Establishing a New Normal for Hospital Care: A Whole of Hospital Approach to Coronavirus Disease 2019 (COVID-19).

Singapore's hospitals had prepared to receive patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), planning various scenarios and levels of surge with a policy of isolating all confirmed cases as inpatients. The National University Hospital adopted a whole of hospital approach to coronavirus disease 2019 (COVID-19) with 3 primary goals: zero hospital-acquired COVID-19, all patients receive timely necessary care, and maintenance of staff morale. These goals to date have been met. A large influx of COVID-19 cases required significant transformation of clinical and operational processes. Isolation room numbers almost tripled and dedicated COVID-19 cohort wards were established, elective care was postponed, and intensive care units were augmented with equipment and manpower. In the wake of the surge, establishing a new normal for hospital care requires maintaining vigilance to detect endemic COVID-19, establishing contingency plans to ramp up in case of another surge, while returning to business as usual.

Oral vs Intravenous Antibiotics for Patients With Klebsiella pneumoniae Liver Abscess: A Randomized, Controlled Noninferiority Study.

BACKGROUND: Klebsiella pneumoniae liver abscess (KLA) is emerging worldwide due to hypermucoviscous strains with a propensity for metastatic infection. Treatment includes drainage and prolonged intravenous antibiotics. We aimed to determine whether oral antibiotics were noninferior to continued intravenous antibiotics for KLA. METHODS: This noninferiority, parallel group, randomized, clinical trial recruited hospitalized adults with liver abscess and K. pneumoniae isolated from blood or abscess fluid who had received ≤7 days of effective antibiotics at 3 sites in Singapore. Patients were randomized 1:1 to oral (ciprofloxacin) or intravenous (ceftriaxone) antibiotics for 28 days. If day 28 clinical response criteria were not met, further oral antibiotics were prescribed until clinical response was met. The primary endpoint was clinical cure assessed at week 12 and included a composite of absence of fever in the preceding week, C-reactive protein <20 mg/L, and reduction in abscess size. A noninferiority margin of 12% was used. RESULTS: Between November 2013 and October 2017, 152 patients (mean age, 58.7 years; 25.7% women) were recruited, following a median 5 days of effective intravenous antibiotics. A total of 106 (69.7%) underwent abscess drainage; 71/74 (95.9%) randomized to oral antibiotics met the primary endpoint compared with 72/78 (92.3%) randomized to intravenous antibiotics (risk difference, 3.6%; 2-sided 95% confidence interval, -4.9% to 12.8%). Effects were consistent in the per-protocol population. Nonfatal serious adverse events occurred in 12/72 (16.7%) in the oral group and 13/77 (16.9%) in the intravenous group. CONCLUSIONS: Oral antibiotics were noninferior to intravenous antibiotics for the early treatment of KLA. CLINICAL TRIALS REGISTRATION: NCT01723150.

Responding to COVID-19: how an academic infectious diseases division mobilized in Singapore.

BACKGROUND: On January 30, COVID-19 was declared a Public Health Emergency of International Concern-a week after Singapore's first imported case and 5 days before local transmission. The National University Hospital (NUH) is Singapore's third largest hospital with 1200 beds, heavy clinical workloads, and major roles in research and teaching. MAIN BODY: With memories of SARS still vivid, there was an urgent requirement for the NUH Division of Infectious Diseases to adapt-undergoing major reorganization to face rapidly changing priorities while ensuring usual essential services and standards. Leveraging on individual strengths, our division mobilized to meet the demands of COVID-19 while engaging in high-level coordination, strategy, and advocacy. We present our experience of the 60 days since the nation's first case. During this time, our hospital has managed 3030 suspect cases, including 1300 inpatients, 37 confirmed cases, and overseen 4384 samples tested for COVID-19. CONCLUSION: Complex hospital adaptations were supported by an unprecedented number of workflows and coordination channels essential to safe and effective operations. The actions we describe, aligned with international recommendations and emerging evidence-based best practices, may serve as a framework for other divisions and institutions facing the spread of COVID-19 globally.

