Andrea Lay-Hoon Kwa

Role of antibiotic prophylaxis in necrotizing pancreatitis: a meta-analysis.

Several studies have yielded conflicting results on the role of antibiotic prophylaxis in improving outcomes in acute necrotizing pancreatitis. A meta-analysis was carried out to investigate the impact of antibiotic prophylaxis in the incidence of infected pancreatic necrosis and mortality.MethodologyRandomized controlled trials and cohort studies investigating impact of prophylactic systemic antibiotic used in acute necrotizing pancreatitis were retrieved from online databases. An overall analysis was done with all studies (Group 1), followed by subgroup analyses with randomized controlled trials (Group 2) and cohort studies (Group 3). Risk ratios (RR) were calculated for the impact of antibiotic prophylaxis in the incidence of infected pancreatic necrosis and mortality in each group using random effects model.ResultsEleven studies involving 864 patients were included. No significant differences in the incidence of infected pancreatic necrosis were observed with prophylactic antibiotic use in all groups. Prophylactic antibiotic use was not associated with significant differences in all-cause mortality in Group 2 (RR = 0.75; p = 0.24) but was associated with a reduction in Groups 1 (RR = 0.66, p = 0.02) and 3 (RR = 0.55, p = 0.04). There was no statistical difference in the incidence of fungal infections and surgical interventions.ConclusionAntibiotic prophylaxis does not significantly reduce the incidence of infected pancreatic necrosis but may affect all-cause mortality in acute necrotizing pancreatitis.

Polymyxin B versus colistin: an update

Polymyxin B and colistin (polymyxin E) are polypeptide antibiotics that were developed in the 1940s, but fell into disfavor due to their high toxicity rates. These two antibiotics were previously regarded to be largely equivalent, due to similarities in their chemical structure and spectrum of activity. In recent years, several pertinent differences, especially in terms of potency and disposition, have been revealed between polymyxin B and colistin. These differences are mainly attributed to the fact that polymyxin B is administered parenterally in its active form, while colistin is administered parenterally as an inactive pro-drug, colistimethate. In this review, we summarize the similarities and differences between polymyxin B and colistin. We also discuss the potential clinical implications of these findings, and provide our perspectives on how polymyxins should be employed to preserve their utility in this era of multi-drug resistance.

mcr-1 in Multidrug-Resistant blaKPC-2-Producing Clinical Enterobacteriaceae Isolates in Singapore

Jocelyn Qi-Min Teo, Rick Twee-Hee Ong, Eryu Xia, Tse-Hsien Koh, Chiea-Chuen Khor, Shannon Jing-Yi Lee, Tze-Peng Lim, Andrea Lay-Hoon Kwa Department of Pharmacy, Singapore General Hospital, Singapore; Saw Swee Hock School of Public Health, National University Health System, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; Department of Pathology, Singapore General Hospital, Singapore; Genome Institute of Singapore, A*Star, Singapore; Office of Clinical Sciences, Duke-NUS Medical School, Singapore; Department of Pharmacy, National University of Singapore, Singapore; Emerging Infectious Diseases, Duke-NUS Medical School, Singapore

Prospective audit and feedback in antimicrobial stewardship: is there value in early reviewing within 48 h of antibiotic prescription?

Antimicrobial stewardship programme (ASP) methodologies are not well defined, with most preferring to wait ≥72-96 h following antibiotic prescription before reviewing patients. However, we hypothesise that early ASP reviews and interventions are beneficial and do not adversely impact patient safety. This study aimed to evaluate the impact of early ASP interventions within 48 h of antibiotic prescription on patient outcomes and safety. A prospective review of ASP interventions made within 48 h of antibiotic prescription in Singapore General Hospital (SGH) from January to December 2012 was conducted. Patient demographics and outcomes were extracted from the database maintained by the ASP team. For culture-directed treatment, there was a shorter mean duration of therapy (DOT) in the accepted group compared with the rejected group (2.26 days vs. 5.56 days; P<0.001). ASP interventions did not alter the length of hospital stay (LOS), 30-day mortality, 14-day Clostridium difficile infection (CDI), 30-day re-admissions and 14-day re-infection (all P>0.05). For empirical treatment, a shorter DOT (3.61 days vs. 6.25 days; P<0.001) and decreased 30-day all-cause mortality (P=0.003) and infection-related mortality (P=0.002) were observed among patients in the accepted group compared with the rejected group. There was no significant difference in LOS, 14-day CDI and 30-day re-admission (all P>0.05). In conclusion, acceptance of early interventions recommended by ASP in SGH was associated with a reduction in DOT without compromising patient safety. This is evident even during empirical therapy when not all clinical information was available.

