Search

Vancomycin is an antibiotic commonly used to treat serious gram-positive infections. Patients requiring prolonged therapy in Singapore routinely receive intermittent vancomycin infusion in the hospital and are switched to continuous infusion for outpatient parenteral antibiotic therapy. During this transition of care, there may be a risk of not achieving therapeutic targets. We evaluated the performance of a model-based dosing algorithm in achieving a therapeutic target within 7 days of care transition. A published population pharmacokinetic model was used as the foundation to guide vancomycin dosing when discharging inpatients on intermittent infusion to outpatient care on continuous infusion. Selected demographic variables (age, weight, and creatinine clearance) were used to devise initial dosing. Patients with guided dosing were compared with historic controls (dosing by clinicians alone). The primary outcome of the study was to achieve vancomycin steady-state concentration of 20-25 mg/L. Compared with historic controls, the proportion of patients attaining a therapeutic target by day 7 was significantly improved (6 of 19 [31.6%] vs 12 of 17 [70.6%], P = .04). Our model-based approach could guide customized dosing to facilitate switching patients from intermittent to continuous infusion during transition of care. Further validation in a larger patient cohort is warranted.

Importance: There is a lack of studies comparing the intended and unintended consequences of prospective review and feedback (PRF) with computerized decision support systems (CDSS), especially in the longer term in antimicrobial stewardship. Objective: To examine the outcomes associated with the sequential implementation of PRF and CDSS and changes to these interventions with long-term use of antibiotics for and incidence of multidrug resistant organisms (MDROs) and other unintended outcomes. Design, Setting, and Participants: This cohort study used an interrupted time series with segmented regression analysis of data from January 2007 to December 2018. Data were extracted from the electronic medical records of patients admitted at a large university teaching hospital with high rates of antibiotic resistance in Singapore. Data were analyzed from June 2019 to June 2020. Exposures: PRF of piperacillin-tazobactam and carbapenems (intervention 1, April 2009), with the addition of hospital-wide CDSS (intervention 2, April 2011), and lifting of CDSS for half of the hospital wards for 6 months (intervention 3, March 2017). Main Outcomes and Measures: Monthly antimicrobial use was measured in defined daily doses (DDDs) per 1000 patient-days. The monthly incidence of MDROs was calculated as number of clinical isolates detected per 1000 inpatient-days over a 6-month period. Unintended outcomes examined included in-hospital mortality and age-adjusted length of stay (LOS). Results: The number of inpatients increased from 56263 in 2007 to 63572 in 2018. During the same period, the mean monthly patient days increased from 33929 in 2007 to 45603 in 2018, and the proportion of patients older than 65 years increased from 45.5% in 2007 to 56.6% in 2018. After intervention 1, there were 0.33 (95% CI, 0.18 to 0.48) more DDDs per 1000 patient-days per month of piperacillin-tazobactam and carbapenems and-11.05 (95% CI,-15.55 to-6.55) fewer DDDs per 1000 patient-days per month for other broad-spectrum antibiotics. After intervention 2, there were-0.22 (95% CI,-0.33 to-0.10) fewer DDDs per 1000 patient-days per month of piperacillin-tazobactam and carbapenems and-2.10 (95% CI,-3.13 to-1.07) fewer DDDs per 1000 patient-days per month for other broad-spectrum antibiotics. After intervention 3, use of piperacillin-tazobactam and carbapenem increased by 0.28 (95% CI, 0.02 to 0.55) DDDs per 1000 patient-days per month. After intervention 2, incidence of Clostridioides difficile decreased (estimate,-0.02 [95% CI,-0.03 to-0.01] cases per 1000 patient-days per month). Conclusions and Relevance: In this cohort study, concurrent PRF and CDSS were associated with limiting the use of piperacillin-tazobactam and carbapenems while reducing use of other antibiotics. Published version