Prevalence of Healthcare-Associated Infections and Antimicrobial Use Among Adult Inpatients in Singapore Acute-Care Hospitals: Results From the First National Point Prevalence Survey.

BACKGROUND: We conducted a national point prevalence survey (PPS) to determine the prevalence of healthcare-associated infections (HAIs) and antimicrobial use (AMU) in Singapore acute-care hospitals. METHODS: Trained personnel collected HAI, AMU, and baseline hospital- and patient-level data of adult inpatients from 13 private and public acute-care hospitals between July 2015 and February 2016, using the PPS methodology developed by the European Centre for Disease Prevention and Control. Factors independently associated with HAIs were determined using multivariable regression. RESULTS: Of the 5415 patients surveyed, there were 646 patients (11.9%; 95% confidence interval [CI], 11.1%-12.8%) with 727 distinct HAIs, of which 331 (45.5%) were culture positive. The most common HAIs were unspecified clinical sepsis (25.5%) and pneumonia (24.8%). Staphylococcus aureus (12.9%) and Pseudomonas aeruginosa (11.5%) were the most common pathogens implicated in HAIs. Carbapenem nonsusceptibility rates were highest in Acinetobacter species (71.9%) and P. aeruginosa (23.6%). Male sex, increasing age, surgery during current hospitalization, and presence of central venous or urinary catheters were independently associated with HAIs. A total of 2762 (51.0%; 95% CI, 49.7%-52.3%) patients were on 3611 systemic antimicrobial agents; 462 (12.8%) were prescribed for surgical prophylaxis and 2997 (83.0%) were prescribed for treatment. Amoxicillin/clavulanate was the most frequently prescribed (24.6%) antimicrobial agent. CONCLUSIONS: This survey suggested a high prevalence of HAIs and AMU in Singapore's acute-care hospitals. While further research is necessary to understand the causes and costs of HAIs and AMU in Singapore, repeated PPSs over the next decade will be useful to gauge progress at controlling HAIs and AMU.

Type I IFNs and IL-18 regulate the antiviral response of primary human γδ T cells against dendritic cells infected with Dengue virus.

Little is known about the cellular mechanisms of innate immunity against dengue virus (DV) infection. Specifically, the γδ T cell response to DV has not been characterized in detail. In this article, we demonstrate that markers of activation, proliferation, and degranulation are upregulated on γδ T cells in PBMC isolated from individuals with acute dengue fever. Primary γδ T cells responded rapidly in vitro to autologous DV-infected dendritic cells by secreting IFN-γ and upregulating CD107a. The anti-DV IFN-γ response is regulated by type I IFN and IL-18 in a TCR-independent manner, and IFN-γ secreting γδ T cells predominantly expressed IL-18Rα. Antagonizing the ATP-dependent P2X7 receptor pathway of inflammasome activation significantly inhibited the anti-DV IFN-γ response of γδ T cells. Overnight priming with IL-18 produced effector γδ T cells with significantly increased ability to lyse autologous DV-infected dendritic cells. Monocytes were identified as accessory cells that augmented the anti-DV IFN-γ response of γδ T cells. Lack of monocytes in culture is associated with lower IL-18 levels in culture supernatant and diminished production of IFN-γ by γδ T cells, whereas addition of exogenous IL-18 restored the IFN-γ response of γδ T cells in monocyte-depleted cocultures with DV-infected DC. Our results indicate that primary γδ T cells contribute to the immune response during DV infection by providing an early source of IFN-γ, as well as by killing DV-infected cells, and suggest that monocytes participate as accessory cells that sense DV infection and amplify the cellular immune response against this virus in an IL-18-dependent manner.

A qualitative study of sign-out processes between primary and on-call residents: relationships in information exchange, responsibility and accountability.

