Stemming the Rise of Antibiotic Use for Community-Acquired Acute Respiratory Infections during COVID-19 Pandemic.

At the start of the COVID-19 pandemic, there was an increase in the use of antibiotics for the treatment of community-acquired respiratory tract infection (CA-ARI) in patients admitted for suspected or confirmed COVID-19, raising concerns for misuse. These antibiotics are not under the usual purview of the antimicrobial stewardship unit (ASU). Serum procalcitonin, a biomarker to distinguish viral from bacterial infections, can be used to guide antibiotic recommendations in suspected lower respiratory tract infection. We modified our stewardship approach, and used a procalcitonin-guided strategy to identify "high yield" interventions for audits in patients admitted with CA-ARI. With this approach, there was an increase in the proportion of patients with antibiotics discontinued within 4 days (16.5% vs. 34.9%, p < 0.001), and the overall duration of antibiotic therapy was significantly shorter [7 (6−8) vs. 6 (3−8) days, p < 0.001]. There was a significant decrease in patients with intravenous-to-oral switch of antibiotics to "complete the course" (45.3% vs. 34.4%, p < 0.05). Of the patients who had antibiotics discontinued, none were restarted on antibiotics within 48 h, and there was no-30-day readmission or 30-day mortality attributed to respiratory infection. This study illustrates the importance of the antimicrobial stewardship during the pandemic and the need for ASU to remain attuned to prescriber's practices, and adapt accordingly to address antibiotic misuse to curb antimicrobial resistance.

Incidence of a subsequent carbapenem-resistant Enterobacteriaceae infection after previous colonisation or infection: a prospective cohort study.

OBJECTIVES: In patients with a history of carbapenemase-producing, carbapenem-resistant Enterobacteriaceae (CP-CRE), the need for CP-CRE targeted treatment in subsequent sepsis episodes is unclear. This study aimed to characterise the incidence of subsequent CP-CRE infective episodes in individuals with prior CP-CRE colonisation and/or infection, and identify predictors for these subsequent CP-CRE infections. METHODS: All adult inpatients with CP-CRE detected from any site between June 2012 and May 2014 at a tertiary-care hospital were prospectively followed for two years to assess for any subsequent CP-CRE infections. Potential factors to which patients were exposed during the follow-up period were collected from medical records and analysed. RESULTS: A total of 171 patients were enrolled. Of 151 patients who entered the follow-up period, 16 (10.6%) developed a subsequent CP-CRE infection. The median time to a subsequent infective episode was 24.5 days (12-105 days). The type of carbapenemase was highly conserved within index and subsequent paired episodes (16 of 17 pairs). Patients with first CP-CRE isolated from intra-abdominal or respiratory sources were ≥7 times more likely to develop a subsequent infection, while most rectal carriers remain colonised. For carriers (n = 133), Klebsiella spp. (OR 4.7) and OXA carbapenemase (OR 9.4) were significant predictors of subsequent infection. In patients with initial infection (n = 18), end-stage renal failure requiring dialysis (OR 22.0) was the only predisposing factor. CONCLUSION: The incidence of subsequent infections in patients with prior colonisation was low. Consideration for CP-CRE targeted therapy is recommended in patients on dialysis and previous CP-CRE infections involving the bloodstream and/or respiratory tract.

Treatment and Outcomes of Infections Caused by Diverse Carbapenemase-Producing Carbapenem-Resistant Enterobacterales.

Background: Diverse sequence types (ST) and various carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) infections, which complicate treatment strategies, have emerged in Singapore. We aim to describe these CP-CRE infections and clinical outcomes according to their carbapenemase types and determine the hierarchy of predictors for mortality that are translatable to clinical practice. Methods: Clinically significant CP-CRE infections were identified in Singapore General Hospital between 2013 and 2016. Retrospectively, all clinically relevant data were retrieved from electronic medical records from the hospital. Univariate analysis was performed. To further explore the relationship between the variables and mortality in different subsets of patients with CP-CRE, we conducted recursive partitioning analysis on all study variables using the "rpart" package in R. Results: One hundred and fifty five patients were included in the study. Among them, 169 unique CP-CRE were isolated. Thirty-day all-cause in-hospital mortality was 35.5% (n = 55). There was no difference in the severity of illness, or any clinical outcomes exhibited by patients between the various carbapenemases. Root node began with patients with Acute Physical and Chronic Health Evaluation (APACHEII) score ≥ 15 (n = 98; mortality risk = 52.0%) and <15 (n = 57; mortality risk = 9.0%). Patients with APACHEII score ≥ 15 are further classified based on presence (n = 27; mortality risk = 23.0%) and absence (n = 71, mortality risk = 62.0%) of bacterial eradication. Without bacterial eradication, absence (n = 54) and presence (n = 17) of active source control yielded 70.0 and 35.0% mortality risk, respectively. Without active source control, the mortality risk was higher for the patients with non-receipt of definite combination therapy (n = 36, mortality risk = 83.0%) when compared to those who received (n = 18, mortality risk = 47.0%). Overall, the classification tree has an area under receiver operating characteristic curve of 0.92, with a sensitivity of 0.87 and specificity of 0.91. Conclusion: Different mortality risks were observed with different treatment strategies. Effective source control and microbial eradication were associated with a lower mortality rate but not active empiric therapy for CP-CRE infection. When source control was impossible, definitive antibiotic combination appeared to be associated with a reduction in mortality.

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.