To determine percentage of patients with sub-therapeutic beta-lactam exposure in our intensive care units (ICU) and to correlate target attainment with clinical outcomes.Multi-centre, prospective, observational study was conducted in ICUs from three hospitals in Singapore from July 2016 to May 2018. Adult patients (≥21 years) receiving meropenem or piperacillin-tazobactam were included. Four blood samples were obtained during a dosing interval to measure and determine attainment of therapeutic targets: unbound beta-lactam concentration above (i) minimum inhibitory concentration (MIC) at 40% (meropenem) or 50% (piperacillin) of dosing interval (40-50%fT MIC) and (ii) 5 × MIC at 100% of dosing interval (100%fT 5 × MIC). Correlation to clinical outcomes was evaluated using Cox regression.Beta-lactam levels were highly variable among 61 patients, with trough meropenem and piperacillin levels at 21.5 ± 16.8 mg/L and 101.6 ± 81.1 mg/L respectively. Among 85 sets of blood samples, current dosing practices were able to achieve 94% success for 40-50%fT MIC and 44% for 100%fT 5 × MIC. Failure to achieve 40-50%fT MIC within 48 h was significantly associated with all-cause mortality (HR: 9.0, 95% CI: 1.8-45.0), after adjustment for APACHE II score. Achievement of 100%fT 5 × MIC within 48 h was significantly associated with shorter length of hospital stay.Current dosing practices may be suboptimal for ICU patients. Beta-lactam TDM may be useful.

Background Earlier studies have reported high antibiotic use in patients hospitalised for coronavirus disease 2019 (COVID-19), resulting in concerns of increasing antimicrobial resistance with increase antibiotic use in this pandemic. Point prevalence survey (PPS) can be a quick tool to provide antibiotic prescribing information to aid antimicrobial stewardship (AMS) activities. Objectives To describe antibiotic utilization and evaluate antibiotic appropriateness in COVID-19 patients using PPS. Methods Adapting Global-PPS on antimicrobial use, the survey was conducted in COVID-19 wards at 2 centres in Singapore on 22 April 2020 at 0800h. Patients on systemic antibiotics were included and evaluated for antibiotic appropriateness. Results Five hundred and seventy-seven patients were screened. Thirty-six (6.2%) patients were on antibiotics and which were started at median of 7 days (inter-quartile rate (IQR), 4, 11) from symptom onset. Fifty-one antibiotics were prescribed in these patients. Overall, co-amoxiclav (26/51, 51.0%) was the most often prescribed antibiotic. Thirty-one out of 51 (60.8%) antibiotic prescriptions were appropriate. Among 20 inappropriate prescriptions, 18 (90.0%) were initiated in patients with low likelihood of bacterial infections. Antibiotic prescriptions were more appropriate when reviewed by infectious diseases physicians (13/31 [41.9%] versus 2/20 [10.0%], p = 0.015), and if reasons for use were stated in notes (31/31 [100.0%] versus 16/20 [80.0%], p = 0.019). Conclusions Despite low prevalence of antibiotic use among confirmed and suspected COVID-19 patients at 2 centres in Singapore, there was significant proportion of inappropriate antibiotics use where bacterial infections were unlikely. AMS teams can tailor stewardship strategies using PPS results.

Background The deployment of antimicrobial stewardship (AMS) teams to deal with the COVID-19 pandemic can lead to a loss of developed frameworks, best practices and leadership resulting in adverse impact on antimicrobial prescribing and resistance. We aim to investigate effects of reduction in AMS resources during the COVID-19 pandemic on antimicrobial prescribing. Methods One of 5 full-time equivalent AMS pharmacists was deployed to support pandemic work and AMS rounds with infectious disease physicians were reduced from 5 to 2 times a week. A survey in acute inpatients was conducted using the Global Point Prevalence Survey methodology in July 2020 and compared with those in 2015 and 2017–2019. Results The prevalence of antimicrobial prescribing (55% in 2015 to 49% in 2019 and 47% in 2020, p = 0.02) and antibacterials (54% in 2015 to 45% in 2019 and 42% in 2020, p Conclusion During the COVID-19 pandemic, there was no increase in antimicrobial prescribing and no significant differences in antimicrobial prescribing quality indicators.

