The Safety of Aztreonam Versus Ceftazidime in Patients Labeled With Penicillin Allergy: A Cohort Study.

PURPOSE: Penicillin allergy is the most common drug allergy among hospitalized patients. Traditionally, aztreonam is recommended for patients labeled with penicillin allergy (PLWPA) in our institutional empirical antibiotic guidelines. Due to a global aztreonam shortage in December 2022, the antimicrobial stewardship unit recommended ceftazidime as a substitute. There is a paucity of real-world data on the safety profile of ceftazidime in PLWPA. Hence, we evaluated tolerability outcomes of ceftazidime use in PLWPA. METHODS: This retrospective cohort study compared PLWPA in Singapore General Hospital who received aztreonam (October 2022-December 2022) or ceftazidime (December 2022-February 2023). Patients were stratified according to their risk of allergic reaction (AR) based on history of penicillin allergy. The severity of AR was based on the Delphi study grading system. The primary outcome was development of AR after initiation of aztreonam or ceftazidime. The secondary tolerability outcomes include hepatotoxicity and neurotoxicity. FINDINGS: There were 168 patients in the study; 69 were men (41.1%) and the median age was 69 years (interquartile range: 59-76 years). Incidence of AR was statistically similar in both arms: 1 of 102 patients (0.98%) in the aztreonam arm vs 2 of 66 patients (3.03%) in the ceftazidime arm (P = 0.33). The patient in the aztreonam arm was deemed at medium risk of having an AR and developed localized rashes (grade 1). Both patients in the ceftazidime arm were deemed at high risk of AR and developed localized skin reaction (grade 1). Hepatotoxicity was observed in 1 patient prescribed aztreonam. No patients in the ceftazidime arm developed adverse events. IMPLICATIONS: Ceftazidime appears to be better tolerated and cheaper compared with aztreonam in PLWPA, and serves as an antimicrobial stewardship strategy to conserve broader-spectrum antibiotics use.

An overview of multimorbidity and polypharmacy in older people living with HIV.

The availability of effective antiretroviral therapy (ART) has revolutionized the care of people living with HIV (PLHIV). As a result, PLHIV now have a life expectancy comparable with that of the general population. PLHIV are increasingly confronted with age-related comorbidities and geriatric syndromes, including frailty and polypharmacy, which occur at a higher prevalence and set in at an earlier age compared with their uninfected counterparts. The underlying pathophysiology for multimorbidity and polypharmacy are multifactorial, multidimensional and complex. Therefore, regular review and optimization of risk factors to maintain physical function, social and psychological health is of utmost importance. With an ever-growing population of older PLHIV, there is a pressing need to provide holistic care to address these emerging issues. Accelerated aging observed in PLHIV suggests that early involvement of a multidisciplinary team, including geriatricians, and implementation of integrated models of care can potentially improve the care of older PLHIV, who are at increased risk of frailty and complex multimorbidity. This article reviews the current global situation, discusses the challenges involved and suggests approaches to deliver comprehensive care for older PLHIV. Geriatr Gerontol Int 2024; 24: 49-59.

National surgical antibiotic prophylaxis guideline in Singapore.

INTRODUCTION: Institutional surgical antibiotic prophylaxis (SAP) guidelines are in place at all public hospitals in Singapore, but variations exist and adherence to guidelines is not tracked consistently. A national point prevalence survey carried out in 2020 showed that about 60% of surgical prophylactic antibiotics were administered for more than 24 hours. This guideline aims to align best practices nationally and provides a framework for audit and surveillance. METHOD: This guideline was developed by the National Antimicrobial Stewardship Expert Panel's National Surgical Antibiotic Prophylaxis Guideline Development Workgroup Panel, which comprises infectious diseases physicians, pharmacists, surgeons and anaesthesiologists. The Workgroup adopted the ADAPTE methodology framework with modifications for the development of the guideline. The recommended duration of antibiotic prophylaxis was graded according to the strength of consolidated evidence based on the scoring system of the Singapore Ministry of Health Clinical Practice Guidelines. RESULTS: This National SAP Guideline provides evidence-based recommendations for the rational use of antibiotic prophylaxis. These include recommended agents, dose, timing and duration for patients undergoing common surgeries based on surgical disciplines. The Workgroup also provides antibiotic recommendations for special patient population groups (such as patients with ß-lactam allergy and patients colonised with methicillin-resistant Staphylococcus aureus), as well as for monitoring and surveillance of SAP. CONCLUSION: This evidence-based National SAP Guideline for hospitals in Singapore aims to align practices and optimise the use of antibiotics for surgical prophylaxis for the prevention of surgical site infections while reducing adverse events from prolonged durations of SAP.

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.

Recommendations for the use of antiretroviral therapy in adults living with HIV in Singapore.

