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Background Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. Method and results This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). Conclusions Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

Background:The risk of environmental contamination by severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in the intensive care unit (ICU) is unclear. We evaluated the extent of environmental contamination in the ICU and correlated this with patient and disease factors, including the impact of different ventilatory modalities.Methods:In this observational study, surface environmental samples collected from ICU patient rooms and common areas were tested for SARS-CoV-2 by polymerase chain reaction (PCR). Select samples from the common area were tested by cell culture. Clinical data were collected and correlated to the presence of environmental contamination. Results were compared to historical data from a previous study in general wards.Results:In total, 200 samples from 20 patient rooms and 75 samples from common areas and the staff pantry were tested. The results showed that 14 rooms had at least 1 site contaminated, with an overall contamination rate of 14% (28 of 200 samples). Environmental contamination was not associated with day of illness, ventilatory mode, aerosol-generating procedures, or viral load. The frequency of environmental contamination was lower in the ICU than in general ward rooms. Eight samples from the common area were positive, though all were negative on cell culture.Conclusion:Environmental contamination in the ICU was lower than in the general wards. The use of mechanical ventilation or high-flow nasal oxygen was not associated with greater surface contamination, supporting their use and safety from an infection control perspective. Transmission risk via environmental surfaces in the ICUs is likely to be low. Nonetheless, infection control practices should be strictly reinforced, and transmission risk via droplet or airborne spread remains.

We aim to describe a case series of critically and non-critically ill COVID-19 patients in Singapore. This was a multicentered prospective study with clinical and laboratory details. Details for fifty uncomplicated COVID-19 patients and ten who required mechanical ventilation were collected. We compared clinical features between the groups, assessed predictors of intubation, and described ventilatory management in ICU patients. Ventilated patients were significantly older, reported more dyspnea, had elevated C-reactive protein and lactate dehydrogenase. A multivariable logistic regression model identified respiratory rate (aOR 2.83, 95% CI 1.24–6.47) and neutrophil count (aOR 2.39, 95% CI 1.34–4.26) on admission as independent predictors of intubation with area under receiver operating characteristic curve of 0.928 (95% CI 0.828–0.979). Median APACHE II score was 19 (IQR 17–22) and PaO2/FiO2 ratio before intubation was 104 (IQR 89–129). Median peak FiO2 was 0.75 (IQR 0.6–1.0), positive end-expiratory pressure 12 (IQR 10–14) and plateau pressure 22 (IQR 18–26) in the first 24 h of ventilation. Median duration of ventilation was 6.5 days (IQR 5.5–13). There were no fatalities. Most COVID-19 patients in Singapore who required mechanical ventilation because of ARDS were extubated with no mortality.

Background The proportion of asymptomatic carriers and transmission risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among household and non-household contacts remains unclear. In Singapore, extensive contact tracing by the Ministry of Health for every diagnosed COVID-19 case, and legally enforced quarantine and intensive health surveillance of close contacts provided a rare opportunity to determine asymptomatic attack rates and SARS-CoV-2 transmission risk factors among community close contacts of patients with COVID-19. Methods This retrospective cohort study involved all close contacts of confirmed COVID-19 cases in Singapore, identified between Jan 23 and April 3, 2020. Household contacts were defined as individuals who shared a residence with the index COVID-19 case. Non-household close contacts were defined as those who had contact for at least 30 min within 2 m of the index case. All patients with COVID-19 in Singapore received inpatient treatment, with access restricted to health-care staff. All close contacts were quarantined for 14 days with thrice-daily symptom monitoring via telephone. Symptomatic contacts underwent PCR testing for SARS-CoV-2. Secondary clinical attack rates were derived from the prevalence of PCR-confirmed SARS-CoV-2 among close contacts. Consenting contacts underwent serology testing and detailed exposure risk assessment. Bayesian modelling was used to estimate the prevalence of missed diagnoses and asymptomatic SARS-CoV-2-positive cases. Univariable and multivariable logistic regression models were used to determine SARS-CoV-2 transmission risk factors. Findings Between Jan 23 and April 3, 2020, 7770 close contacts (1863 household contacts, 2319 work contacts, and 3588 social contacts) linked to 1114 PCR-confirmed index cases were identified. Symptom-based PCR testing detected 188 COVID-19 cases, and 7582 close contacts completed quarantine without a positive SARS-CoV-2 PCR test. Among 7518 (96·8%) of the 7770 close contacts with complete data, the secondary clinical attack rate was 5·9% (95% CI 4·9–7·1) for 1779 household contacts, 1·3% (0·9–1·9) for 2231 work contacts, and 1·3% (1·0–1·7) for 3508 social contacts. Bayesian analysis of serology and symptom data obtained from 1150 close contacts (524 household contacts, 207 work contacts, and 419 social contacts) estimated that a symptom-based PCR-testing strategy missed 62% (95% credible interval 55–69) of COVID-19 diagnoses, and 36% (27–45) of individuals with SARS-CoV-2 infection were asymptomatic. Sharing a bedroom (multivariable odds ratio [OR] 5·38 [95% CI 1·82–15·84]; p=0·0023) and being spoken to by an index case for 30 min or longer (7·86 [3·86–16·02]; p

Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in individual patients. In a prospective observational study, standard dosing (mean 2.5 mg/kg daily) was administered in 13 adult patients. Serial blood samples were obtained at steady state, and plasma polymyxin B concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The best-fit estimates of clearance and daily doses were used to derive the observed area under the curve (AUC) in concentration–time profiles. For comparison, 5 different population pharmacokinetic models of polymyxin B were conditioned using patient-specific dosing and demographic (if applicable) variables to predict polymyxin B AUC of the same patient. The predictive performance of the models was assessed by the coefficient of correlation, bias, and precision. The correlations between observed and predicted AUC in all 5 models examined were poor (r2 < 0.2). Nonetheless, the models were reasonable in capturing AUC variability in the patient population. Therapeutic drug monitoring currently remains the only viable approach to individualized dosing.

Patients with COVID-19 are known to be at risk of developing both venous, arterial and microvascular thrombosis, due to an excessive immuno-thrombogenic response to the SARS-CoV-2 infection. Overlapping syndromes of COVID-19 associated coagulopathy with consumptive coagulopathy and microangiopathy can be seen in critically ill patients as well. Blood was collected from 12 Intensive Care Unit (ICU) patients with severe COVID-19 who were on either mechanical ventilation or on high flow oxygen with a PaO2/FiO2 ratio of

We describe the clinical, laboratory and radiological features of 3 critically ill patients with COVID-19 who developed severe encephalopathy. The first patient did not regain consciousness when sedation was removed at the end of 2 weeks of intensive care. He had received treatment with convalescent plasma. His clinical examination was remarkable for intact brainstem reflexes, roving eye movements, later transient ocular flutter; and then what appeared to be slow ocular dipping. He had no coherent volitional response to the environment. The second patient recovered with measurable cognitive deficits after a prolonged period of encephalopathy. He had received combination treatment with interferon beta 1b and lopinavir/ritonavir. The third patient remained in persistent, severe agitated delirium and died 3 months into his illness. The MRI of the 3 patients showed multifocal abnormalities predominantly in the cerebral white matter, with varying involvement of the grey matter, brainstem and spinal cord. Case 1's MRI changes were consistent with acute disseminated encephalomyelitis. The patients also displayed blood markers, to varying degree, of autoimmunity and hypercoagulability. We were not able to convincingly show, from microbiological as well as immunological evaluation, if the effects of COVID-19 on these patients' nervous system were a direct consequence of the virus, proinflammatory-thrombotic state or a combination. Patient 1 responded partially to empirical, albeit delayed, therapy with intravenous immunoglobulins. Patient 2 recovered with no specific treatment. These cases illustrate the need to understand the full spectrum of encephalopathy associated with COVID-19 so as to better guide its management., Highlights • We describe three severe COVID-19 patients with encephalopathy. • We hypothesize possible underlying pathophysiology; viral, parainfectious or both. • We discuss the dilemma we faced in their diagnosis and management.

