disruptions to health services, due to cases overburdening the health system or response measures limiting usual programmatic activities. We aimed to quantify the extent to which disruptions to services for HIV, tuberculosis, and malaria in low-income and middle-income countries with high burdens of these diseases could lead to additional loss of life over the next 5 years. Methods: Assuming a basic reproduction number of 3·0, we constructed four scenarios for possible responses to the COVID-19 pandemic: no action, mitigation for 6 months, suppression for 2 months, or suppression for 1 year. We used established transmission models of HIV, tuberculosis, and malaria to estimate the additional impact on health that could be caused in selected settings, either due to COVID-19 interventions limiting activities, or due to the high demand on the health system due to the COVID-19 pandemic. Findings: In high-burden settings, deaths due to HIV, tuberculosis, and malaria over 5 years could increase by up to 10%, 20%, and 36%, respectively, compared with if there was no COVID-19 pandemic. The greatest impact on HIV was estimated to be from interruption to antiretroviral therapy, which could occur during a period of high health system demand. For tuberculosis, the greatest impact would be from reductions in timely diagnosis and treatment of new cases, which could result from any prolonged period of COVID-19 suppression interventions. The greatest impact on malaria burden could be as a result of interruption of planned net campaigns. These disruptions could lead to a loss of life-years over 5 years that is of the same order of magnitude as the direct impact from COVID-19 in places with a high burden of malaria and large HIV and tuberculosis epidemics. Interpretation: Maintaining the most critical prevention activities and health-care services for HIV, tuberculosis, and malaria could substantially reduce the overall impact of the COVID-19 pandemic. Funding: Bill & Melinda Gates Foundation, Wellcome Trust, UK Department for International Development, and Medical Research Council.