The objective of this study was to correlate resistance mutations of extended spectrum beta-lactamases (ESBL) and AmpC beta-lactamases and virulence factors (VF) with 30-day mortality in patients treated with either piperacillin-tazobactam or carbapenems. A post-hoc analysis on 123 patients with ceftriaxone-resistant Escherichia coli and Klebsiella pneumoniae bacteremia treated empirically with piperacillin-tazobactam and carbapenems was performed. Beta-lactamase resistance mutations and VF were identified by whole genome sequencing (WGS). The primary endpoint was 30-day mortality. Multivariate analyses were performed using logistic regression. WGS showed diverse multilocus sequence types (MLST) in 43 K. pneumoniae strains, while ST131 predominated in E. coli strains (57/80). CTX-M was most commonly detected (76/80 [95%] of E. coli; 39/43 [91%] of K pneumoniae.), followed by OXA (53/80 [66%] of E. coli; 34/43 [79%] of K. pneumoniae). A significant correlation was found between the number of genes encoding third-generation cephalosporin-resistant beta-lactamases and 30-day mortality (p = 0.045). The positive association was not significant after controlling for empiric carbapenem, Pitt score 3 and K. pneumoniae (OR 2.43, P = 0.073). None of the VF was associated with 30-day mortality. No association was found between 30-day mortality and any ESBL and AmpC beta-lactamases or VF when piperacillin-tazobactam or carbapenems were given. No significant association between 30-day mortality and active empiric therapy was found.

Introduction The multi-disciplinary antimicrobial stewardship team at the study hospital conducts prospective review and feedback on all inpatient orders of piperacillin–tazobactam and carbapenems. In addition, the team provides non-antibiotic recommendations (i.e. additional investigations and infectious disease reviews). This study aimed to describe the impact of these recommendations on patient outcomes. Methods Patients on carbapenem and piperacillin–tazobactam who received at least one non-antibiotic recommendation between January 2012 and August 2014 were included in this study. Acceptance and rejection of non-antibiotic recommendations by the managing physician were compared. The primary outcome was 30-d mortality. Results Non-antibiotic recommendations were made in 166 patients. There were no differences in baseline characteristics between patients for whom recommendations were accepted and patients for whom recommendations were rejected. Thirty-day mortality (18.0% vs. 34.5%, P = 0.02) was significantly lower in patients who had at least one non-antibiotic recommendation accepted. Multi-variate analysis found that Charlson's comorbidity score [odds ratio (OR) 1.20, 95% confidence interval (CI) 1.03–1.42, P = 0.03], APACHE II score (OR 1.10, 95% CI 1.01–1.19, P P = 0.02) and acceptance of at least one non-antibiotic recommendation (OR 0.39, 95% CI 0.17–0.88, P = 0.02) were independently associated with 30-d mortality. Conclusions During prospective review and feedback of piperacillin–tazobactam and carbapenems, acceptance of non-antibiotic recommendations was found to be associated with a reduction in 30-d mortality.

Introduction AmpC β-lactamases are found in Enterobacter species, Serratia species, Citrobacter freundii, Providencia species and Morganella morganii (‘ESCPM’). Carbapenems are commonly used to treat severe ‘ESCPM’ infections. Carbapenem-sparing agents are needed because of increasing carbapenem resistance worldwide. Use of cefepime and piperacillin-tazobactam has limited supportive clinical data. We evaluated the efficacy of non-carbapenems vs. carbapenems in ‘ESCPM’ bacteraemia. Methods A retrospective cohort study was conducted on patients with ‘ESCPM’ bacteraemia. Primary outcome was 30-day mortality. Analyses were performed on patients who received carbapenems vs. piperacillin-tazobactam or cefepime monotherapy as empirical and definitive therapy. Propensity score for carbapenem therapy was adjusted for in multivariate analyses for 30-day mortality. Results A total of 241 patients were included. The most common bacterium isolated was Enterobacter species (58.1%). Common sources were urinary (22.8%) and vascular lines (22.0%). Carbapenems (28.6%) and piperacillin-tazobactam (28.6%) were the commonest empirical antibiotics. Carbapenems (54.8%) and cefepime (23.7%) were the most common definitive antibiotics. Median Pitt bacteraemia score was 1 (interquartile range [IQR], 0-2). Overall, 30-day mortality was 12.9%. Adjusted multivariate analyses for empirical and definitive antibiotic treatment models yielded risk factors for 30-day mortality, including higher Pitt bacteraemia score (empirical: adjusted OR [aOR] 1.21 for each point increase, 95% confidence interval [CI]:1.01-1.45; definitive: aOR 1.33 for each point increase, 95% CI:1.06-1.69) and age (empirical: aOR 1.04 for each year increase, 95% CI:1.01-1.08). Empirical piperacillin-tazobactam (aOR 0.29, 95% CI:0.07-1.27) and definitive cefepime (aOR 0.65, 95% CI:0.12-3.55) were not associated with 30-day mortality. Conclusions Compared with carbapenem therapy, empirical piperacillin-tazobactam and definitive cefepime were not associated with 30-day mortality in ‘ESCPM’ bacteraemia.

