Adjunctive Pascolizumab in Rifampicin-Susceptible Pulmonary Tuberculosis: Proof-of-Concept, Partially-Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial.

BACKGROUND: Interleukin 4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanized anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. METHODS: Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo, and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: (1) nonrandomized 0.05 mg/kg (n = 4); (2) nonrandomized 0.5 mg/kg (n = 4); (3) randomized 2.5 mg/kg (n = 9) or placebo (n = 3); and (4) randomized 10 mg/kg (n = 9) or placebo (n = 3). Coprimary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE) in all cohorts (1-4). Coprimary efficacy outcome was week 8 sputum culture time-to-positivity (TTP) in randomized cohorts (3-4) combined. RESULTS: Pascolizumab levels exceeded IL-4 50% neutralizing dose for 8 weeks in 78%-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (P = .185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 log10 TTP/day; 95% Bayesian credible interval 0.006 to 0.015 log10 TTP/day). CONCLUSIONS: There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials. CLINICAL TRIALS REGISTRATION: NCT01638520.

Technology-enabled virtual ward for COVID management of the elderly and immunocompromised in Singapore: a descriptive cohort.

BACKGROUND: To address the hospital bed demand for Delta and Omicron surges in Singapore, the National University Health System (NUHS) developed a COVID Virtual Ward to relieve bed pressures on its three acute hospitals-National University Hospital, Ng Teng Fong General Hospital, Alexandra Hospital. To serve a multilingual population, the COVID Virtual Ward featuring protocolized teleconsultation of high-risk patients, use of a vital signs chatbot, supplemented by home visits where necessary. This study aims to evaluate the safety, outcomes and utilisation of the Virtual Ward as a scalable response to COVID-19 surges. METHODS: This is a retrospective cohort study of all patients admitted to the COVID Virtual Ward between 23 September to 9 November 2021. Patients were defined as "early discharge" if they were referred from inpatient COVID-19 wards and "admission avoidance" if they were referred directly from primary care or emergency services. Patient demographics, utilisation measures and clinical outcomes were extracted from the electronic health record system. The primary outcomes were escalation to hospital and mortality. Use of the vital signs chatbot was evaluated by examining compliance levels, need for automated reminders and alerts triggered. Patient experience was evaluated using data extracted from a quality improvement feedback form. RESULTS: 238 patients were admitted to the COVID Virtual Ward from 23 September to 9 November, of whom 42% were male, 67.6% of Chinese ethnicity. 43.7% were over the age of 70, 20.5% were immunocompromised, and 36.6% were not fully vaccinated. 17.2% of patients were escalated to hospital and 2.1% of patients died. Patients who were escalated to hospital were more likely to be immunocompromised or to have a higher ISARIC 4C-Mortality Score. There were no missed deteriorations. All patients received teleconsults (median of 5 teleconsults per patient, IQR 3-7). 21.4% of patients received home visits. 77.7% of patients engaged with the vital signs chatbot, with a compliance rate of 84%. All patients would recommend the programme to others in their situation. CONCLUSIONS: Virtual Wards are a scalable, safe and patient-centered strategy to care for high risk COVID-19 patients at home. TRIAL REGISTRATION: NA.

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.

Epidemiology and risk factors for invasive fungal disease in liver transplant recipients in a tertiary transplant center.

BACKGROUND: Invasive fungal disease (IFD) in liver transplant recipients causes significant morbidity and mortality. We aim to describe institutional epidemiology and risk factors for IFD in the liver transplant population. METHODS: We conducted a retrospective cohort study of all adult liver transplant recipients in our institution from 2005 to October 2015 to describe the epidemiology of patients with proven and probable IFD according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. To determine risk factors for IFD, a case-control study was also conducted. Cases were defined as liver transplant recipients with proven or probable IFD, and controls were defined as liver transplant recipients without IFD. Each case was matched to two controls by age (±10 years of age), gender, and time of transplant (within one year of the case). RESULTS: 28/554 (5.1%) patients developed IFD. Candidiasis (n = 11; 39.3%), Aspergillosis (n = 10; 35.7%), and Cryptococcosis (n = 3; 10.7%) were the most common fungal infections in the proven and probable IFD groups. Mold infections occurred in 13 (46.4%) cases. Reoperation, roux-en-y anastomosis, and massive intraoperative transfusion of ≥40 units of cellular blood products were major risk factors for IFD in the multivariate analysis. CONCLUSION: Candida and Aspergillus are the most common causes of IFD in liver transplantation in our center. There is significant overlap in risk factors for such infections post-transplantation. In our cohort, critically ill patients with complicated perioperative course seem to predispose them to mold infections post-transplantation, but larger studies are required to better delineate risk factors for mold infection as well as determine the efficacy and optimal duration of mold prophylaxis in liver transplantation. With increasing echinocandin use for antifungal prophylaxis, it is also important to monitor for emerging antifungal resistance.

