Population pharmacokinetics of extended-infusion piperacillin-tazobactam in hospitalized patients with nosocomial infections.

While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50% fT>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50% fT>MIC for MICs of ≥8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize fT>MIC in certain hospitalized populations.

The effect of a whole-system approach in an antimicrobial stewardship programme at the Singapore General Hospital.

Inappropriate antibiotic use contributes to antimicrobial resistance. Multi-faceted antimicrobial stewardship programmes (ASPs) are recommended for sustainable changes in prescribing practices. A multi-disciplinary ASP was established in October 2008 and piloted in the Departments of General Surgery, Renal Medicine and Endocrinology sequentially. To improve the quality of patient care via optimising the (1) choice, (2) dose, (3) route and (4) duration of antibiotics, a "whole-system" approach incorporating prospective review with immediate concurrent feedback (ICF), prescriber education (public or individualised), de-escalation of therapy, dose optimisation and parenteral-to-oral conversion, while recognising the autonomy of primary prescribers, was adopted. The audited department received a quarterly outcomes report and any common unaccepted practices would be addressed. Outcomes were analysed for 12 months post-ASP implementation. A total of 1,535 antibiotic prescriptions were reviewed. Antimicrobial use in 376 (24.5%) prescriptions was inappropriate. Of 596 interventions made, 70.2% were accepted. A reduction in audited antibiotics consumption resulted in acquisition cost savings of S$198,575 for the hospital. Patients' cost-savings attributable to ASP-initiated interventions were $91,194. The overall all-cause mortality rate and median monthly inpatient-days pre- and post-intervention remained stable. A "whole-system" ASP was effective in optimising antibiotic use in our hospital, without compromising clinical outcomes.

Utility and safety of procalcitonin in an antimicrobial stewardship program (ASP) in patients with malignancies.

As data on procalcitonin utility in antibiotics discontinuation [under an antimicrobial stewardship program (ASP)] in patients with malignancies are lacking, we aimed to evaluate the utility of procalcitonin in an ASP in patients with malignancies. We conducted a retrospective review of the ASP database of all patients with malignancies in whom at least one procalcitonin level was taken and our ASP had recommended changes in carbapenem regimen, from January to December 2011. We compared clinical outcomes between two groups of patients: patients whose physicians accepted and those whose physicians rejected ASP interventions. There were 749 carbapenem cases reviewed. Ninety-nine were suggested to either de-escalate, discontinue antibiotics, or narrow the spectrum of empiric treatment, based on procalcitonin trends. While there was no statistical difference in the mortality within 30 days post-ASP intervention (accepted: 8/65 patients vs. rejected: 9/34 patients; p = 0.076), the median duration of carbapenem therapy was significantly shorter (5 vs. 7 days; p = 0.002). Procalcitonin use safely facilitates decisions on antibiotics discontinuation and de-escalation in patients with malignancies in the ASP.

Impact of the COVID-19 pandemic on a tertiary care public hospital in Singapore: resources and economic costs.

BACKGROUND: The COVID-19 pandemic has prompted hospitals to respond with stringent measures. Accurate estimates of costs and resources used in outbreaks can guide evaluations of responses. We report on the financial expenditure associated with COVID-19, the bed-days used for COVID-19 patients and hospital services displaced due to COVID-19 in a Singapore tertiary hospital. METHODS: We conducted a retrospective cost analysis from January to December 2020 in the largest public hospital in Singapore. Costs were estimated from the hospital perspective. We examined financial expenditures made in direct response to COVID-19; hospital admissions data related to COVID-19 inpatients; and the number of outpatient and emergency department visits, non-emergency surgeries, inpatient days in 2020, compared with preceding years of 2018 and 2019. Bayesian time-series was used to estimate the magnitude of displaced services. RESULTS: USD $41.96 million was incurred in the hospital for COVID-19-related expenses. Facilities set-up and capital assets accounted for 51.6% of the expenditure; patient-care supplies comprised 35.1%. Of the 19,611 inpatients tested for COVID-19 in 2020, 727 (3.7%) had COVID-19. The total inpatient- and intensive care unit (ICU)-days for COVID-19 patients in 2020 were 8009 and 8 days, respectively. A decline in all hospital services was observed from February following a raised disease outbreak alert level; most services quickly resumed when the lockdown was lifted in June. CONCLUSION: COVID-19 led to an increase in healthcare expenses and a displacement in hospital services. Our findings are useful for informing economic evaluations of COVID-19 response and provide some information about the expected costs of future outbreaks.