Severe Clostridioides difficile infection (CDI) is associated with poorer outcomes. We aimed to identify risk factors and treatment outcomes of severe CDI. This was a retrospective cohort study. Eligible patients from January to December 2012 were recruited. Severity definitions were in accordance with SHEA/IDSA 2010 guideline. Treatment outcomes were (1) diarrhoea persistence, (2) CDI recurrence, (3) major complications despite treatment and (4) 30-day mortality. Two hundred and seventy-two patients were included and 40% had severe CDI. High APACHE II score (aOR 1.112, 95% CI 1.014–1.219; p 0.05), major complications 1.2% versus 11% (p

Antimicrobial stewardship is used to combat antimicrobial resistance. In Singapore, a tertiary hospital has integrated a computerised decision support system, called Antibiotic Resistance Utilisation and Surveillance-Control (ARUSC), into the electronic inpatient prescribing system. ARUSC is launched either by the physician to seek guidance for an infectious disease condition or via auto-trigger when restricted antibiotics are prescribed. This paper describes the implementation of ARUSC over three phases from 1 May 2011 to 30 April 2013, compared factors between ARUSC launches via auto-trigger and for guidance, examined factors associated with acceptance of ARUSC recommendations, and assessed user acceptability. During the study period, a monthly average of 9072 antibiotic prescriptions was made, of which 2370 (26.1%) involved ARUSC launches. Launches via auto-trigger comprised 48.1% of ARUSC launches. In phase 1, 23% of ARUSC launches were completed. This rose to 38% in phase 2, then 87% in phase 3, as escapes from the ARUSC programme were sequentially disabled. Amongst completed launches for guidance, 89% of ARUSC recommendations were accepted versus 40% amongst completed launches via auto-trigger. Amongst ARUSC launches for guidance, being from a medical department [adjusted odds ratio (aOR)=1.20, 95% confidence interval (CI) 1.04-1.37] and ARUSC launch during on-call (aOR=1.81, 95% CI 1.61-2.05) were independently associated with acceptance of ARUSC recommendations. Junior physicians found ARUSC useful. Senior physicians found ARUSC reliable but admitted to having preferences for antibiotics that may conflict with ARUSC. Hospital-wide implementation of ARUSC encountered hurdles from physicians. With modifications, the completion rate improved.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are increasing, and they are associated with an increased risk of mortality in hospitalized patients. Linear regression is commonly used to identify concurrent trends, but it cannot quantify the relationship between risk factors and resistance. We developed a model to quantify the impact of antibiotic consumption on the prevalence of CRAB over time. Data were collected from January 2007 to June 2013 from our institution. Quarterly antibiotic consumption was expressed as defined daily dose/1,000 inpatient days. Six-month prevalence of CRAB was expressed as a percentage of all nonrepeat A. baumannii isolates tested. Individual trends were identified using linear regression. Antibiotic consumption from 2007 to 2011 was input as a step function in a relationship with CRAB. Model fit was evaluated by visual inspection and the residual sum of squares. The final model was validated using the best-fit (95% confidence interval) parameter estimates and antibiotic consumption to predict CRAB prevalence from January 2012 to June 2013. Cefepime, ertapenem, and piperacillin-tazobactam consumption and CRAB prevalence increased significantly over time. CRAB prevalence was best correlated to ertapenem (use sensitive; r 2 = 0.76), and accounting for additional concurrent antibiotic use did not significantly improve model fit. Prospective validation with ertapenem consumption correlated well with CRAB observations, suggesting good predicting ability of the model. Our model provided the quantitative impact of antibiotic consumption on CRAB. We plan to further refine this model to account for multiple risk factors. Interventions should focus on controlling risk factors with the highest impact on resistance.