SARS-CoV-2 Infection in Travelers Returning from Wuhan Data on travelers returning from areas with many cases of Covid-19 may be useful in estimating incidence. The authors report follow-up data on...

Since the outbreak of the 2019 novel coronavirus (COVID-19), the role of physiotherapy for patients with COVID-19 infection has been highlighted by various international guidelines. Despite that, clinical information regarding the rehabilitation of patients with COVID-19 infection remains limited. In this case series, we provide a novel insight into the physiotherapy management in patients infected with COVID-19 in Singapore. The main findings are: (1) Respiratory physiotherapy interventions were not indicated in the majority of the patients with COVID-19 in this case series; (2) During rehabilitation, exertional or position-related desaturation is a common feature observed in critically ill patients with COVID-19 infection locally. This clinical phenomenon of exertional or positional-related desaturation has significantly slowed down the progression of rehabilitation in our patients. As such, it can potentially result in a significant burden on healthcare resources to provide rehabilitation to these patients. Based on these findings, we have highlighted several recommendations for the provision of rehabilitation in patients who are critically ill with COVID-19.

Introduction The multi-disciplinary antimicrobial stewardship team at the study hospital conducts prospective review and feedback on all inpatient orders of piperacillin–tazobactam and carbapenems. In addition, the team provides non-antibiotic recommendations (i.e. additional investigations and infectious disease reviews). This study aimed to describe the impact of these recommendations on patient outcomes. Methods Patients on carbapenem and piperacillin–tazobactam who received at least one non-antibiotic recommendation between January 2012 and August 2014 were included in this study. Acceptance and rejection of non-antibiotic recommendations by the managing physician were compared. The primary outcome was 30-d mortality. Results Non-antibiotic recommendations were made in 166 patients. There were no differences in baseline characteristics between patients for whom recommendations were accepted and patients for whom recommendations were rejected. Thirty-day mortality (18.0% vs. 34.5%, P = 0.02) was significantly lower in patients who had at least one non-antibiotic recommendation accepted. Multi-variate analysis found that Charlson's comorbidity score [odds ratio (OR) 1.20, 95% confidence interval (CI) 1.03–1.42, P = 0.03], APACHE II score (OR 1.10, 95% CI 1.01–1.19, P P = 0.02) and acceptance of at least one non-antibiotic recommendation (OR 0.39, 95% CI 0.17–0.88, P = 0.02) were independently associated with 30-d mortality. Conclusions During prospective review and feedback of piperacillin–tazobactam and carbapenems, acceptance of non-antibiotic recommendations was found to be associated with a reduction in 30-d mortality.

Objective Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. This study aims to describe the thrombotic and bleeding rates in COVID-19 patients admitted to intensive care units (ICU) in Singapore. Design Retrospective observational study involving all consecutive adult COVID-19 patients who required ICU admission between 23 January 2020 and 30 April 2020. Setting National multicenter study involving all eight public hospitals in Singapore. Patients 111 consecutive COVID-19 patients who required ICU admission were included. Measurements and Main Results Primary outcome was any venous or arterial thrombotic events occurred in ICU. Other measures included (1) the overall, venous and arterial thrombotic events throughout the hospitalisation, (2) major and minor bleeding events. The overall thrombotic rate in ICU was 11.7% (n=13), with 1.8% (n=2) venous and 9.9% (n=11) arterial events. The overall thrombotic rates throughout hospitalisation, censored at 30 April 2020, increased to 18.0% (n=20) with 6.3% (n=7) venous and 11.7% (n=13) arterial events. Major and minor bleeding rates were 14.8% (n=16) and 3.7% (n=4), respectively. Two-third of the patients received pharmacological thromboprophylaxis in ICU. Conclusions Critically ill COVID-19 patients in Singapore have lower VTE but higher arterial thrombosis rates with higher bleeding manifestations than other reported cohorts. Standard thromboprophylaxis may be sufficient to prevent thrombotic complications in patients with similar demographics. Disclosures No relevant conflicts of interest to declare.