Use of procalcitonin (PCT) to guide discontinuation of antibiotic use in an unspecified sepsis is an antimicrobial stewardship program (ASP).

Clinicians have used procalcitonin (PCT) (biomarker to differentiate bacterial from non-bacterial sepsis) to guide use of antibiotics in patients. As the data for utility of PCT to discontinue antibiotics in an antimicrobial stewardship program (ASP) are lacking, we aim to describe the outcomes of patients in whom PCT was used to discontinue antibiotics under our ASP. An antimicrobial stewardship (AS) team intervened to discontinue antibiotics in patients with persistent fever or leucocytosis, source of sepsis unknown or negative bacteriological cultures, who had completed an adequate course of antibiotic therapy and had a PCT of <0.5 µg/L. Main outcomes evaluated were 14-day re-infection, 30-day mortality and readmission. Antibiotic therapy was discontinued in 42 patients in 1 year. Unknown source of sepsis was found in 38% of the patients (including possible malignant fever) and culture-negative pneumonia was found in 21%. Two patients died of advanced cancer. One patient decided for comfort care and died one week later. One patient died due to a second episode of pneumonia 37 days after first PCT test. Six patients were readmitted within 30 days due to non-infectious causes. Three patients were readmitted due to culture-negative pneumonia. None had a 14-day re-infection. PCT used to discontinue antibiotics under our ASP did not compromise patients' outcome.

Empowerment of nurses in antibiotic stewardship: a social ecological qualitative analysis.

BACKGROUND: Inappropriate antibiotics use and antimicrobial resistance (AMR) are increasingly becoming global health issues of great concern. Despite the established antibiotic stewardship programmes (ASPs) in many countries, limited efforts have been made to engage nurses and clearly define their roles in ASPs. AIM: An exploratory qualitative study was conducted to understand the facilitators and barriers that impact nurses' involvement and empowerment in antibiotic stewardship. METHODS: Focus group discussions (FGDs) were conducted with purposively sampled nurses from three major public hospitals in Singapore. FGDs were audio-recorded and transcribed verbatim. Data were analysed using Applied Thematic Analysis and interpreted using the Social Ecological Model. FINDINGS: At the intrapersonal level, nurses felt empowered in carrying out their roles in antibiotic administration. They saw themselves as gatekeepers to ensure that the prescribed antibiotics were administered appropriately. However, nurses felt they lacked the knowledge and expertise in antibiotic use and AMR prevention. At the interpersonal level, this deficit in knowledge and expertise in antibiotic use impacted how they were perceived by patients and caregivers as well as their interactions with the primary care team when voicing outpatient safety concerns and antibiotic administration suggestions. At the organizational level, nurses relied on drug administration guidelines to ensure appropriate antibiotic administration and as a safety net when physicians questioned their clinical practice. At the community level, nurses felt there was a lack of awareness and knowledge on antibiotic use among the general population. CONCLUSION: These findings provide important insights to harness the contributions of nurses, and to formally acknowledge and enlarge their roles in ASPs.

NLRP3 inflammasome pathway has a critical role in the host immunity against clinically relevant Acinetobacter baumannii pulmonary infection.

