Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures.

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.

Discontinuation of Antibiotics in Patients with Neurological Conditions - A Study on the Impact of an Antimicrobial Stewardship Program (ASP) in a Tertiary Institution.

BACKGROUND: Up to 50% of antibiotics are prescribed either unnecessarily or inappropriately in most hospitals worldwide. In the largest tertiary hospital in Singapore, patients with neurological conditions were often initiated on antibiotics for change in mental state or isolated fevers. We hypothesize that Antimicrobial Stewardship Program (ASP) interventions to discontinue empirical antibiotics in neurological patients with no clinical evidence of bacterial infection are safe. The aim of this study was to compare clinical impact and safety outcomes of ASP interventions between accepted and rejected groups. METHODS: A retrospective review of the ASP database was conducted for all patients admitted to the neurology department in Singapore General Hospital between January 2014 and December 2017. Interventions were followed up and patients were classified into two intervention groups, the accepted and rejected groups. Demographic data, age-adjusted Charlson co-morbidity index, duration of antibiotic therapy, length of hospital stay post-ASP intervention (PLOS), infection-related readmissions and mortality were compared between the two groups. Data were expressed as mean ± standard deviation for continuous variables, and unpaired Student's t-test was performed to determine intergroup differences between mean values. RESULTS: The ASP team recommended 184 interventions, with an overall acceptance rate of 82.6% (152/184). There was no significant difference in demographics and age-adjusted Charlson co-morbidity index between the two groups. The accepted group had a shorter duration of therapy by 1.67 days (4.99±2.50 days vs. 6.66±2.34 days; P<0.01) and a shorter PLOS by 2 days, although this was not statistically significant (22.5±22.2 days vs. 24.5±51.4 days; P=0.83). There were no significant differences between the two groups in 14-day mortality and readmission rates. CONCLUSION: In neurological patients with no clinical evidence of bacterial infections, ASP interventions to discontinue empirical antibiotics were not associated with increased mortality and readmissions but were associated with significant reduction in duration of therapy.

Discontinuation of antibiotic therapy within 24 hours of treatment initiation for patients with no clinical evidence of bacterial infection: a 5-year safety and outcome study from Singapore General Hospital Antimicrobial Stewardship Program.

BACKGROUND: Overprescribing antibiotics for patients with no bacterial infection is of growing global concern. It is important for timely Antimicrobial Stewardship Program (ASP) intervention to discontinue antibiotics for patients whose symptoms can be explained by non-infective causes, and without availability of bacterial cultures and susceptibilities reports. This study aimed to evaluate clinical outcomes and safety of early ASP review in these patients. METHODS: A retrospective review of the ASP database (January 2010 to December 2014) was conducted to identify patients for whom ASP recommended discontinuation of empiric antibiotics within 24 hours of prescribing. Demographics were collected. Clinical outcomes - duration of therapy, length of hospital stay (LOS), infection-related readmissions, and all-cause mortality - were compared between interventions accepted and rejected groups. Continuous data were analysed via unpaired Student's t-test. Categorical data were analysed using χ2 test or Fisher's exact test, as appropriate. RESULTS: The ASP team recommended 794 interventions (overall acceptance rate of 72.9%, 579 of 794). There were no significant between-group differences in underlying demographics, and Charlson comorbidity index score. However, the interventions acceptance group had significantly shorter duration of therapy by 2.61 days (2.72 ± 3.04 vs. 5.33 ± 2.54 days; P < 0.01) and LOS by 7.41 days (7.98 ± 13.14 vs. 15.39 ± 22.62 days; P < 0.01), with estimated cost savings of SGD10 817 per patient. There were no significant between-group differences in 14-day mortality and readmission rates. CONCLUSION: Prompt ASP interventions at Singapore General Hospital were associated with significant reductions in duration of therapy and LOS, with cost savings. It was demonstrated that it is safe to discontinue antibiotics within 24 hours of prescribing for patients with no evidence of bacterial infections.

A multidisciplinary antimicrobial stewardship programme safely decreases the duration of broad-spectrum antibiotic prescription in Singaporean adult renal patients.