Objective.Extensively drug resistant (XDR) Acinetobacter baumannii infections are increasing. Knowledge of risk factors can help to prevent these infections.Methods.We designed a 1: 1: 1 case-case-control study to identify risk factors for XDR A. baumannii bacteremia in Singapore and Thailand. Case group 1 was defined as having infection due to XDR A. baumannii, and case group 2 was defined as having infection due to non-XDR A. baumannii. The control group comprised patients with blood cultures obtained to determine possible infection.Results.There were 93 patients in each group. Pitt bacteremia score (adjusted odds ratio [aOR], 2.570 [95% confidence interval (CI), 1.528–4.322]), central venous catheters (CVCs; aOR, 12.644 [95% CI, 2.143–74.620]), use of carbapenems (aOR, 54.391 [95% CI, 3.869–764.674]), and piperacillin-tazobactam (aOR, 55.035 [95% CI, 4.803–630.613]) were independently associated with XDR A. baumannii bacteremia. In case group 2, Pitt bacteremia score (aOR, 1.667 [95% CI, 1.265–2.196]) and third-generation cephalosporins (aOR, 2.965 [95% CI, 1.224–7.182]) were independently associated with non-XDR A. baumannii bacteremia. Concurrent infections (aOR, 3.527 [95% CI, 1.479–8.411]), cancer (aOR, 3.172 [95% CI, 1.135–8.865]), and respiratory source (aOR, 2.690 [95% CI, 1.160–6.239]) were associated with an increased risk of 30-day mortality. Survivors received more active empirical therapy (16.7% vs 9.6%; P = .157), had fewer cases of XDR bacteremia (45.8% vs 52.6%; P = .452), and received higher median definitive polymyxin B doses (840,000 units vs 700,000 units; P = .339)Conclusions.Use of CVC and broad spectrum antibiotics were unique risk factors of XDR A. baumannii bacteremia. Effective antimicrobial stewardship together with use of a CVC bundle may reduce the incidence of these infections. Risk factors of acquisition and mortality may help identify patients for early initiation of polymyxin B therapy.

The Infectious Diseases Society of America 2011 MRSA treatment guidelines recommend considering modifying therapy when there is persistent MRSA bacteremia of 7 d or longer, with a change in antibiotic preferred rather than the addition of other antibiotics to vancomycin. This is mainly due to studies suggesting treatment successes with alternative salvage therapy such as daptomycin, coupled with the lack of published efficacy with combination therapy.

Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are a common cause of bacteraemia in endemic countries and may be associated with high mortality; carbapenems are considered the drug of choice. Limited data suggest piperacillin-tazobactam could be equally effective. We aimed to compare 30-day mortality of patients treated empirically with piperacillin-tazobactam versus a carbapenem in a multi-centre retrospective cohort study in Singapore. Only patients with active empiric monotherapy with piperacillin-tazobactam or a carbapenem were included. A propensity score for empiric carbapenem therapy was derived and an adjusted multivariate analysis of mortality was conducted. A total of 394 patients had ESBL-Escherichia.coli and ESBL-Klebsiella pneumoniae bacteraemia of which 23.1% were community acquired cases. One hundred and fifty-one received initial active monotherapy comprising piperacillin-tazobactam (n = 94) or a carbapenem (n = 57). Patients who received carbapenems were less likely to have health-care associated risk factors and have an unknown source of bacteraemia, but were more likely to have a urinary source. Thirty-day mortality was comparable between those who received empiric piperacillin-tazobactam and a carbapenem (29 [30.9%] vs. 17 [29.8%]), P = 0.89). Those who received empiric piperacillin-tazobactam had a lower 30-day acquisition of multi-drug resistant and fungal infections (7 [7.4%] vs. 14 [24.6%]), P