Aminoglycoside-associated acute kidney injury in elderly patients with and without shock.

OBJECTIVES: Multiresistant Gram-negative pathogens pose major healthcare concerns with a limited therapeutic armamentarium. Aminoglycosides (AG) are under-utilized due to nephrotoxicity. We aimed to evaluate AG-associated acute kidney injury (AG-AKI) in elderly inpatients, with and without shock. METHODS: We examined the incidence and predictors of AG-AKI by KDIGO criteria and extended renal dysfunction (ERD) in patients aged >60 years. ERD represented a composite of hospital mortality or absence of renal recovery over 6 months following AG-AKI. RESULTS: Two hundred and seventy-eight patients (aged 74 ±â€Š8 years) were studied; 43% and 19% received >7 and >10 days of AG therapy, respectively, and 70% gentamicin (versus amikacin). Thirteen per cent had shock and 17% developed AG-AKI. Comparing all patients with shock versus no shock, AG-AKI developed in 33% versus 14%, respectively (P = 0.005); correspondingly among 47 patients with AG-AKI, more with shock had stage 2/3 AKI (92% versus 43%) and dialysis (50% versus 9%) (P < 0.01), but more had other strong AKI confounders than AG therapy alone (83% versus 40%, P = 0.02). Multivariate analyses identified mechanical ventilation, frusemide administration and AG therapy >10 days as predictors of AG-AKI (P < 0.05), whereas shock, pneumonia and frusemide administration predicted more severe stage 2/3 AG-AKI (P < 0.05). Hospital mortality was 30% versus 7% with AG-AKI versus none (P < 0.001). Twenty-three of 211 (11%) patients with extended analysis had ERD, with 47% experiencing renal recovery following AG-AKI. Mechanical ventilation and contrast administration during index hospitalization predicted ERD (P < 0.05). CONCLUSIONS: AG-AKI is common in the elderly, with a significant risk of ERD, but the cause and severity are greatly influenced by critical illness and shock, more so than AG therapy alone.

Elevated serum lactate dehydrogenase aids prediction of mortality in Pneumocystis jirovecii pneumonia without underlying human immunodeficiency virus infection - Derivation of a clinical risk score.

Pneumocystis jirovecii pneumonia (PCP) is associated with significant mortality amongst patients without underlying human immunodeficiency virus infection (HIV). We sought to develop a risk score to predict mortality in this population. We reviewed patients with a presumed or confirmed PCP and a negative HIV test from 2006-2023. We constructed a multivariable model to identify parameters independently associated with mortality and the adjusted odds ratios were converted to weights to derive a risk score. Subsequently, we compared the performance of our score to the CURB-65 score by means of area under receiver operating characteristic curve (AUC). In total, we examined 93 patients with PCP without HIV. Mortality was 31.2%. Risk factors for mortality included older age, male sex and high serum lactate dehydrogenase levels (LDH) and C-reactive protein levels. A risk score was derived comprising age> 65 years (2 points), male sex (2 points) and LDH> 770 U/L (3 points). Our risk score (AUC 0.71, 95%CI 0.60-0.82) performed better than the CURB-65 score (AUC 0.53, 95%CI 0.41-0.66). A low-risk score of 0-1 had excellent negative predictive value for mortality (97.5%). In conclusion, a risk score comprising age, sex and LDH can predict mortality in PCP without underlying HIV and help with prognostication.

Volvariella volvacea brain Abscess in an immunocompromised host-An emerging fungal pathogen in Asia.

Volvariella volvacea is a fungus found in tropical regions, commonly associated with straw mushrooms. This is a 50-year-old Singaporean female post living donor renal transplant who presented with fever, cough and headache. She was diagnosed to have Volvariella volvacea brain abscess. She was treated with combination anti-fungal therapy without surgical debridement and remains stable. The pathogenicity of this rare fungus in immunocompromised hosts is demonstrated here and is of significance particularly in Asia where ingestion of straw mushrooms may be a risk factor for invasive fungal disease.