Vancomycin-resistant Enterococci in Singaporean hospitals: 5-year results of a multi-centre surveillance programme.

INTRODUCTION: Vancomycin-resistant enterococci (VRE) have emerged as one of the major nosocomial antimicrobial-resistant pathogens globally. In this article, we describe the epidemiology of VRE in Singaporean public hospitals in the 5 years following the major local VRE outbreak in 2005. MATERIALS AND METHODS: A passive laboratory surveillance programme identified non-duplicate VRE isolates from 7 hospitals from 2006 to 2010. Descriptive statistics and time-series analysis was performed on all clinical VRE isolates for each individual hospital as well as for the combined dataset. RESULTS: There were a total of 418 VRE isolates over 5 years, of which 102 isolates (24.4%) were from clinical cultures. Between 0.4% and 0.7% of all clinical enterococcal isolates were resistant to vancomycin. The overall incidence-density of VRE did not change over time in Singapore despite 2 separate outbreaks in tertiary hospitals in 2009 and 2010. Incidence-density of clinical VRE cases fell in 2 secondary hospitals, while another 2 hospitals experienced no significant VRE infections after 2008. CONCLUSION: The prevalence of VRE clinical isolates remains low in Singaporean public sector hospitals. However, the presence of at least 2 outbreaks in separate hospitals over the past 5 years indicates the need for continued vigilance in order to prevent any further increase in VRE prevalence locally.

Independent predictors for mortality in patients with positive Stenotrophomonas maltophilia cultures.

INTRODUCTION: Stenotrophomonas maltophilia is an emerging pathogen in nosocomial infections that may result in high mortality. S. maltophilia often present as part of a polymicrobial culture and it is not well established when treatment is indicated. We aimed to identify predictors of mortality in patients with positive cultures of S. maltophilia. MATERIALS AND METHODS: A retrospective cohort study in a tertiary care medical centre was performed in 150 adult patients with positive cultures of S. maltophilia. Patients' demographics, underlying diseases, severity of illness, length of hospitalisation, prior antibiotic exposure, number/types of indwelling catheters, culture sites, and appropriateness of empiric therapy were collected. Logistic regression was used to determine the independent risk factor(s) for infection-attributed mortality. RESULTS: Ninety-nine males and 51 females were studied. The mean (SD) age and APACHE II score of the patients were 61.9 (16.0) and 14.0 (6.1), respectively. The respiratory tract was the most frequent site (55.3%) where S. maltophilia was isolated. Infection-attributed mortality was observed in 22 of the 150 patients (14.7 %). Admission to ICU [Odds ratio (OR), 3.767; 95% confidence interval (CI), 1.277-11.116, P = 0.016], and delayed effective treatment (OR, 18.684; 95% CI, 4.050-86.188; P <0.001) were identified as independent risk factors for mortality. CONCLUSIONS: Predictors of mortality in patients with positive cultures of S. maltophilia were identified, which may guide clinicians in patient assessment and devising therapeutic decisions. Further studies are needed to validate our results.

Pharmacokinetics of polymyxin B1 in patients with multidrug-resistant Gram-negative bacterial infections.

Polymyxin B is increasingly used clinically for the treatment of multidrug-resistant Gram-negative infections, despite very limited understanding of its disposition in humans. The disposition of intravenous polymyxin B1 in 9 adult patients was characterized. Random blood samples (specifically timed in relation to the dose administered) were obtained, and the serum concentrations of polymyxin B1 were assayed using a validated methodology by liquid chromatography mass spectroscopy. The serum concentration profiles of all the patients were analyzed by a population pharmacokinetic analysis using the nonparametric adaptive grid program. The mean volume of distribution and elimination half-life were found to be 47.2 L and 13.6 h, respectively. This is the 1st case series to date in which the pharmacokinetics of polymyxin B1 after intravenous administration are described. The results of the series in conjunction with pharmacodynamic and susceptibility surveillance studies could facilitate an approach to the design of optimal dosing regimens.

The impact of multidrug resistance on the outcomes of critically ill patients with Gram-negative bacterial pneumonia.

Multidrug resistance (MDR) in Gram-negative bacteria is on the rise, but its effect on patient outcomes is not well established. The outcomes of 129 adult surgical intensive care unit (SICU) patients treated for Gram-negative pneumonia were evaluated in relation to demographics, bacterial etiology, and infections due to MDR bacteria (defined as resistant to all agents except for aminoglycosides and polymyxins). The mean (SD) age and acute physiology and chronic health evaluation (APACHE) II scores were 63.8 (14.6) years and 20.8 (8.2), respectively. Forty-one patients (31.8%) were infected with MDR bacteria. Infection-attributed mortality was associated with baseline APACHE II scores (odds ratio [OR] 1.093; 95% confidence interval [CI] 1.029-1.162), MDR (OR 4.628; 95% CI 1.533-13.973), and infection with Stenotrophomonas maltophilia (OR 13.465; 95% CI 2.896-62.614). In SICU patients with Gram-negative pneumonia, MDR was associated with a higher rate of infection-attributed mortality, after adjusting for the severity of illness. Our results warrant further investigations with a prospective study.

Nebulized colistin in the treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa.

Twenty-one patients with multidrug-resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa pneumonia were treated with nebulized polymyxin E (colistin). Overall clinical and microbiological response rates were 57.1% and 85.7%, respectively. Nebulized colistin may be reasonably efficacious and safe for treatment of MDR pneumonia. Its role in therapy warrants further investigation in comparative studies.