Menino Osbert Cotta

Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials

RATIONALE Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. OBJECTIVES In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics. METHODS We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. MEASUREMENTS AND MAIN RESULTS We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure. CONCLUSIONS Compared with intermittent dosing, administration of β-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality.

A Systematic Review of the Definitions, Determinants, and Clinical Outcomes of Antimicrobial De-escalation in the Intensive Care Unit

Antimicrobial de-escalation (ADE) is a strategy to reduce the spectrum of antimicrobials and aims to prevent the emergence of bacterial resistance. We present a systematic review describing the definitions, determinants and outcomes associated with ADE. We included 2 randomized controlled trials and 12 cohort studies. There was considerable variability in the definition of ADE. It was more frequently performed in patients with broad-spectrum and/or appropriate antimicrobial therapy (P= .05 to .002), when more agents were used (P= .002), and in the absence of multidrug-resistant pathogens (P< .05). Where investigated, lower or improving severity scores were consistently associated with ADE (P= .04 to <.001). The pooled effect of ADE on mortality is protective (relative risk, 0.68; 95% confidence interval, .52-.88). Because the determinants of ADE are markers of clinical improvement and/or of lower risk of treatment failure this effect on mortality cannot be retained as evidence. None of the studies were designed to investigate the effect of ADE on antimicrobial resistance.

The ADMIN-ICU survey: a survey on antimicrobial dosing and monitoring in ICUs

OBJECTIVES There is little evidence and few guidelines to inform the most appropriate dosing and monitoring for antimicrobials in the ICU. We aimed to survey current practices around the world. METHODS An online structured questionnaire was developed and sent by e-mail to obtain information on local antimicrobial prescribing practices for glycopeptides, piperacillin/tazobactam, carbapenems, aminoglycosides and colistin. RESULTS A total of 402 professionals from 328 hospitals in 53 countries responded, of whom 78% were specialists in intensive care medicine (41% intensive care, 30% anaesthesiology, 14% internal medicine) and 12% were pharmacists. Vancomycin was used as a continuous infusion in 31% of units at a median (IQR) daily dose of 25 (25-30) mg/kg. Piperacillin/tazobactam was used as an extended infusion by 22% and as a continuous infusion by 7%. An extended infusion of carbapenem (meropenem or imipenem) was used by 27% and a continuous infusion by 5%. Colistin was used at a daily dose of 7.5 (3.9-9) million IU (MIU)/day, predominantly as a short infusion. The most commonly used aminoglycosides were gentamicin (55%) followed by amikacin (40%), with administration as a single daily dose reported in 94% of the cases. Gentamicin was used at a daily dose of 5 (5-6) mg/day and amikacin at a daily dose of 15 (15-20) mg/day. Therapeutic drug monitoring of vancomycin, piperacillin/tazobactam and meropenem was used by 74%, 1% and 2% of the respondents, respectively. Peak aminoglycoside concentrations were sampled daily by 28% and trough concentrations in all patients by 61% of the respondents. CONCLUSIONS We found wide variability in reported practices for antibiotic dosing and monitoring. Research is required to develop evidence-based guidelines to standardize practices.

Measuring antimicrobial prescribing quality in Australian hospitals: development and evaluation of a national antimicrobial prescribing survey tool

OBJECTIVES Antimicrobial stewardship (AMS) programmes have been developed with the intention of reducing inappropriate and unnecessary use of antimicrobials, while improving the quality of patient care and locally helping prevent the development of antimicrobial resistance. An important aspect of AMS programmes is the qualitative assessment of prescribing through antimicrobial prescribing surveys (APS), which are able to provide information about the prescribing behaviour within institutions. Owing to lack of standardization of audit tools and the resources required, qualitative methods for the assessment of antimicrobial use are not often performed. The aim of this study was to design an audit tool that was appropriate for use in all Australian hospitals, suited to local user requirements and included an assessment of the overall appropriateness of the prescription. METHODS In November 2011, a pilot APS was conducted across 32 hospitals to assess the usability and generalizability of a newly designed audit tool. Following participant feedback, this tool was revised to reflect the requirements of the respondents. A second pilot study was then performed in November 2012 across 85 hospitals. RESULTS These surveys identified several areas that can be targets for quality improvement at a national level, including: documentation of indication; surgical prophylaxis prescribed for >24 h; compliance with prescribing guidelines; and the appropriateness of the prescription. CONCLUSIONS By involving the end users in the design and evaluation, we have been able to provide a practical and relevant APS tool for quantitative and qualitative data collection in a wide range of Australian hospital settings.

Using periodic point‐prevalence surveys to assess appropriateness of antimicrobial prescribing in Australian private hospitals

Appropriateness of antimicrobial use is a measure of key importance in evaluating safety and quality of prescribing but has been difficult to define and assess on a wide scale. Published work is limited and has generally focused on tertiary public hospitals, whereas the private sector provides a significant proportion of care in many countries. Information on prescribing in the private hospital context is needed to identify where intervention might be required. An antimicrobial prescribing survey tool was utilised to assess the appropriateness of antimicrobial prescribing among large private hospitals in Australia.