Pseudomonas aeruginosa (PA) bacteraemia is associated with high morbidity and mortality. We assessed clinical outcomes in patients with PA bacteraemia treated with piperacillin-tazobactam (TZP) versus other antibiotics, and monotherapy versus combination, all with proven activity by disc testing without minimum inhibitory concentration (MIC) data.All patients with PA bacteraemia in 2007 to 2008 were reviewed for demographic, comorbidity, clinical, laboratory, treatment and outcome data. Primary outcome was 30-day mortality. Secondary outcomes included microbiological clearance, clinical response and length of stay (LOS).Median age for 91 patients was 65 years. Median Simplified Acute Physiology Score (SAPS) II score was 30. Monotherapy was used in 77 cases: 42 on ceftazidime, 17 on TZP, 10 on carbapenems, and 8 on other antipseudomonal antibiotics. The 30-day mortality was 20.9%, and similar between ceftazidime and TZP versus other antibiotics respectively. More patients in combination versus monotherapy group had cardiovascular diseases, diabetes mellitus and vascular access as source of bacteraemia. Patients on monotherapy had higher 30-day mortality (24.7% vs 0%, P = 0.037). Multivariate analysis identified SAPS II score (OR = 1.097, 95% CI, 1.032 to 1.166, P = 0.003) and cancer (OR = 4.873, 95% CI, 1.235 to 19.223, P = 0.024) as independent predictors of 30-day mortality.TZP appeared to be an effective culture-guided antibiotic for PA bacteraemia. High 30-day mortality in monotherapy might be confounded by comorbidity, illness severity and sample size. Cancer patients and a high SAPS II score were independent predictors of 30-day mortality.

Objectives To evaluate the safety and clinical outcomes of patients who received carbapenem de-escalation as guided by an antimicrobial stewardship programme (ASP) in a setting where ESBL-producing Enterobacteriaceae are endemic. Methods Patients receiving meropenem or imipenem underwent a prospective ASP review for eligibility for de-escalation according to defined institutional guidelines. Patients in whom carbapenem was de-escalated or not de-escalated, representing the acceptance and rejection of the ASP recommendation, respectively, were compared. The primary outcome was the clinical success rate; secondary outcomes included the 30 day readmission and mortality rates, the duration of carbapenem therapy, the incidence of adverse drug reactions due to antimicrobials, the acquisition of carbapenem-resistant Gram-negative bacteria and the occurrence of Clostridium difficile-associated diarrhoea (CDAD). Results The de-escalation recommendations for 300 patients were evaluated; 204 (68.0%) were accepted. The patient demographics and disease severity were similar. The clinical success rates were similar [de-escalated versus not de-escalated, 183/204 (89.7%) versus 85/96 (88.5%), P = 0.84], as was the survival at hospital discharge [173/204 (84.8%) versus 79/96 (82.3%), P = 0.58]. In the de-escalated group, the duration of carbapenem therapy was shorter (6 versus 8 days, P Conclusions This study suggests that the ASP-guided de-escalation of carbapenems led to comparable clinical success, fewer adverse effects and a lower incidence of the development of resistance. This approach is safe and practicable, and should be a key component of an ASP.

Surgical site infection (SSI) is a common and preventable complication of surgery, but the relative importance of individual measures recommended by guidelines has not been determined. Elective general surgical, neurological, and orthopedic procedures requiring antibiotic prophylaxis from a 3-month period were retrospectively studied to determine concordance with SSI prevention guidelines and to identify factors which predicted the development of SSIs. A total of 216 surgeries were reviewed, with 18 SSIs (8.3%). A mean of 1.4 antibiotic prophylaxis errors per surgery were identified, with correct antibiotic type identified for 64%, antibiotic timing for 83%, supplemental antibiotic dosing for 34%, and antibiotic duration of less than 24 h for 44%. Normothermia was present in 79% of surgeries, and normoglycemia was present in 17%. Univariate analysis of the SSI rate identified four significant factors. Antibiotic prophylaxis for less than 24 h postoperatively (odds ratio [OR], 0.213; 95% confidence interval [95% CI]0.060 to 0.757) and neurosurgery (OR, 0.118; 95% CI, 0.15 to 0.903) correlated with a reduced risk of SSI. The mean number of prophylaxis errors (OR, 1.6; 95% CI, 1.02 to 2.4) and a duration of surgical drainage for more than 3 days (OR, 2.679; 95% CI, 1.009 to 7.113) predicted SSI. By multivariate analysis, errors in individual antibiotic prophylaxis measures were not significantly associated with SSI; however, the presence of more than two errors was significant (OR, 4.030; 95% CI, 1.018 to 15.96). A strong correlation was identified between the degree of concordance to SSI prevention guidelines and the SSI rate ( P = 0.001, Mantel-Haenszel linear-by-linear association chi-square test).