OBJECTIVE: To review a quality improvement event on the process of sign-outs between the primary and on-call residents. DESIGN: A retrospective qualitative study using semi-structured interviews. SETTING: A tertiary academic medical center in Singapore with 283 inpatient Medicine beds served by 28 consultants, 29 registrars, 45 residents and 30 interns during the day but 5 residents and 3 interns at night. PARTICIPANTS: Residents, registrars and consultants. INTERVENTION: Quality improvement event on sign-out. MAIN OUTCOME: Effectiveness of sign-out comprises exchange of patient information, professional responsibility and task accountability. RESULTS: The following process of sign-outs was noted. Primary teams were accountable to the on-call resident by selecting at-risk patients and preparing contingency plans for sign-out. Structured information exchanged included patient history, active problems and plans of care. On-call residents took ownership of at-risk patients by actively asking questions during sign-out and reporting back the agreed care plan. On-call residents were accountable to the primary team by reporting back at-risk patients the next day. CONCLUSION: A structured information exchange at sign-out increased the on-call resident's ability to care for at-risk patients when it was supported by two-way transfers of responsibility and accountability.

Pharmacokinetics of ertapenem in outpatients with complicated urinary tract infections.

OBJECTIVES: Ertapenem is a broad-spectrum carbapenem antibiotic used to treat severe bacterial infections. In view of its dosing convenience, it is increasingly used as outpatient therapy. The objective of this study was to determine the pharmacokinetics and renal disposition of ertapenem in outpatients with complicated urinary tract infections. METHODS: Ertapenem was administered as a daily intravenous infusion of 1 g over 30 min. At steady-state, blood and urine samples were collected over one dosing interval. Drug concentrations in serum and urine were determined using a validated liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was used to characterize ertapenem serum and urine profiles. The likelihood of the standard dosing achieving a favourable pharmacokinetic-pharmacodynamic exposure was evaluated using Monte Carlo simulations. RESULTS: Ten adult male patients were studied. Concentration-time profiles of ertapenem in both serum (r(2) =0.997) and urine (r(2) =0.982) were captured satisfactorily. Mean values for volume of distribution, clearance and elimination t½ were 4.8 L, 0.7 L/h and 6.1 h, respectively. A high ertapenem concentration (>128 mg/L) could be attained in the urine at 40% of the dosing interval. CONCLUSIONS: The pharmacokinetics of ertapenem in serum and urine were characterized. Our simulations suggested that a sufficiently high ertapenem concentration could be achieved in urine to overcome low to intermediate resistance. Clinical investigations to validate our findings are warranted.

The global spread of healthcare-associated multidrug-resistant bacteria: a perspective from Asia.

Since antibiotics were first used, each new introduced class has been followed by a global wave of emergent resistance, largely originating in Europe and North America where they were first used. Methicillin-resistant Staphylococcus aureus spread from the United Kingdom and North America across Europe and then Asia over more than a decade. Vancomycin-resistant enterococci and Klebsiella pneumoniae carbapenemase-producing K. pneumoniae followed a similar path some 20 years later. Recently however, metallo-ß-lactamases have originated in Asia. New Delhi metallo-ß-lactamase-1 was found in almost every continent within a year of its emergence in India. Metallo-ß-lactamase enzymes are encoded on highly transmissible plasmids that spread rapidly between bacteria, rather than relying on clonal proliferation. Global air travel may have helped facilitate rapid dissemination. As the antibiotic pipeline offers little in the short term, our most important tools against the spread of antibiotic resistant organisms are intensified infection control, surveillance, and antimicrobial stewardship.

Progression from new methicillin-resistant Staphylococcus aureus colonisation to infection: an observational study in a hospital cohort.