Patients with chronic kidney disease have increased risk of infections. Thus, physicians may favour prolonged broad-spectrum antibiotic use. Studies focused on antimicrobial stewardship programmes (ASPs) in renal patients are currently lacking. Here we describe the role of a multidisciplinary ASP and the impact of ASP interventions in renal patients. A multidisciplinary ASP was initiated at a tertiary hospital in Singapore. Patients prescribed broad-spectrum parenteral antibiotics were identified daily and were subjected to prospective review with immediate concurrent feedback. ASP data from January 2010 to December 2011 were analysed for all renal patients. Outcome measures included the duration and appropriateness of antibiotics, intervention acceptance rates, cost savings and safety outcomes. A total of 2084 antibiotic courses were reviewed, of which 24% were inappropriate, with meropenem most commonly prescribed inappropriately (31.0%). The commonest reasons for inappropriate use were wrong choice (51.0%) and wrong duration (21.4%). In total, 634 recommendations were made, with high acceptance rates (73.3%). Recommendations to discontinue antibiotics (33.4%) and to optimise doses (17.2%) comprised the bulk of ASP work. A mean reduction of -1.28 days of antibiotic use was observed among patients with interventions accepted versus those rejected (P<0.001), with direct cost savings of SGD$90,045. No difference in 30-day mortality (P=0.91) was observed between the accepted and rejected intervention groups. In conclusion, a multidisciplinary ASP resulted in a shorter duration of antibiotic use without compromising safety in renal patients. Continued effort is needed to produce a long-term impact on antibiotic prescription and resistance.

Impact of Antimicrobial Stewardship Program (ASP) on Outcomes in Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSIs) in an Acute-Tertiary Care Hospital.

INTRODUCTION: Acute bacterial skin and skin structure infections (ABSSSIs) are among the most common infections treated in hospitals, but to date, there has been little information with regards to the implementation of Antimicrobial Stewardship Programs (ASPs) for patients with ABSSSIs. Hence, we aim to evaluate the impact of ASPs on the following outcomes in patients with ABSSSIs: duration of therapy and hospital stay, 14-day reinfection, infection-related readmissions and mortality. METHODS: A retrospective review of the ASP database was conducted, focusing on selected outcomes (as above) among all patients in whom the institution's ASP recommended a change in antibiotic regimen-de-escalation of the antibiotic based on culture results; discontinuation of the antibiotic; narrowing of the empirical coverage; and intravenous-to-oral (i.v.-to-p.o.) switch between September 2009 and December 2012. Data were expressed as mean ± standard deviation for continuous variables, and unpaired Student's t test was performed to determine intergroup differences between mean values. For categorical variables, data were presented as number and percentage and analyzed using the χ (2) test or Fisher's exact test, as appropriate. RESULTS: ASP recommended 407 interventions with an overall acceptance rate of 66.8%. ASP interventions significantly reduced median duration of therapy by 2 [from a median (interquartile range, IQR) of 8 (6-12) days to 6 (4-9) days] and median length of stay by 5 days [from median (IQR) of 12 (5-32) days to 7 (3-18) days]. This led to an estimated total cost avoidance of USD 0.7 million. There were no significant differences in the 14-day reinfection, infection-related readmission and mortality rates between patients whose physicians accepted and those who rejected ASP interventions. CONCLUSION: Interventions recommended by the ASP in Singapore General Hospital were safe and associated with a significant reduction in duration of therapy and hospital stay. The results of our study have affirmed the role of ASP in optimizing the care of patients with ABSSSI.

Microbiology and audit of vascular access-associated bloodstream infections in multi-ethnic Asian hemodialysis patients in a tertiary hospital.

BACKGROUND: In view of high mortality and morbidity rates associated with vascular access-associated bloodstream infection (VAABSI) in hemodialysis patients, clinical practice guidelines recommend empiric antibiotic therapy for suspected vascular access-related infections. We aim to describe the microbiology of confirmed VAABSI and evaluate the choice of empiric antibiotics, and whether they are prescribed in concordance with the in-house antibiotic guidelines. METHODS: This was a single-center, retrospective, observational study conducted in a tertiary hospital. All adult hemodialysis patients aged 21 years and above who had confirmed VAABSI with positive blood culture results dated from January 2011 to June 2012 were recruited. Relevant information was retrieved electronically from the hospital patient online database, SCM 5.5 Sunrise Enterprise Gateway. RESULTS: A total of 144 episodes of VAABSI were recorded from 118 patients. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) accounted for 64.2% (68/106) of the gram-positive infections. Gram-negative organisms grew in 26.4% (38/144) of blood cultures and Pseudomonas aeruginosa was the most common organism isolated. The recommended in-house guideline was used as empiric therapy in 24 episodes of VAABSI (16.7%). Five patients died due to VAABSI and none were prescribed antibiotics in concordance with in-house guidelines. CONCLUSIONS: Empiric antibiotics against MSSA and MRSA, as well as gram-negative organisms, especially P. aeruginosa, should be used in patients with suspected vascular access-related infections in our institution. Monitoring of microbiological profile is necessary to guide timely administration of appropriate empiric antibiotics. Further studies are necessary to evaluate the relationship between adherence to in-house guidelines and patients' outcomes.