Antibiotic utilisation and resistance over the first decade of nationally funded antimicrobial stewardship programmes in Singapore acute-care hospitals.

OBJECTIVE: The aim of this study was to describe the time series of broad-spectrum antibiotic utilisation and incidence of antibiotic-resistant organisms during the implementation of antimicrobial stewardship programmes (ASP) in Singapore. METHODS: An observational study was conducted using data from 2011 to 2020 in seven acute-care public hospitals. We applied joinpoint regressions to investigate changes in antibiotic utilisation rate and incidence density of antibiotic-resistant organisms. RESULTS: Across the seven hospitals, quarterly broad-spectrum antibiotic utilisation rate remained stable. Half-yearly incidence density of antibiotic-resistant organisms with two joinpoints at first half (H1) of 2012 and second half (H2) of 2014 decreased significantly in the second and third period with a half-yearly percentage change (HPC) of -2.9% and - 0.5%, respectively. Across the five hospitals with complete data, half-yearly broad-spectrum antibiotic utilisation rate with one joinpoint decreased significantly from H1 of 2011 to H2 of 2018 (HPC - 4.0%) and H2 of 2018 to H2 2020 (HPC - 0.5%). Incidence density of antibiotic-resistant organisms decreased significantly in the two joinpoint periods from H1 of 2012 to H2 of 2014 (HPC - 2.7%) and H2 of 2014 to H2 of 2020 (HPC - 1.0%). Ceftriaxone with one joinpoint decreased significantly from H1 of 2011 to H1 of 2014 (HPC - 6.0%) and H1 of 2014 to H2 of 2020 (HPC - 1.8%) and ceftriaxone-resistant E. coli and K. pneumoniae decreased significantly in later periods, from H2 of 2016 to H2 of 2020 (HPC - 2.5%) and H1 of 2012 to H2 of 2015 (HPC - 4.6%) respectively. Anti-pseudomonal antibiotics with one joinpoint decreased significantly from H1 of 2011 to H2 of 2014 (HPC - 4.5%) and H2 of 2014 to H2 of 2020 (HPC - 0.8%) and that of quinolones with one joinpoint at H1 of 2015 decreased significantly in the first period. C. difficile with one joinpoint increased significantly from H1 of 2011 to H1 of 2015 (HPC 3.9%) and decreased significantly from H1 of 2015 to H2 of 2020 (HPC - 4.9%). CONCLUSIONS: In the five hospitals with complete data, decrease in broad-spectrum antibiotic utilisation rate was followed by decrease in incidence density of antibiotic-resistant organisms. ASP should continue to be nationally funded as a key measure to combat antimicrobial resistance in acute care hospitals.

Optimizing Vancomycin Dosing in Chronic Kidney Disease by Deriving and Implementing a Web-Based Tool Using a Population Pharmacokinetics Analysis.

Background: Chronic kidney disease (CKD) patients requiring intravenous vancomycin bear considerable risks of adverse outcomes both from the infection and vancomycin therapy itself, necessitating especially precise dosing to avoid sub- and supratherapeutic vancomycin exposure. Methods: In this retrospective study, we performed a population pharmacokinetic analysis to construct a vancomycin dose prediction model for CKD patients who do not require renal replacement therapy. The model was externally validated on an independent cohort of patients to assess its prediction accuracy. The pharmacokinetic parameter estimates and the equations were productized into a Web application (VancApp) subsequently implemented in routine care. The association between VancApp-based dosing and time-to-target concentration attainment, 30-day mortality, and nephrotoxicity were assessed postimplementation. Results: The model constructed from an initial cohort (n = 80) revealed a population clearance and volume of distribution of 1.30 L/h and 1.23 L/kg, respectively. External model validation (n = 112) demonstrated a mean absolute prediction error of 1.25 mg/L. Following 4 months of clinical implementation of VancApp as an optional alternative to usual care [VancApp (n = 22) vs. usual care (n = 21)], patients who had received VancApp-based dosing took a shorter time to reach target concentrations (median: 66 vs. 102 h, p = 0.187) and had fewer 30-day mortalities (14% vs. 24%, p = 0.457) compared to usual care. While statistical significance was not achieved, the clinical significance of these findings appear promising. Conclusion: Clinical implementation of a population pharmacokinetic model for vancomycin in CKD can potentially improve dosing precision in CKD and could serve as a practical means to improve vital clinical outcomes.

Post-hemodialysis dosing of 1 vs. 2 g of ceftazidime in anuric end-stage renal disease patients on low-flux dialysis and its pharmacodynamic implications on clinical use.