Deranged Coagulation Profile Secondary to Cefazolin Use: Case Report.

Cefazolin is a widely used first-generation cephalosporin. While generally well tolerated, several case reports have described severe coagulopathy induced by intravenous (IV) cefazolin. This was seen particularly in patients with impaired renal function, where antibiotic choice is limited and may require specific dose adjustments. Altered renal handling of antibiotics and their metabolites may potentiate toxicity and side effects. We report a case of a 72-year-old Chinese man who had been treated for methicillin-sensitive staphylococcus aureus (MSSA, coagulase-positive) infective endocarditis with cefazolin and, consequently, developed significantly elevated international normalised ratio (INR) while on therapy. This resolved within 48 h after cessation of cefazolin and administration of oral vitamin K. Malnourished patients with pre-existing or acute kidney injury may be at an increased risk of cefazolin-related coagulopathy.

An Epidemiological Meta-Analysis on the Worldwide Prevalence, Resistance, and Outcomes of Spontaneous Bacterial Peritonitis in Cirrhosis.

Background and Aims: Spontaneous bacterial peritonitis (SBP) is a common and potentially fatal complication of liver cirrhosis. This study aims to analyze the prevalence of SBP among liver cirrhotic patients according to geographical location and income level, and risk factors and outcomes of SBP. Methods: A systematic search for articles describing prevalence, risk factors and outcomes of SBP was conducted. A single-arm meta-analysis was performed using generalized linear mix model (GLMM) with Clopper-Pearson intervals. Results: Ninety-Nine articles, comprising a total of 5,861,142 individuals with cirrhosis were included. Pooled prevalence of SBP was found to be 17.12% globally (CI: 13.63-21.30%), highest in Africa (68.20%; CI: 12.17-97.08%), and lowest in North America (10.81%; CI: 5.32-20.73%). Prevalence of community-acquired SBP was 6.05% (CI: 4.32-8.40%), and 11.11% (CI: 5.84-20.11%,) for healthcare-associated SBP. Antibiotic-resistant microorganisms were found in 11.77% (CI: 7.63-17.73%) of SBP patients. Of which, methicillin-resistant Staphylococcus aureus was most common (6.23%; CI: 3.83-9.97%), followed by extended-spectrum beta-lactamase producing organisms (6.19%; CI: 3.32-11.26%), and lastly vancomycin-resistant enterococci (1.91%; CI: 0.41-8.46%). Subgroup analysis comparing prevalence, antibiotic resistance, and outcomes between income groups was conducted to explore a link between socioeconomic status and SBP, which revealed decreased risk of SBP and negative outcomes in high-income countries. Conclusion: SBP remains a frequent complication of liver cirrhosis worldwide. The drawn link between income level and SBP in liver cirrhosis may enable further insight on actions necessary to tackle the disease on a global scale.

The Case for Intermittent Carbapenem Dosing in Stable Haemodialysis Patients.

PURPOSE: Antimicrobial resistant infections are common in patients on haemodialysis, often needing long courses of carbapenems. This results in a longer hospital stay and risk of iatrogenic complications. However, carbapenems can be given intermittently to allow for earlier discharge. We aim to describe the clinical outcomes of intermittent versus daily meropenem in stable, intermittently haemodialysed patients. METHODS: In total, 103 records were examined retrospectively. Data collected include demographics, clinical interventions and outcomes such as hospital length of stay (LOS), 30-day readmission rates and adverse events. FINDINGS: Mean age 61.6 ± 14.2 years, 57.3% male. Most common bacteria cultured were Klebsiella pneumoniae (16.5%). The most common indication was pneumonia (27.2%). Mean duration of therapy on meropenem was 12.4 ± 14.4 days; eight patients needed more than 30 days of meropenem. In total, 55.3% did not have intervention for source control; 86.4% received daily dosing of meropenem; 7.8% patients received intermittent dosing of meropenem only, and 5.8 patients received both types of dosing regimens. LOS of the index admission was shorter for the intermittent arm (15.5 ± 7.6 days versus daily: 30.2 ± 24.5 days), though 30-day readmission was higher (50% versus daily: 38.2%). IMPLICATIONS: We recommend further rigorous randomised controlled trials to investigate the clinical utility of intermittent meropenem dosing in patients on stable haemodialysis.