Objectives A wide range of duration of viral RNA shedding in patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) has been observed. We aimed to investigate factors associated with prolonged and intermittent viral RNA shedding in a retrospective cohort of symptomatic COVID‐19 patients. Methods Demographic, clinical and laboratory data from hospitalised COVID‐19 patients from a single centre with two consecutive negative respiratory reverse transcription‐polymerase chain reaction (RT‐PCR) results were extracted from electronic medical records. Kaplan–Meier survival curve analysis was used to assess the effect of clinical characteristics on the duration and pattern of shedding. Plasma levels of immune mediators were measured using Luminex multiplex microbead‐based immunoassay. Results There were 201 symptomatic patients included. Median age was 49 years (interquartile range 16–61), and 52.2% were male. Median RNA shedding was 14 days (IQR 9–18). Intermittent shedding was observed in 77 (38.3%). We did not identify any factor associated with prolonged or intermittent viral RNA shedding. Duration of shedding was inversely correlated with plasma levels of T‐cell cytokines IL‐1β and IL‐17A at the initial phase of infection, and patients had lower levels of pro‐inflammatory cytokines during intermittent shedding. Conclusions Less active T‐cell responses at the initial phase of infection were associated with prolonged viral RNA shedding, suggesting that early immune responses are beneficial to control viral load and prevent viral RNA shedding. Intermittent shedding is common and may explain re‐detection of viral RNA in recovered patients., We studied 201 patients with PCR‐confirmed COVID‐19 infection. We found median RNA shedding was 14 days and intermittent RNA shedding was observed in 38.3%. The only associated clinical factor with prolonged RNA shedding was invasive mechanical ventilation. Importantly, we observed in a subset of patients with cytokine analysis, that prolonged RNA shedding was associated with EGF, FGF‐2, GRO‐α and RANTES at the initial phase of infection. Intermittent RNA shedding was associated with lower levels of pro‐inflammatory cytokines.

Background Early formulations of Takeda’s tetravalent dengue vaccine candidate (TAK-003) have demonstrated notably higher neutralizing antibody responses against serotype 2 than other serotypes. Here, we assessed the immunogenicity and tolerability in adults living in Singapore of two TAK-003 formulations: an early formulation, referred to as HD-TDV, and a new formulation with 10-fold lower serotype 2 potency, referred to as TDV (NCT02425098). Methods Subjects aged 21–45 years were stratified by baseline dengue serostatus and randomised 1:1 to receive a single dose of either HD-TDV or TDV. Immunogenicity was evaluated at Days 15, 30, 90, 180, and 365 post-vaccination as geometric mean titres (GMTs) of neutralising antibodies and seropositivity rates. Viremia was assessed per vaccine strain. Solicited and unsolicited adverse events (AEs) were assessed by severity and causality. Results Of 351 subjects randomised, 176 received HD-TDV and 175 received TDV. Peak GMTs against all serotypes were observed at Day 30, with highest GMTs against DENV-2 in both groups. In subjects seronegative at baseline, the response to DENV-2 was less dominant with TDV (Day 30 GMTs: 813 for TDV, 10,966 for HD-TDV). In these subjects, DENV-4 seropositivity rates and GMTs were higher with TDV (Day 30 GMTs: 58 for TDV, 21 for HD-TDV; seropositivity rates: 76% for TDV, 60% for HD-TDV). Viremia mainly occurred for TDV-2 in both vaccine groups, with a lower incidence in TDV recipients, and mostly resolved by Day 30. Both vaccine formulations showed an acceptable safety profile with similar overall rates of solicited and unsolicited AEs across vaccine groups. Conclusions These results suggest a more balanced immune response with the new formulation TDV compared with the early formulation HD-TDV, particularly in subjects who were seronegative prior to vaccination, and support the choice of the new formulation for the phase 3 efficacy assessment.