In Vitro Pharmacodynamics of Various Antibiotics in Combination against Extensively Drug-Resistant Klebsiella pneumoniae

ABSTRACT Extensively drug-resistant (XDR) Klebsiella pneumoniae is an emerging pathogen in Singapore. With limited therapeutic options available, combination antibiotics may be the only viable option. In this study, we aimed to elucidate effective antibiotic combinations against XDR K. pneumoniae isolates. Six NDM-1-producing and two OXA-181-producing K. pneumoniae strains were exposed to 12 antibiotics alone and in combination via time-kill studies. A hollow-fiber infection model (HFIM) with pharmacokinetic validation was used to simulate clinically relevant tigecycline-plus-meropenem dosing regimens against 2 XDR K. pneumoniae isolates over 240 h. The emergence of resistance against tigecycline was quantified using drug-free and selective (tigecycline at 3× the MIC) media. The in vitro growth rates were determined and serial passages on drug-free and selective media were carried out on resistant isolates obtained at 240 h. Both the polymyxin B and tigecycline MICs ranged from 1 to 4 mg/liter. In single time-kill studies, all antibiotics alone demonstrated regrowth at 24 h, except for polymyxin B against 2 isolates. Tigecycline plus meropenem was found to be bactericidal in 50% of the isolates. For the isolates that produced OXA-181-like carbapenemases, none of the 55 tested antibiotic combinations was bactericidal. Against 2 isolates in the HFIM, tigecycline plus meropenem achieved a >90% reduction in bacterial burden for 96 h before regrowth was observed until 109 CFU/ml at 240 h. Phenotypically stable and resistant isolates, which were recovered from tigecycline-supplemented plates post-HFIM studies, had lower growth rates than those of their respective parent isolates, possibly implying a substantial biofitness deficit in this population. We found that tigecycline plus meropenem may be a potential antibiotic combination for XDR K. pneumoniae infections, but its efficacy was strain specific.

Prevalence of Healthcare-Associated Infections and Antimicrobial Use Among Adult Inpatients in Singapore Acute-Care Hospitals: Results From the First National Point Prevalence Survey.

Background We conducted a national point prevalence survey (PPS) to determine the prevalence of healthcare-associated infections (HAIs) and antimicrobial use (AMU) in Singapore acute-care hospitals. Methods Trained personnel collected HAI, AMU, and baseline hospital- and patient-level data of adult inpatients from 13 private and public acute-care hospitals between July 2015 and February 2016, using the PPS methodology developed by the European Centre for Disease Prevention and Control. Factors independently associated with HAIs were determined using multivariable regression. Results Of the 5415 patients surveyed, there were 646 patients (11.9%; 95% confidence interval [CI], 11.1%-12.8%) with 727 distinct HAIs, of which 331 (45.5%) were culture positive. The most common HAIs were unspecified clinical sepsis (25.5%) and pneumonia (24.8%). Staphylococcus aureus (12.9%) and Pseudomonas aeruginosa (11.5%) were the most common pathogens implicated in HAIs. Carbapenem nonsusceptibility rates were highest in Acinetobacter species (71.9%) and P. aeruginosa (23.6%). Male sex, increasing age, surgery during current hospitalization, and presence of central venous or urinary catheters were independently associated with HAIs. A total of 2762 (51.0%; 95% CI, 49.7%-52.3%) patients were on 3611 systemic antimicrobial agents; 462 (12.8%) were prescribed for surgical prophylaxis and 2997 (83.0%) were prescribed for treatment. Amoxicillin/clavulanate was the most frequently prescribed (24.6%) antimicrobial agent. Conclusions This survey suggested a high prevalence of HAIs and AMU in Singapores acute-care hospitals. While further research is necessary to understand the causes and costs of HAIs and AMU in Singapore, repeated PPSs over the next decade will be useful to gauge progress at controlling HAIs and AMU.

Clinical Efficacy of Polymyxin Monotherapy versus Nonvalidated Polymyxin Combination Therapy versus Validated Polymyxin Combination Therapy in Extensively Drug-Resistant Gram-Negative Bacillus Infections.