BACKGROUND: Patients newly colonised with methicillin-resistant Staphylococcus aureus (MRSA) are at higher risk of clinical MRSA infection. At present, there are limited data on the duration or magnitude of this risk in a hospital population with a known time of MRSA acquisition. METHODS: A retrospective cohort study of 909 adult patients known to have newly identified MRSA colonisation during admission to National University Hospital, Singapore between 1 July 2007 and 30 June 2011 was undertaken. Patients were excluded if they had history of previous MRSA colonisation or infection, or if they had been a hospital inpatient in the preceding 12 months. Data were collected on the development of MRSA infection requiring hospitalisation up to 30 June 2012. RESULTS: Of 840 patients newly colonised with MRSA as identified on active surveillance and not clinical specimens, 546 were men (65.0%) and the median age was 65 years (range 18-103 years). Median follow up was 24 months (range 0 -64 months, 85.1% followed >6 months). Clinical infection occurred in 121 patients (14.4%) with median time to infection of 22 days (95% CI 14-31). Overall 71.9% (87/121) of infected patients developed infection within 60 days of the date MRSA colonisation was detected. However, 17/121 patients (14.0%) developed clinical infection more than six months after documented MRSA acquisition. The most common sites of clinical infection were skin and soft tissue (49/121, 40.5%, 95% CI 31.7-49.8), respiratory tract (37/121, 30.6%, 95% CI 22.5-39.6) and bone and joint infections (14/121, 11.6%, 95% CI 6.5-18.7). Thirteen patients (13/121, 10.7%, 95% CI 5.8-17.7) had bacteraemias, of which six (5.0% 95% CI 1.8-10.5) were primary and seven (5.7%, 95% CI 2.3-11.6) were secondary to infection at other sites. Crude mortality at 30 days and six months was higher in patients with MRSA infection than colonisation alone (aOR 5.49, 95% CI 2.75-10.95, p<0.001 and aOR 2.94, 95% CI 1.78-4.85, p<0.001 respectively). CONCLUSION: Risk of clinical infection is highest soon after MRSA acquisition. Prevention of MRSA acquisition in hospital will have significant impact on morbidity and mortality for patients.

Efficacy of continuous infusion of vancomycin for the outpatient treatment of methicillin-resistant Staphylococcus aureus infections.

OBJECTIVES: Recently published guidelines on the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend against administering vancomycin by continuous infusion on the basis of insufficient studies comparing this with intermittent infusion. We compared outcomes of patients treated with continuous infusion and intermittent infusion of vancomycin. PATIENTS AND METHODS: Data for outpatients treated with continuous infusion and intermittent infusion of vancomycin were compared utilizing rates of clinical failure defined as the need for unplanned re-admission, change of antibiotics or extension of therapy. RESULTS: A total of 244 patients met the inclusion criteria, with 188 receiving continuous infusion and 56 intermittent infusion of vancomycin. The endpoint occurred in 21.3% and 30.4% of those receiving continuous infusion and intermittent infusion, respectively (relative risk 0.701, 95% CI 0.432-1.136, P = 0.159). Patient characteristics differed slightly between the two groups; however, logistic regression to adjust for differences in age, co-morbidity, subtherapeutic levels and prosthetic devices did not substantially alter this result. CONCLUSIONS: No difference in rates of clinical failure of continuous infusion and intermittent infusion of vancomycin was observed in this outpatient cohort.

Confirmed adult dengue deaths in Singapore: 5-year multi-center retrospective study.

BACKGROUND: Dengue re-emerges in Singapore despite decades of effective vector control; the infection predominantly afflicts adults. Severe dengue not fulfilling dengue hemorrhagic fever (DHF) criteria according to World Health Organization (WHO) 1997 guideline was increasingly reported. A new WHO 2009 guideline emphasized warning signs and a wider range of severe dengue manifestations. We aim to evaluate the utility of these two guidelines in confirmed adult dengue fatalities. METHODS: We conducted a multi-center retrospective chart review of all confirmed adult dengue deaths in Singapore from 1 January 2004 to 31 December 2008. RESULTS: Of 28 adult dengue deaths, median age was 59 years. Male gender comprised 67.9% and co-morbidities existed in 75%. From illness onset, patients presented for admission at a median of 4 days and death occurred at a median of 12 days. Intensive care admission was required in 71.4%. Probable dengue was diagnosed in 32.1% by WHO 1997 criteria and 78.6% by WHO 2009. The earliest warning sign was persistent vomiting at a median of 1.5 days. Hematocrit change ≥20% concurrent with platelet count <20 × 10^9/L was associated with the shortest interval to death at a median of 3 days. Only 35.7% of death cases fulfilled DHF criteria by WHO 1997 versus severe dengue in 100.0% by WHO 2009 criteria. Deaths were due to shock and organ failure. Acute renal impairment occurred in 71.4%, impaired consciousness 57.1% and severe hepatitis 53.6%. CONCLUSIONS: In our adult fatal dengue cohort, WHO 2009 criteria had higher sensitivity in diagnosing probable dengue and severe dengue compared with WHO 1997. As warning signs, persistent vomiting occurred early and hematocrit change ≥20% concurrent with platelet count <20 × 10^9/L preceded death most closely.

