Yiying Cai

Risk Factors, Molecular Epidemiology and Outcomes of Ertapenem-Resistant, Carbapenem-Susceptible Enterobacteriaceae: A Case-Case-Control Study

Background Increasing prevalence of ertapenem-resistant, carbapenem-susceptible Enterobacteriaceae (ERE) in Singapore presents a major therapeutic problem. Our objective was to determine risk factors associated with the acquisition of ERE in hospitalized patients; to assess associated patient outcomes; and to describe the molecular characteristics of ERE. Methods A retrospective case-case-control study was conducted in 2009 at a tertiary care hospital. Hospitalized patients with ERE and those with ertapenem-sensitive Enterobacteriaceae (ESE) were compared with a common control group consisting of patients with no prior gram-negative infections. Risk factors analyzed included demographics; co-morbidities; instrumentation and antibiotic exposures. Two parallel multivariate logistic regression models were performed to identify independent variables associated with ERE and ESE acquisition respectively. Clinical outcomes were compared between ERE and ESE patients. Results Twenty-nine ERE cases, 29 ESE cases and 87 controls were analyzed. Multivariate logistic regression showed that previous hospitalization (Odds ratio [OR], 10.40; 95% confidence interval [CI], 2.19–49.20) and duration of fluoroquinolones exposure (OR, 1.18 per day increase; 95% CI, 1.05–1.34) were unique independent predictors for acquiring ERE. Duration of 4th-generation cephalosporin exposure was found to predict for ESE acquisition (OR, 1.63 per day increase; 95% CI, 1.05–2.54). In-hospital mortality rates and clinical response rates were significantly different between ERE and ESE groups, however ERE infection was not a predictor of mortality. ERE isolates were clonally distinct. Ertapenem resistance was likely to be mediated by the presence of extended-spectrum β-lactamases or plasmid-borne AmpC in combination with impermeability due to porin loss and/or efflux pumps. Conclusion Prior hospitalization and duration of fluoroquinolone treatment were predictors of ERE acquisition. ERE infections were associated with higher mortality rates and poorer clinical response rates when compared to ESE infections.

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.

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.

Carbapenem Resistance in Gram-Negative Bacteria: The Not-So-Little Problem in the Little Red Dot

Singapore is an international travel and medical hub and faces a genuine threat for import and dissemination of bacteria with broad-spectrum resistance. In this review, we described the current landscape and management of carbapenem resistance in Gram-negative bacteria (GNB) in Singapore. Notably, the number of carbapenem-resistant Enterobacteriaceae has exponentially increased in the past two years. Resistance is largely mediated by a variety of mechanisms. Polymyxin resistance has also emerged. Interestingly, two Escherichia coli isolates with plasmid-mediated mcr-1 genes have been detected. Evidently, surveillance and infection control becomes critical in the local setting where resistance is commonly related to plasmid-mediated mechanisms, such as carbapenemases. Combination antibiotic therapy has been proposed as a last-resort strategy in the treatment of extensively drug-resistant (XDR) GNB infections, and is widely adopted in Singapore. The diversity of carbapenemases encountered, however, presents complexities in both carbapenemase detection and the selection of optimal antibiotic combinations. One unique strategy introduced in Singapore is a prospective in vitro combination testing service, which aids physicians in the selection of individualized combinations. The outcome of this treatment strategy has been promising. Unlike countries with a predominant carbapenemase type, Singapore has to adopt management strategies which accounts for diversity in resistance mechanisms.

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 procalcitonin-based guideline promotes shorter duration of antibiotic use safely in acute pancreatitis

We read with interest the article by Hoeboer et al. Like critically ill patients in the intensive care unit (ICU), patients with acute pancreatitis (AP) develops systemic inflammatory response syndrome, which is difficult to distinguish from sepsis. Hence, physicians often prescribe broad-spectrum prophylactic antibiotics for fear of undertreatment. This is exacerbated by the fact that early studies have reported findings in favor of prophylactic antibiotics in AP. However, these positive findings have been attributed to poor study designs, and recent randomized trials have shown that routine antibiotic prophylaxis did not confer benefits, but resulted in increased hospitalization costs and antimicrobial resistance. In light of the current situation, the Singapore General Hospital (SGH) Antimicrobial Stewardship Team (ASP) developed a procalcitonin-based guideline for AP in collaboration with the General Surgery Department, to guide prudent antibiotic prescribing (Fig. 1). Procalcitonin was employed as it can predict bacterial infections in critically ill patients and allowed early diagnosis of infected necrosis in AP. While the guideline was widely implemented in SGH, adherence was not enforced and eventual adherence was autonomously decided by the primary physician. Hence, we aim to evaluate the adherence to and impact of the guideline on antibiotic utilization and patient outcomes. A retrospective study was performed for all patients admitted from JanuaryeDecember 2011 with a primary diagnosis of AP (ICD-9 code 577.0). Patients were excluded if they were severely immunosuppressed; for patients with recurrent AP, only the first episode was included. Included patients were segregated into two groups: adherence (Group I) and non-adherence to protocol (Group II). The allocation of patients to either group was decided independently by the two study members; if a lack of consensus was observed, the opinion of a third member was sought. The study was approved by the institutional ethics committee. The primary outcome was difference in intravenous antibiotic use (days of therapy); in addition, an adjusted outcome was estimated using multi-variable regression, to correct for differences in baseline. Secondary outcomes included differences in 30-day crude mortality, days to enteral feeding, days to resolution of fever and white blood cell (WBC) count. Sample size requirements were estimated based on the PRORATA trial; assuming a mean of 10.8 days therapy in the non-adherence group, approximately 95 patients per group provided power of 80% (two-sided

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.