ABSTRACT Polymyxins have emerged as a last-resort treatment of extensively drug-resistant (XDR) Gram-negative Bacillus (GNB) infections, which present a growing threat. Individualized polymyxin-based antibiotic combinations selected on the basis of the results of in vitro combination testing may be required to optimize therapy. A retrospective cohort study of hospitalized patients receiving polymyxins for XDR GNB infections from 2009 to 2014 was conducted to compare the treatment outcomes between patients receiving polymyxin monotherapy (MT), nonvalidated polymyxin combination therapy (NVCT), and in vitro combination testing-validated polymyxin combination therapy (VCT). The primary and secondary outcomes were infection-related mortality and microbiological eradication, respectively. Adverse drug reactions (ADRs) between treatment groups were assessed. A total of 291 patients (patients receiving MT, n = 58; patients receiving NVCT, n = 203; patients receiving VCT, n = 30) were included. The overall infection-related mortality rate was 23.0% (67 patients). In the multivariable analysis, treatment of XDR GNB infections with MT (adjusted odds ratio [aOR], 8.49; 95% confidence interval [CI], 1.56 to 46.05) and NVCT (aOR, 5.75; 95% CI, 1.25 to 25.73) was associated with an increased risk of infection-related mortality compared to that with treatment with VCT. A higher Acute Physiological and Chronic Health Evaluation II (APACHE II) score (aOR, 1.14; 95% CI 1.07 to 1.21) and a higher Charlson comorbidity index (aOR, 1.28; 95% CI, 1.11 to 1.47) were also independently associated with an increased risk of infection-related mortality. No increase in the incidence of ADRs was observed in the VCT group. The use of an individualized antibiotic combination which was selected on the basis of the results of in vitro combination testing was associated with significantly lower rates of infection-related mortality in patients with XDR GNB infections. Future prospective randomized studies will be required to validate these findings.

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

Candidemia in a major regional tertiary referral hospital – epidemiology, practice patterns and outcomes

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.

Evaluating Polymyxin B-Based Combinations against Carbapenem-Resistant Escherichia coli in Time-Kill Studies and in a Hollow-Fiber Infection Model.

BackgroundCandidemia is a common cause of nosocomial bloodstream infections, resulting in high morbidity and mortality. This study was conducted to describe the epidemiology, species distribution, antifungal susceptibility patterns and outcomes of candidemia in a large regional tertiary referral hospital.MethodsA retrospective surveillance study of patients with candidemia was conducted at Singapore General Hospital between July 2012 and December 2015. In addition, incidence densities and species distribution of candidemia episodes were analysed from 2008 to 2015.ResultsIn the period of 2012 to 2015, 261 candidemia episodes were identified. The overall incidence was 0.14/1000 inpatient-days. C. glabrata (31.4%), C. tropicalis (29.9%), and C. albicans (23.8%) were most commonly isolated. The incidence of C. glabrata significantly increased from 2008 to 2015 (Coefficient 0.004, confidence interval 0–0.007, p = 0.04). Fluconazole resistance was detected primarily in C. tropicalis (16.7%) and C. glabrata (7.2%). fks mutations were identified in one C. albicans and one C. tropicalis. Candidemia episodes caused by C. tropicalis were more commonly encountered in patients with haematological malignancies (p = 0.01), neutropenia (p < 0.001) and higher SAPS II scores (p = 0.02), while prior exposure to echinocandins was associated with isolation of C. parapsilosis (p = 0.001). Echinocandins (73.3%) were most commonly prescribed as initial treatment. The median (range) time to initial treatment was 1 (0–9) days. The 30-day in-hospital mortality rate was 49.8%. High SAPS II score (Odds ratio, OR 1.08; 95% confidence interval, CI 1.05–1.11) and renal replacement therapy (OR 5.54; CI 2.80–10.97) were independent predictors of mortality, while drain placement (OR 0.44; CI 0.19–0.99) was protective.ConclusionsDecreasing azole susceptibilities to C. tropicalis and the emergence of echinocandin resistance suggest that susceptibility patterns may no longer be sufficiently predicted by speciation in our institution. Candidemia is associated with poor outcomes. Strategies optimising antifungal therapy, especially in the critically-ill population, should be explored.