Ward-level factors associated with methicillin-resistant Staphylococcus aureus acquisition-an electronic medical records study in Singapore.

BACKGROUND: Methicillin-Resistant Staphylococcus aureus (MRSA) is endemic in hospitals worldwide. Intrahospital transfers may impact MRSA acquisition risk experienced by patients. In this study, we investigated ward characteristics and connectivity that are associated with MRSA acquisition. METHODS: We analysed electronic medical records on patient transfers and MRSA screening of in-patients at an acute-care tertiary hospital in Singapore to investigate whether ward characteristics and connectivity within a network of in-patient wards were associated with MRSA acquisition rates over a period of four years. RESULTS: Most patient transfers concentrated in a stable core network of wards. Factors associated with increased rate of MRSA acquisition were MRSA prevalence among patients transferred from other wards (rate ratio (RR): 7.74 [95% confidence interval (CI): 3.88, 15.44], additional 5 percentage point), critical care ward (RR: 1.72 [95% CI: 1.09, 2.70]) and presence of MRSA cohorting beds (RR: 1.39 [95% CI: 1.03, 1.90]. Oncology ward (RR: 0.66 [95% CI: 0.46, 0.94]) (compared to medical ward), and median length of stay (RR: 0.70 [95% CI: 0.55, 0.90], additional 1.5 days) were associated with lower acquisition rates. In addition, we found evidence of interaction between MRSA prevalence among patients transferred from other wards and weighted in-degree although the latter was not associated with MRSA acquisition after controlling for confounders. CONCLUSION: Wards with higher MRSA prevalence among patients transferred from other wards were more likely to have higher MRSA acquisition rate. Its effect further increased in wards receiving greater number of patients. In addition, critical care ward, presence of MRSA cohorting beds, ward specialty, and median length of stay were associated with MRSA acquisition.

Scenarios to Manage the Demand for N95 Respirators for Healthcare Workers During the COVID-19 Pandemic.

BACKGROUND: By estimating N95 respirator demand based on simulated epidemics, we aim to assist planning efforts requiring estimations of respirator demand for the healthcare system to continue operating safely in the coming months. METHODS: We assess respiratory needs over the course of mild, moderate and severe epidemic scenarios within Singapore as a case study using a transmission dynamic model. The number of respirators required within the respiratory isolation wards and intensive care units was estimated over the course of the epidemic. We also considered single-use, extended-use and prolonged-use strategies for N95 respirators for use by healthcare workers treating suspected but negative (misclassified) or confirmed COVID-19 patients. RESULTS: Depending on the confirmed to misclassified case ratio, from 1:0 to 1:10, a range of 117.1 million to 1.1 billion masks are required for single-use. This decreases to 71.6-784.4 million for extended-use and 12.8-148.2 million for prolonged-use, representing a 31.8-38.9% and 86.5-89.1% reduction, respectively. CONCLUSION: An extended-use policy should be considered when short-term supply chains are strained but planning measures are in place to ensure long-term availability. With severe shortage expectations from a severe epidemic, as some European countries have experienced, prolonged use is necessary to prolong supply.

Cost-effectiveness analysis of hospital infection control response to an epidemic respiratory virus threat.

The outbreak of influenza A pandemic (H1N1) 2009 prompted many countries in Asia, previously strongly affected by severe acute respiratory syndrome (SARS), to respond with stringent measures, particularly in preventing outbreaks in hospitals. We studied actual direct costs and cost-effectiveness of different response measures from a hospital perspective in tertiary hospitals in Singapore by simulating outbreaks of SARS, pandemic (H1N1) 2009, and 1918 Spanish influenza. Protection measures targeting only infected patients yielded lowest incremental cost/death averted of 23,000 (US dollars) for pandemic (H1N1) 2009. Enforced protection in high-risk areas (Yellow Alert) and full protection throughout the hospital (Orange Alert) averted deaths but came at an incremental cost of up to $2.5 million/death averted. SARS and Spanish influenza favored more stringent measures. High case-fatality rates, virulence, and high proportion of atypical manifestations impacted cost-effectiveness the most. A calibrated approach in accordance with viral characteristics and community risks may help refine responses to future epidemics.