Antimicrobial stewardship is used to combat antimicrobial resistance. In Singapore, a tertiary hospital has integrated a computerised decision support system, called Antibiotic Resistance Utilisation and Surveillance-Control (ARUSC), into the electronic inpatient prescribing system. ARUSC is launched either by the physician to seek guidance for an infectious disease condition or via auto-trigger when restricted antibiotics are prescribed. This paper describes the implementation of ARUSC over three phases from 1 May 2011 to 30 April 2013, compared factors between ARUSC launches via auto-trigger and for guidance, examined factors associated with acceptance of ARUSC recommendations, and assessed user acceptability. During the study period, a monthly average of 9072 antibiotic prescriptions was made, of which 2370 (26.1%) involved ARUSC launches. Launches via auto-trigger comprised 48.1% of ARUSC launches. In phase 1, 23% of ARUSC launches were completed. This rose to 38% in phase 2, then 87% in phase 3, as escapes from the ARUSC programme were sequentially disabled. Amongst completed launches for guidance, 89% of ARUSC recommendations were accepted versus 40% amongst completed launches via auto-trigger. Amongst ARUSC launches for guidance, being from a medical department [adjusted odds ratio (aOR)=1.20, 95% confidence interval (CI) 1.04-1.37] and ARUSC launch during on-call (aOR=1.81, 95% CI 1.61-2.05) were independently associated with acceptance of ARUSC recommendations. Junior physicians found ARUSC useful. Senior physicians found ARUSC reliable but admitted to having preferences for antibiotics that may conflict with ARUSC. Hospital-wide implementation of ARUSC encountered hurdles from physicians. With modifications, the completion rate improved.

Background Prospective review and feedback (PRF) of antibiotic prescriptions is a tenet of antimicrobial stewardship (ASP), but labour intensive. Clinical Decision Support Systems (CDSS) have the potential to automate some of this work. We hypothesised that increasing prescriber engagement with the CDSS would reduce the requirement for PRF by the ASP team and improve prescribing behaviour without causing harm Methods A parallel-group, 1:1 block-cluster randomized, cross-over study was conducted in 32 medical and surgical wards from March 2017 to August 2017. Participants in Arm A were allocated to voluntary use of CDSS by the clinician at first prescription of piperacillin–tazobactam or a carbapenem, while in Arm B, CDSS use was compulsory. PRF continued for both arms. Results Six hundred fourty-one and 616 participants were included in Arms A and B, respectively. At baseline, Charlson’s co-morbidity and APACHE II scores were comparable. Initial antibiotic prescriptions were similar, and the majority were for respiratory (67.0% vs. 68.2%) or urinary (17% vs. 19.6%) infections. CDSS recommendations were provided to 20.6% of participants in Arm A and 99.4% in Arm B (P < 0.01). Arm B adopted a higher number of CDSS antibiotic de-escalation (1.1% vs. 2.6%), dose optimization (9.7% vs. 30.7%), antibiotic optimization (8.9% vs. 31.3%), and duration setting recommendations (10.9% vs. 50%). The proportion of participants receiving PRF recommendations were not, however, significantly different between arms (8% vs. 11.5%, P = 0.13). The types of PRF recommendations and prescriber acceptance rates were also similar. The duration of antibiotic use was significantly shorter when prescribers were compelled to use the CDSS (daily defined doses ≤3: 71.8% in Arm B, 64.9% in Arm A, P < 0.01). There was no evidence of harm from the CDSS, with similar 30-day mortality (HR 0.87, 95% CI 0.67–1.12), 30-day re-infection (20.6% vs. 23.1%, P = 0.29) and 30-day re-admission rates (14.4% vs. 14.1%, P = 0.91). The median length of hospital admission was also similar (15 IQR 5–64 vs. 15, IQR 4–70 days). Conclusion Compulsory use of a CDSS at antibiotic prescription did not reduce the requirement for PRF, but limited the duration of antibiotic courses, without compromising clinical outcomes Disclosures All authors: No reported disclosures.