Ceftazidime is a cost-effective antimicrobial against Gram-negative pathogens associated with sepsis in end-stage renal disease (ESRD) hemodialysis patients with potential for wider use with the advent of ceftazidime-avibactam. Dosing ceftazidime post-hemodialysis appears attractive and convenient, but limited in vivo data on pharmacodynamic efficacy (PE) attainment, defined as >70% of the interdialytic period drug concentrations exceed susceptible pathogens minimal inhibitory concentrations (MICs) (%TMIC), warrants further assessment. We therefore evaluated PE and tolerability of 1 against 2 g regime in anuric ESRD patients on low-flux hemodialysis. Two doses of 1 or 2 g ceftazidime were administered post-hemodialysis prior to 48- and 72-hour interdialytic intervals in ESRD inpatients without active infections. Peak and trough concentrations (mg/L) were assayed using a validated liquid chromatography-tandem mass spectrometry method. Proportion of patients achieving PE for known pathogens with MICs ≤ 8 mg/L and adverse effects were assessed. Six (43%) and eight (57%) adult patients received 1 and 2 g dose, respectively. Median (25th-75th percentile), peak, 48- and 72-hour trough ceftazidime concentrations were 78 (60-98) vs. 158 (128-196), 37 (23-37) vs. 49 (39-71), and 13 (12-20) vs. 26 (21-41) mg/L, respectively, resulting in 100% TMIC for both doses. One patient on the 1-g dose experienced mild pruritus. Reliable and safe PE attainment over both 48- and 72-hour interdialytic interval was achievable with 1 g of ceftazidime dosed post-hemodialysis. The 2 g dose was equally effective and well tolerated but may not be necessary. These findings need validation in non-anuric patients, high-flux hemodialysis, and during avibactam co-administration.

Surveillance of broad-spectrum antibiotic prescription in Singaporean hospitals: a 5-year longitudinal study.

BACKGROUND: Inappropriate prescription of antibiotics may contribute towards higher levels antimicrobial resistance. A key intervention for improving appropriate antibiotic prescription is surveillance of prescription. This paper presents the results of a longitudinal surveillance of broad-spectrum antibiotic prescription in 5 public-sector hospitals in Singapore from 2006 to 2010. METHODOLOGY/PRINCIPAL FINDINGS: Quarterly antibiotic prescription data were obtained and converted to defined daily doses (DDDs) per 1,000 inpatient-days. The presence of significant trends in antibiotic prescription over time for both individual and combined hospitals was tested by regression analysis and corrected for autocorrelation between time-points. Excluding fluoroquinolones, there was a significant increase in prescription of all monitored antibiotics from an average of 233.12 defined daily doses (DDD)/1,000 inpatient-days in 2006 to 254.38 DDD/1,000 inpatient-days in 2010 (Coefficient = 1.13, 95%CI: 0.16-2.09, p = 0.025). Increasing utilization of carbapenems, piperacillin/tazobactam, and Gram-positive agents were seen in the majority of the hospitals, while cephalosporins were less prescribed over time. The combined expenditure for 5 hospitals increased from USD9.9 million in 2006 to USD16.7 million in 2010. CONCLUSIONS/SIGNIFICANCE: The rate of prescription of broad-spectrum antibiotics in Singaporean hospitals is much higher compared to those of European hospitals. This may be due to high rates of antimicrobial resistance. The increase in expenditure on monitored antibiotics over the past 5 years outstripped the actual increase in DDD/1,000 inpatient-days of antibiotics prescribed. Longitudinal surveillance of antibiotic prescription on a hospital and countrywide level is important for detecting trends for formulating interventions or policies. Further research is needed to understand the causes for the various prescription trends and to act on these where necessary.

Prevalence of invasive fungal disease in hematological patients at a tertiary university hospital in Singapore.

BACKGROUND: The use of newer azoles as prophylaxis in hematological patients undergoing stem cell transplantation or immunosuppressive chemotherapy has been shown to decrease the risk of developing invasive fungal disease (IFD). However, the cost-effectiveness of such a strategy is dependent on the local epidemiology of IFD. We conducted an audit of hematological patients with IFD in our institution in order to derive the prevalence and types of IFD that occur locally. FINDINGS: We conducted a retrospective chart review of all hematological patients who developed possible, probable or definite IFD according to EORTC/MSG criteria in the period from Oct 2007 to Apr 2010. The prevalence of IFD was determined via correlation with institutional database records of all hematological patients treated at our institution over the same time period.There were 39 cases of IFD diagnosed during the study period, with 8 (20.5%) possible, 19 (48.7%) probable and 12 (30.8%) definite cases of IFD. Aspergillus spp. accounted for 83.9% of all probable and definite infections. There was 1 case each of Rhinocladelia spp., Coprinopsis cinerea, Exserohilum spp. sinusitis and Rhizopus spp. sinusitis. IFD occurred in 12 of 124 (9.7%) AML and 4 of 103 (3.9%) ALL patients treated at our institution respectively. There were 10 (16.1%) infections among 62 allogeneic HSCT recipients, six of whom were having concurrent graft-versus-host disease (GVHD). Five other cases occurred after allogeneic HSCT failure, following salvage chemotherapy for disease relapse. The prevalence of IFD during induction chemotherapy was 8.9% (11 of 124 cases) for AML and 1.0% (1 of 103 cases) for ALL. Fluconazole prophylaxis had been provided for 28 out of the 39 (71.8%) cases, while 4 (10.3%) were on itraconazole prophylaxis. The in-hospital mortality was 28.2% (11 of 39 cases), of which 5 (12.8%) deaths were attributed to IFD. CONCLUSIONS: The burden of IFD is high in our institution, especially in allogeneic HSCT recipients and patients on induction chemotherapy for AML. A prophylactic strategy directed against invasive mould infections for local high-risk patients may be considered as the comparative costs of treatment, prolonged hospitalisation and subsequent delayed chemotherapy favours such an approach.