Pseudo-outbreak of Rhizobium radiobacter infection resulting from laboratory contamination of saline solution.

We report a pseudo-outbreak of Rhizobium radiobacter infections resulting from contamination by a saline dispenser in the microbiology laboratory. Isolates from clinical specimens had identical antimicrobial susceptibilities and electrophoretic fingerprints. The episode resolved with autoclaving of the dispenser. This demonstrates the importance of timely, thorough investigation of unusual organisms, particularly when they appear as a cluster.

A cost analysis of Outpatient Parenteral Antibiotic Therapy (OPAT): an Asian perspective.

The concept of Outpatient Parenteral Antibiotic Therapy (OPAT) is relatively new in Asia. This study compared the actual costs and outcomes of care involving OPAT with conventional inpatient-only care at a university hospital in Singapore. Actual costs were obtained for selected patients enrolled in OPAT after 1 January 2005 and these costs were directly compared with those of age-, gender- and diagnosis-matched patients managed as inpatients only prior to the availability of OPAT in the preceding 12 months. Outcomes of patients were also considered. The OPAT and inpatient-only groups comprised 72 and 93 enrollments, respectively. Mean treatment duration for OPAT patients was 42.5 days versus 19 days for those receiving inpatient-only care (P < 0.001). The mean total treatment cost for OPAT and inpatient-only care was US$12 736 and $12 403, respectively (P = 0.706). Mean cost per day for care including an OPAT episode was US$278 versus $457 per day for inpatient-only care (P < 0.001). There was no difference in outcomes between the two groups. OPAT is a viable alternative to inpatient care as it is safe, effective and results in lower daily costs. The trend to longer treatment courses is worthy of further review.

Risk factors for nephrotoxicity associated with continuous vancomycin infusion in outpatient parenteral antibiotic therapy.

OBJECTIVES: Continuous vancomycin infusion is increasingly used for outpatient management of infections, but the relationship between vancomycin and nephrotoxicity is controversial. We investigated the risk factors associated with nephrotoxicity in this setting. METHODS: A retrospective cohort study of patients receiving continuous vancomycin infusion as outpatient parenteral antibiotic therapy (OPAT) was performed. The likelihood of developing nephrotoxicity (> or =50% increase in serum creatinine from baseline) was evaluated in relation to demographic variables, underlying co-morbidities, infectious disease diagnoses, concomitant drug exposures and vancomycin concentration. Logistic regression was used to determine the association of various variables. Classification and regression tree analysis was used to determine the most significant breakpoint for continuous variables. RESULTS: We examined 102 adult patients between January 2004 and June 2007. The mean +/- SD age, baseline serum creatinine and steady-state vancomycin concentration were 48.2 +/- 17.6 years, 78.0 +/- 32.5 micromol/L and 15.5 +/- 10.8 mg/L, respectively. The majority of the patients (66.7%) were treated for bone and joint infection. The cumulative incidence of nephrotoxicity was 15.7%. Nephrotoxicity was found to be associated with hypertension [odds ratio (OR) 5.302 (95% confidence interval (CI) 1.159-24.246), P = 0.031], exposure to aminoglycosides [OR 6.594 (95% CI 1.026-42.385), P = 0.047], loop diuretics [OR 8.123 (95% CI 1.449-45.528), P = 0.017], and steady-state vancomycin concentration > or =28 mg/L [OR 21.236 (95% CI 2.687-167.857), P = 0.004]. CONCLUSIONS: We have identified independent risk factors for nephrotoxicity in patients receiving continuous infusion vancomycin in OPAT. A serum steady-state vancomycin concentration > or =28 mg/L markedly increases the risk.