Impact of an Antimicrobial Stewardship Intervention on the Appropriateness of Carbapenem Use at a Tertiary Hospital in Malaysia.

Introduction Carbapenems are broad-spectrum antibiotics used to treat infections caused by multidrug-resistant organisms. The inappropriate use of carbapenem results in the development of antimicrobial resistance. The aim of this study was to determine the impact of an antimicrobial stewardship intervention on the appropriateness of carbapenem use. Method The study includes a baseline/pre-intervention audit, an intervention, and a post-intervention study to examine the impact of antimicrobial stewardship activities on carbapenem use. Audit and data collection were carried out by filling up an audit form. The indicator for this study will be the appropriateness of carbapenem use (appropriate, suboptimal, or inappropriate) pre- and post-intervention. Results The overall appropriateness of carbapenem prescription in the medical wards increased from 65% to 83.3% following the implementation of antimicrobial stewardship intervention. The most common indication of carbapenem usage in our study was hospital-acquired pneumonia/ventilator-associated pneumonia. Conclusion Antimicrobial stewardship intervention is effective in improving the appropriateness of carbapenem use. Tailored stewardship programs are required to better control carbapenem use and combat antimicrobial resistance.

A double whammy: The association between comorbidities and severe dengue among adult patients-A matched case-control study.

BACKGROUND: Dengue infection is the most prevalent mosquito-borne viral infection globally. Concurrently, there has also been an upsurge of non-communicable comorbidities. We aimed to investigate the association between these comorbidities and the development of severe dengue. METHODS: We performed a retrospective, case-control study involving 117 cases with severe dengue and 351 controls with non-severe dengue; matched according to gender, age (+/- 5 years old), and admission date (+/- 2 weeks). We analyzed the data using conditional odds ratio (cOR) and adjusted conditional odds ratio (AcOR) using univariate and multivariable conditional logistic regression respectively. RESULTS: Six main comorbidities namely obesity, diabetes mellitus, hypertension, hyperlipidemia, chronic pulmonary disease, and ischemic heart disease were observed among cases and controls. Multivariable conditional logistic regression model found only hypertension to be independently associated with the development of severe dengue (ACOR 2.46; 95% CI:1.09-5.53). Among symptoms at presentation, lethargy, vomiting, bleeding manifestations, and abdominal pain were associated with increased odds of severe dengue, although the associations were not statistically significant. Headache (ACOR: 0:32; 95% CI: 0.21-0.51) and skin rash (ACOR: 0.42; 95% CI: 0.22-0.81) were associated with significantly lower odds of severe dengue. Severe dengue patients were also found to have significantly higher white cell count, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, creatine kinase, and lactate dehydrogenase on admission, while platelet and albumin were significantly lower compared to non-severe dengue patients. CONCLUSIONS: Our study found a significant association between hypertension and the development of severe dengue in adult patients. For clinical practice, this finding suggests that dengue patients with underlying hypertension warrant closer clinical monitoring for deterioration. The association between significant derangement in various laboratory parameters and severe dengue as shown in this study is in keeping with previous reports. While further substantiation by larger prospective studies will be desirable, this association may serve to inform the dengue triaging process.

Self-reported symptom study of COVID-19 chemosensory dysfunction in Malaysia.

Alterations in the three chemosensory modalities-smell, taste, and chemesthesis-have been implicated in Coronavirus Disease 2019 (COVID-19), yet emerging data suggest a wide geographic and ethnic variation in the prevalence of these symptoms. Studies on chemosensory disorders in COVID-19 have predominantly focused on Caucasian populations whereas Asians remain understudied. We conducted a nationwide, multicentre cross-sectional study using an online questionnaire on a cohort of RT-PCR-confirmed adult COVID-19 patients in Malaysia between 6 June and 30 November 2020. The aim of our study was to investigate their presenting symptoms and assess their chemosensory function using self-ratings of perceived smell, taste, chemesthesis, and nasal blockage. In this cohort of 498 patients, 41.4% reported smell and/or taste loss when diagnosed with COVID-19, which was the commonest symptom. Blocked nose, loss of appetite, and gastrointestinal disturbances were independent predictors of smell and/or taste loss on multivariate analysis. Self-ratings of chemosensory function revealed a reduction in smell, taste, and chemesthesis across the entire cohort of patients that was more profound among those reporting smell and/or taste loss as their presenting symptom. Perceived nasal obstruction accounted for only a small proportion of changes in smell and taste, but not for chemesthesis, supporting viral disruption of sensorineural mechanisms as the dominant aetiology of chemosensory dysfunction. Our study suggests that chemosensory dysfunction in COVID-19 is more widespread than previously reported among Asians and may be related to the infectivity of viral strains.Study Registration: NMRR-20-934-54803 and NCT04390165.

Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial.

Importance: Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed. Objective: To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19. Design, Setting, and Participants: The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients' symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild to moderate disease. Interventions: Patients were randomized in a 1:1 ratio to receive either oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging. Main Outcomes and Measures: The primary outcome was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events. Results: Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7] years; 267 women [54.5%]), 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR], 1.25; 95% CI, 0.87-1.80; P = .25). For all prespecified secondary outcomes, there were no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09). The most common adverse event reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group). Conclusions and Relevance: In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04920942.

Clinical manifestations, laboratory profile and outcomes of dengue virus infection in hospitalised older patients.

BACKGROUND: Due to an ageing population, dengue among older patients is encountered more frequently in many countries. Our study aimed to explore the clinico-laboratory parameters and outcomes among dengue-infected older patients in comparison with younger patients. METHODS: This retrospective chart review involved dengue patients with dengue non-structural protein 1 (NS1) antigen positivity admitted to a tertiary hospital in Malaysia from January to July 2015. A comparison was made between older people (aged ≥60 y) and others. RESULTS: Among 406 dengue patients, 43 (10.6%) were older people. Older dengue patients were less likely to present with persistent vomiting (adjusted OR [AOR] 0.247, 95% CI 0.093 to 0.656, p=0.005), while restlessness and confusion were more common at presentation (AOR 3.356, 95% CI 1.024 to 11.003, p=0.046). Older patients had significantly lower albumin upon admission (38 vs 40 g/L, p=0.036) and during hospital stay (35 vs 37 g/L, p=0.015). Compared with younger patients, older patients were more likely to have experienced nadir platelet counts of <50×109/L (AOR 2.897, 95% CI to 1.176 to 7.137, p=0.021). They were also more likely to require an extended hospital stay (AOR 3.547, 95% CI 1.575 to 7.986, p=0.002). CONCLUSIONS: Diagnosis of dengue in older people may be challenging because of atypical presentations. Increased vigilance is necessary as there is an increased tendency to develop severe thrombocytopenia, hypoalbuminemia and prolonged hospitalisation in older people.

Efficacy of Early Treatment With Favipiravir on Disease Progression Among High-Risk Patients With Coronavirus Disease 2019 (COVID-19): A Randomized, Open-Label Clinical Trial.

BACKGROUND: The role of favipiravir in preventing disease progression in coronavirus disease 2019 (COVID-19) remains uncertain. We aimed to determine its effect in preventing disease progression from nonhypoxia to hypoxia among high-risk COVID-19 patients. METHODS: This was an open-label, randomized clinical trial conducted at 14 public hospitals across Malaysia (February-July 2021) among 500 symptomatic, RT-PCR-confirmed COVID-19 patients, aged ≥50 years with ≥1 comorbidity, and hospitalized within first 7 days of illness. Patients were randomized 1:1 to favipiravir plus standard care or standard care alone. Favipiravir was administered at 1800 mg 2×/day on day 1 followed by 800 mg 2×/day until day 5. The primary endpoint was rate of clinical progression from nonhypoxia to hypoxia. Secondary outcomes included rates of mechanical ventilation, intensive care unit (ICU) admission, and in-hospital mortality. RESULTS: Of 500 patients randomized (mean [SD] age, 62.5 [8.0] years; 258 women [51.6%]; 251 [50.2%] had COVID-19 pneumonia), 487 (97.4%) patients completed the trial. Clinical progression to hypoxia occurred in 46 (18.4%) patients on favipiravir plus standard care and 37 (14.8%) on standard care alone (OR, 1.30; 95% CI: .81-2.09; P = .28). All 3 prespecified secondary endpoints were similar between both groups. Mechanical ventilation occurred in 6 (2.4%) vs 5 (2.0%) (OR, 1.20; 95% CI: .36-4.23; P = .76), ICU admission in 13 (5.2%) vs 12 (4.8%) (OR, 1.09; 95% CI: .48-2.47; P = .84), and in-hospital mortality in 5 (2.0%) vs 0 (OR, 12.54; 95% CI: .76-207.84; P = .08) patients. CONCLUSIONS: Among COVID-19 patients at high risk of disease progression, early treatment with oral favipiravir did not prevent their disease progression from nonhypoxia to hypoxia. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT04818320).