Objectives To evaluate the safety and clinical outcomes of patients who received carbapenem de-escalation as guided by an antimicrobial stewardship programme (ASP) in a setting where ESBL-producing Enterobacteriaceae are endemic. Methods Patients receiving meropenem or imipenem underwent a prospective ASP review for eligibility for de-escalation according to defined institutional guidelines. Patients in whom carbapenem was de-escalated or not de-escalated, representing the acceptance and rejection of the ASP recommendation, respectively, were compared. The primary outcome was the clinical success rate; secondary outcomes included the 30 day readmission and mortality rates, the duration of carbapenem therapy, the incidence of adverse drug reactions due to antimicrobials, the acquisition of carbapenem-resistant Gram-negative bacteria and the occurrence of Clostridium difficile-associated diarrhoea (CDAD). Results The de-escalation recommendations for 300 patients were evaluated; 204 (68.0%) were accepted. The patient demographics and disease severity were similar. The clinical success rates were similar [de-escalated versus not de-escalated, 183/204 (89.7%) versus 85/96 (88.5%), P = 0.84], as was the survival at hospital discharge [173/204 (84.8%) versus 79/96 (82.3%), P = 0.58]. In the de-escalated group, the duration of carbapenem therapy was shorter (6 versus 8 days, P Conclusions This study suggests that the ASP-guided de-escalation of carbapenems led to comparable clinical success, fewer adverse effects and a lower incidence of the development of resistance. This approach is safe and practicable, and should be a key component of an ASP.

To the Editor: Clostridium difficile–associated disease (CDAD) has increased in incidence across North America and Europe (1). Recent reports document the emergence of an epidemic strain of C. difficile, NAP1/BI/027, associated with increased virulence (2,3). However, less information is available regarding CDAD epidemiology in Asia. We examined the incidence of C. difficile among hospitalized patients in Singapore from 2001 through 2006 and conducted a case–control study to evaluate risk factors for testing positive for C. difficile toxin (CDT) in our population. Tan Tock Seng Hospital (TTSH) is a 1,200-bed, acute-care general hospital in Singapore that serves an urban population of 4 million. We calculated CDAD incidence using the number of patients testing positive for CDT per 10,000 patient days from 2001 through 2006. We used this calculation because CDT testing would have been ordered for clinical indications. CDT testing was performed by using the same ELISA (Premier Toxins AB Meridian Bioscience, Inc., Cincinnati, OH, USA) throughout the entire period of investigation. Case-patients and controls were selected from patients hospitalized at TTSH from January 1 through December 31, 2004. Microbiology laboratory records were used to define 3 groups. Case-patients were defined as CDT-positive inpatients (group 1). Two sets of negative controls were defined: the first (group 2) consisted of patients who tested negative for CDT. However, because false-negatives could nullify differences between groups 1 and 2, we defined a second set of negative controls (group 3) from among 18,000 inpatients not tested for CDT. Seventy patients were selected from each group by using a random number generator program. Forty-eight, 61, and 56 records were retrieved for groups 1, 2, and 3, respectively. Standardized forms were used to extract data from hospital medical records. Demographic data and hospitalization details, including ward type (6-bed, 4-bed, or single room), were collected. We examined antimicrobial drug use within 30 days of admission and within 30 days of CDT testing. We also evaluated the use of proton pump inhibitors (PPIs) and H2 blockers because these have been reported as risk factors (1,4–6). Outcomes ascertained included the time to discharge after CDT testing, and death within 30 days after CDT testing. The study was approved by the institutional ethics review board. Characteristics of case-patients and controls were compared by using the Wilcoxon rank sum test for continuous variables and the Fisher exact test for categorical variables. Variables significantly associated with CDT in the univariate analysis were selected for inclusion in the multivariate regression model. A 2-sided p value 14 days) than in those who had shorter hospital stays (