Since the advent of combination antiretroviral therapy (ART), the mortality attributable to HIV infection has been reduced by 80%. Newer antiretroviral agents are highly efficacious, have minimal side effects as compared to older drugs, and can be formulated as combination tablets, which reduces patients' pill burden. Despite these advances, 680,000 people died of AIDS-related illnesses worldwide in 2020. The National ART and Monitoring Recommendations by the National HIV Programme are created to guide physicians on the prescribing of ART based on the patients' needs. These recommendations are based on international guidelines and tailored to the local context and unique domestic considerations. It is hoped that with the publication of these recommendations, the care of people living with HIV can be enhanced, bringing us closer to the ending of HIV in our lifetime.

Quantification of Fosfomycin in Combination with Nine Antibiotics in Human Plasma and Cation-Adjusted Mueller-Hinton II Broth via LCMS.

Fosfomycin-based combination therapy has emerged as an attractive option in our armamentarium due to its synergistic activity against carbapenem-resistant Gram-negative bacteria (CRGNB). The ability to simultaneously measure fosfomycin and other antibiotic drug levels will support in vitro and clinical investigations to develop rational antibiotic combination dosing regimens against CRGNB infections. We developed an analytical assay to measure fosfomycin with nine important antibiotics in human plasma and cation-adjusted Mueller-Hinton II broth (CAMHB). We employed a liquid-chromatography tandem mass spectrometry method and validated the method based on accuracy, precision, matrix effect, limit-of-detection, limit-of-quantification, specificity, carryover, and short-term and long-term stability on U.S. Food & Drug Administration (FDA) guidelines. Assay feasibility was assessed in a pilot clinical study in four patients on antibiotic combination therapy. Simultaneous quantification of fosfomycin, levofloxacin, meropenem, doripenem, aztreonam, piperacillin/tazobactam, ceftolozane/tazobactam, ceftazidime/avibactam, cefepime, and tigecycline in plasma and CAMHB were achieved within 4.5 min. Precision, accuracy, specificity, and carryover were within FDA guidelines. Fosfomycin combined with any of the nine antibiotics were stable in plasma and CAMHB up to 4 weeks at -80 °C. The assay identified and quantified the respective antibiotics administered in the four subjects. Our assay can be a valuable tool for in vitro and clinical applications.

Therapeutic drug monitoring of meropenem and piperacillin-tazobactam in the Singapore critically ill population - A prospective, multi-center, observational study (BLAST 1).

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Current dosing practices may be suboptimal for ICU patients. Beta-lactam TDM may be useful.

From Bench-Top to Bedside: A Prospective In Vitro Antibiotic Combination Testing (iACT) Service to Guide the Selection of Rationally Optimized Antimicrobial Combinations against Extensively Drug Resistant (XDR) Gram Negative Bacteria (GNB).

INTRODUCTION: Combination therapy is increasingly utilized against extensively-drug resistant (XDR) Gram negative bacteria (GNB). However, choosing a combination can be problematic as effective combinations are often strain-specific. An in vitro antibiotic combination testing (iACT) service, aimed to guide the selection of individualized and rationally optimized combination regimens within 48 hours, was developed. We described the role and feasibility of the iACT service in guiding individualized antibiotic combination selection in patients with XDR-GNB infections. METHODS: A retrospective case review was performed in two Singapore hospitals from April 2009-June 2014. All patients with XDR-GNB and antibiotic regimen guided by iACT for clinical management were included. The feasibility and role of the prospective iACT service was evaluated. The following patient outcomes were described: (i) 30-day in-hospital all-cause and infection-related mortality, (ii) clinical response, and (iii) microbiological eradication in patients with bloodstream infections. RESULTS: From 2009-2014, the iACT service was requested by Infectious Disease physicians for 39 cases (20 P. aeruginosa, 13 A. baumannii and 6 K. pneumoniae). Bloodstream infection was the predominant infection (36%), followed by pneumonia (31%). All iACT recommendations were provided within 48h from request for the service. Prior to iACT-guided therapy, most cases were prescribed combination antibiotics empirically (90%). Changes in the empiric antibiotic regimens were recommended in 21 (54%) cases; in 14 (36%) cases, changes were recommended as the empiric regimens were found to be non-bactericidal in vitro. In 7 (18%) cases, the number of antibiotics used in combination empirically was reduced by the iACT service. Overall, low 30-day infection-related mortality (15%) and high clinical response (82%) were observed. Microbiological eradication was observed in 79% of all bloodstream infections. CONCLUSIONS: The iACT service can be feasibly employed to guide the timely selection of rationally optimized combination regimens, and played a role in reducing indiscreet antibiotic use.

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

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.

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.

Nonattenuated Polymyxin B Used for the Treatment of Extreme-Drug Resistant Acinetobacter baumannii-Related Infections in Patients with Preexisting End Stage Renal Failure.

Recent pharmacokinetic studies have suggested that nonrenal clearance predominates the elimination of polymyxin B. We present 2 patients with preexisting end stage renal failure, who were given nonattenuated doses of polymyxin B for the treatment of extreme-drug resistant organism. No evidence of adverse events occurred and microbiological clearance was documented.