Dengue fever complicated by hemophagocytic lymphohistiocytosis: Report of 2 cases and bone marrow findings.

Hemophagocytic lymphohistiocytosis is a rare but severe complication of dengue infection which carries a high mortality. This report highlights the importance of early recognition of this condition as prompt appropriate treatment improves outcomes.

Safety, potential efficacy, and pharmacokinetics of specific polyclonal immunoglobulin F(ab')2 fragments against avian influenza A (H5N1) in healthy volunteers: a single-centre, randomised, double-blind, placebo-controlled, phase 1 study.

BACKGROUND: Human infection with the avian influenza A H5N1 virus results in disease with a high fatality rate, against which antiviral treatments have limited efficacy. We aimed to investigate the safety, pharmacokinetics, and therapeutic potential of specific polyclonal immunoglobulin equine F(ab')2 fragments raised against influenza A/Vietnam/1194/2004 virus (H5N1 subtype) in healthy volunteers. METHODS: We did a randomised, double-blind, placebo-controlled, single-centre phase 1 study. In stage 1 (one infusion) and stage 2 (five infusions) of the trial, we randomly assigned healthy male volunteers to receive once-daily intravenous infusions of 0·85 U/kg body weight of F(ab')2 or once-daily saline placebo. Randomisation was done centrally, with one block of four patients and one block for substitutes (three actives, one placebo) in stage 1, and two blocks of six patients (five actives and one placebo) and the same block for substitutes in stage 2. The primary objective was assessment of the clinical and laboratory safety of F(ab')2, which was monitored for 22 days in the group that received one dose (assessments on days 0-2, 4, 8, 15, and 22) and 33 days in the group that received five doses (days 0-6, 8, 10, 12, 19, 26, and 33). A final post-study safety assessment was done at 120 days. We also assessed pharmacokinetic outcomes, and assayed haemagglutination and seroneutralisation activity. Analysis was done according to intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT02295813. FINDINGS: We enrolled 16 healthy Asian men between Sept 28 and Dec 28, 2012, and randomly assigned 13 to one or five doses of F(ab')2 and three to placebo. F(ab')2 was well tolerated, and no deaths or serious adverse events occurred. Three patients had mild adverse events (one each of blepharospasm, sinusitis, and pyrexia). The pyrexia (38°C) was regarded as probably related to the infusion, and resolved after 37 min. Our laboratory assessments of blood and urine samples and physical examinations of heart rate, electrocardiogram readings, and weight showed no clinically significant safety issues. Mean peak plasma concentrations were 19·3 µg/mL (SD 3·5) with the one dose schedule and 23·0 µg/mL (4·5) with the five-dose schedule. F(ab')2 were still detectable in plasma on average up to 5 days after five doses. Haemagglutination inhibition was only increased after the third dose, but in-vitro seroneutralisation activity was transiently increased after each of the five doses to concentrations regarded as clinically beneficial in infected patients. INTERPRETATION: F(ab')2 showed good safety, tolerability, and therapeutic potential for managing of H5N1 exposed patients. FUNDING: Fab'entech.