Antimicrobial Stewardship in Australian Hospitals and Other Settings

Australia’s model of antimicrobial stewardship (AMS) has evolved significantly over recent years, from a long-standing national approach of antimicrobial prescribing guidelines and antimicrobial prescribing restrictions to recent advances including the first National Antimicrobial Resistance Strategy and incorporating mandatory AMS as part of hospital accreditation standards. AMS programs are most commonly found in the hospital setting. Various models are used throughout the country based on the local context and resources available. Programs implemented at Alfred Health and the Royal Brisbane and Women’s Hospital represent two successful models in tertiary referral settings that accommodate a general ward setting as well as specialized areas with a high infection burden. Measurement of outcomes related to AMS activities remains poorly standardized, with process indicators such as antimicrobial utilization forming a large proportion of outcome measurement. Presently there is no requirement for any AMS outcome measurements to be reported externally. Point prevalence surveys of appropriateness of prescribing and compliance with prescribing guidelines are widely used at a national level. Despite this, there is still a paucity of published Australian data to support the effect of AMS on patient clinical outcomes. Private hospitals, the community, veterinary medicine and aged care sectors represent an important area for future AMS expansion within Australia. The AMS focus has traditionally been on prescribing restrictions (through the Commonwealth funding agencies); however, recent work has described other areas for improvement and development in both settings. AMS in Australia continues to evolve. The recent development of an Australian strategic plan to link antimicrobial utilization and resistance surveillance with policy represents an important step forward for the future of AMS in Australia.

Implementing antimicrobial stewardship in the Australian private hospital system: A qualitative study

OBJECTIVE To explore organisational factors and barriers contributing to limited uptake of antimicrobial stewardship (AMS) in Australian private hospitals and to determine solutions for AMS implementation. METHODS A qualitative study using a series of focus group discussions was conducted in a large private hospital making use of a semistructured interview guide to facilitate discussion among clinical and non-clinical stakeholders. A thematic analysis using five sequential components that mapped and interpreted emergent themes surrounding AMS implementation was undertaken by a multidisciplinary team of researchers. RESULTS Analysis revealed that autonomy of consultant specialists was perceived as being of greater significance in private hospitals compared with public hospitals. Use of an expert team providing antimicrobial prescribing advice and education without intruding on existing patient-specialist relationships was proposed by participants as an acceptable method of introducing AMS in private hospitals. There was more opportunity for nursing and pharmacist involvement, as well as empowering patients. Opportunities were identified for the hospital executive to market an AMS service as a feature that promoted excellence in patient care. CONCLUSIONS Provision of advice from experts, championing by clinical leaders, marketing by hospital executives and involving nurses, pharmacists and patients should be considered during implementation of AMS in private hospitals.

Antibiotic dose optimization in critically ill patients

The judicious use of existing antibiotics is essential for preserving their activity against infections. In the era of multi-drug resistance, this is of particular importance in clinical areas characterized by high antibiotic use, such as the ICU. Antibiotic dose optimization in critically ill patients requires sound knowledge not only of the altered physiology in serious infections - including severe sepsis, septic shock and ventilator-associated pneumonia - but also of the pathogen-drug exposure relationship (i.e. pharmacokinetic/pharmacodynamic index). An important consideration is the fact that extreme shifts in organ function, such as those seen in hyperdynamic patients or those with multiple organ dysfunction syndrome, can have an impact upon drug exposure, and constant vigilance is required when reviewing antibiotic dosing regimens in the critically ill. The use of continuous renal replacement therapy and extracorporeal membrane oxygenation remain important interventions in these patients; however, both of these treatments can have a profound effect on antibiotic exposure. We suggest placing emphasis on the use of therapeutic drug monitoring and dose individualization when optimizing therapy in these settings.

Antimicrobial stewardship of β-lactams in intensive care units

Stewardship of all antimicrobials, including β-lactam antibiotics, has gained in prominence over the last decade. Appropriate use of these agents has become vitally important; especially in the treatment and management of the critically ill. Opportunities therefore exist to develop innovations to optimise the use of antimicrobials in places like the intensive care unit. The next few years represent an important window in which routine antimicrobial stewardship principles such as surveillance of local ecology, minimising overlap of spectrum of activity and prompt de-escalation upon review of cultures can be integrated with new technologies including improved diagnostic techniques, individualised dosing strategies and computerised decision support. It is important though, that these measures to improve stewardship in the intensive care unit continue to be critically evaluated in the literature.

Even high-dose extended infusions may not yield desired concentrations of β-lactams: the value of therapeutic drug monitoring

Abstract A 35-year-old patient in intensive care with severe burn injury developed episodes of sepsis. Blood culture yielded a multidrug-resistant Pseudomonas aeruginosa and treatment was commenced with amikacin (minimum inhibitory concentration (MIC) 2–4 mg/L, dose 20 mg/kg adjusted body weight 24-hourly) and meropenem (MIC 8 mg/L, dose 2 g IV 8-hourly and later 6-hourly). Despite the use of extended infusions with β-lactam therapeutic drug monitoring and doses that were more than 2.5 times higher than standard meropenem doses, resistance emerged. This case report describes the application of therapeutic drug monitoring to optimize β-lactam therapy in a difficult-to-treat critically ill patient.