The opportunistic Gram-negative bacterium Acinetobacter baumannii (AB) is a leading cause of life-threatening nosocomial pneumonia. Outbreaks of multidrug resistant (MDR)-AB belonging to international clones (ICs) I and II with limited treatment options are major global health threats. However, the pathogenesis mechanisms of various AB clonal groups are understudied. Although inflammation-associated interleukin-1ß (IL-1ß) levels and IL-1 receptor antagonist polymorphisms were previously implicated in MDR-AB-related pneumonia in patients, whether inflammasomes has any role in the host defense and/or pathogenesis of clinically relevant A. baumannii infection is unknown. Using a sublethal mouse pneumonia model, we demonstrate that an extensively drug-resistant clinical isolate (ICII) of A. baumannii exhibits reduced/delayed early pulmonary neutrophil recruitment, higher lung persistence, and, most importantly, elicits enhanced IL-1ß/IL-18 production and lung damage through NLRP3 inflammasome, in comparison with A. baumannii-type strain. A. baumannii infection-induced IL-1ß/IL-18 production is entirely dependent on NLRP3-ASC-caspase-1/caspase-11 pathway. Using Nlrp3-/- mice infection models, we further show that while NLRP3 inflammasome pathway contributes to host defense against A. baumannii clinical isolate, it is dispensable for protection against A. baumannii-type strain. Our study reveals a novel differential role for NLRP3 inflammasome pathway in the immunity against clinically relevant A. baumannii infections, and highlights inflammasome pathway as a potential immunomodulatory target.

Rhodococcus equi pneumonia in a patient with human immunodeficiency virus: case report and review.

Rhodococcus equi is a facultative, intracellular, gram-positive coccobacillus increasingly reported as an opportunistic pathogen in patients positive for human immunodeficiency virus (HIV). An HIV-positive man developed R. equi pneumonia and sepsis. He failed to improve despite surgical drainage of localized infection and many empiric antibiotics. Time-kill studies of R. equi isolated from the patient were performed against various antimicrobial agents to optimize therapy. Levofloxacin seemed to offer excellent in vitro bactericidal activity. Antagonism was observed with certain antibiotic combinations. Our anecdotal case report suggests that fluoroquinolones such as levofloxacin may offer superior efficacy to standard therapy in rhodococcal infections; their clinical utility deserves further investigation. In view of potential antagonism, prospective susceptibility testing for various drugs and drug combinations should be considered when clinically indicated.

Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy.

We report a case of hypersensitivity pneumonitis, possibly due to aerosolized colistin therapy for severe multi-resistant Gram-negative pneumonia. Microbiological eradication was achieved with colistin therapy, which was stopped after 12 days in view of rising eosinophilia and possible lung fibrosis. The eosinophil count started to normalize 3 days after stopping colistin therapy and the patient was eventually weaned to minimal ventilatory support.

Reducing antimicrobial resistance through appropriate antibiotic usage in Singapore.

Two alarming trends threaten the future utility of antimicrobial agents: rise of antimicrobial resistance and decline in development of new antibiotics. The continuing emergence and spread of antimicrobial-resistant microbes--a global public health issue--exacerbates the problem of paucity of new antimicrobial agents. Singapore's public sector hospitals currently have some of the highest rates of antimicrobial resistance worldwide, evolving with surprising speed over the past two decades. Because there was no systematic surveillance until fairly recently, this healthcare problem has not been emphasised. In contrast, it is difficult to assess the scale of antimicrobial resistance in the community in view of the lack of recent research, although indirect evidence suggests that this is also a source of concern. A panel comprising representatives from multiple professional healthcare societies was convened to address the issue of antimicrobial resistance in Singapore, focusing on the conservation of antibiotics against resistance. From a review of the medical literature, potentially successful strategies involve facilitating prudent and appropriate use of antimicrobial agents in tandem with other interventions in infection control. Presently, there is a lack of data on the appropriate use of antibiotics in Singapore. The recommendations of the panel are: The professions should look into ways and means to support systematic data collection on antibiotic use and appropriateness of use; The Ministry of Health should take a more active and positive role in regulating antibiotic usage; Hospitals should actively support effective antimicrobial stewardship programmes; Educators should coordinate programmes to give greater emphasis on appropriate antimicrobial prescription, and support good clinical practice; and, Local and regional branches of pharmaceutical companies should adopt the Pharmaceutical Research and Manufacturers of America's updated code of conduct on interactions with physicians as a step towards re-aligning the industry-physician relationship in the direction of educational and informational support.