A comparison of assays for accurate copy number measurement of the low-affinity Fc gamma receptor genes FCGR3A and FCGR3B.

The FCGR3 locus encoding the low affinity activating receptor FcγRIII, plays a vital role in immunity triggered by cellular effector and regulatory functions. Copy number of the genes FCGR3A and FCGR3B has previously been reported to affect susceptibility to several autoimmune diseases and chronic inflammatory conditions. However, such genetic association studies often yield inconsistent results; hence require assays that are robust with low error rate. We investigated the accuracy and efficiency in estimating FCGR3 CNV by comparing Sequenom MassARRAY and paralogue ratio test-restriction enzyme digest variant ratio (PRT-REDVR). In addition, since many genetic association studies of FCGR3B CNV were carried out using real-time quantitative PCR, we have also included the evaluation of that method's performance in estimating the multi-allelic CNV of FCGR3B. The qPCR assay exhibited a considerably broader distribution of signal intensity, potentially introducing error in estimation of copy number and higher false positive rates. Both Sequenom and PRT-REDVR showed lesser systematic bias, but Sequenom skewed towards copy number normal (CN = 2). The discrepancy between Sequenom and PRT-REDVR might be attributed either to batch effects noise in individual measurements. Our study suggests that PRT-REDVR is more robust and accurate in genotyping the CNV of FCGR3, but highlights the needs of multiple independent assays for extensive validation when performing a genetic association study with multi-allelic CNVs.

The high-affinity human IgG receptor Fc gamma receptor I (FcγRI) is not associated with vascular leakage of dengue.

BACKGROUND: Dengue is a major public health problem in many tropical and sub-tropical countries. Vascular leakage and shock are identified as the major causes of deaths in patients with severe dengue. Studies have suggested the potential role of Fc gamma receptors I (FcγRI) in the pathogenesis of dengue. We hypothesized that the circulating level of Fcγ receptor I could potentially be used as an indicator in assisting early diagnosis of severe dengue. RESULTS: A selected cohort of 66 dengue patients including 42 dengue with signs of vascular leakage, and 24 dengue without signs of vascular leakage were identified and were afterwards referred to as 'cases' and 'controls' respectively. Thirty seven normal healthy controls were also recruited in this study. The circulating level of FcγRI was quantified from the serum using enzyme-link immunosorbent assay (ELISA). The levels of FcγRI in both groups of patients with and without vascular leakage were found to be significantly higher than the normal healthy controls (P < 0.001). However, there was no significant difference found between patients with vascular leakage and those without vascular leakage (p = 0.777). CONCLUSION: We suggest that FcγRI is not associated with the vascular leakage in dengue. However, further studies are necessary to delineate the role of FcγRI in antibody-dependent enhancement (ADE) mechanism.

An evaluation of the World Health Organization's 1997 and 2009 dengue classifications in hospitalized dengue patients in Malaysia.

INTRODUCTION: The latest revised version of the World Health Organization's dengue classification was released in 2009. A handful of studies have taken initiatives to evaluate the old and revised guidelines to determine early signs and symptoms of severe dengue. This retrospective study aimed to compare the classification of dengue using both the 1997 and 2009 guidelines in a selected cohort of dengue patients from Peninsular Malaysia between 2008 and 2012. METHODOLOGY: Adult dengue patients were recruited from tertiary hospitals in two different states, Selangor and Kelantan, in Peninsular Malaysia. Their clinical manifestations were assessed. RESULTS: A total of 281 confirmed dengue patients were enrolled; the mean duration of illness at admission was five days. Of these, 88.6%, 10.7%, and 0.7% were classified according to the 1997 guidelines as having dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), respectively. When the WHO 2009 guidelines were applied, 17.1%, 78.3%, and 4.6% were classified as dengue without warning signs, dengue with warning signs, and severe dengue, respectively. CONCLUSIONS: Our data suggests that the revised WHO 2009 guidelines stratify a much larger proportion of patients into a category that requires a higher level of medical and nursing care.