Diagnostic and medical needs for therapeutic drug monitoring of antibiotics

Therapeutic drug monitoring (TDM) of antibiotics has been practiced for more than half a century, but it is still not widely applied for infected patients. It has a traditional focus on limiting toxicity of specific classes of antibiotics such as aminoglycosides and vancomycin. With more patients in critical care with higher levels of sickness severity and immunosuppression as well as an increasingly obese and ageing population, an increasing risk of suboptimal antibiotic exposure continues to escalate. As such, the value of TDM continues to expand, especially for beta-lactams which constitute the most frequently used antibiotic class. To date, the minimum inhibitory concentration (MIC) of infectious microbes rather than classification in terms of susceptible and resistant can be reported. In parallel, increasingly sophisticated TDM technology is becoming available ensuring that TDM is feasible and can deliver personalized antibiotic dosing schemes. There is an obvious need for extensive studies that will quantify the improvements in clinical outcome of individual TDM-guided dosing. We suggest that a broad diagnostic and medical investigation of the TDM arena, including marke

Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes

What are the current approaches to optimising antimicrobial dosing in the intensive care unit?

Antimicrobial dosing in the intensive care unit (ICU) can be problematic due to various challenges including unique physiological changes observed in critically ill patients and the presence of pathogens with reduced susceptibility. These challenges result in reduced likelihood of standard antimicrobial dosing regimens achieving target exposures associated with optimal patient outcomes. Therefore, the aim of this review is to explore the various methods for optimisation of antimicrobial dosing in ICU patients. Dosing nomograms developed from pharmacokinetic/statistical models and therapeutic drug monitoring are commonly used. However, recent advances in mathematical and statistical modelling have resulted in the development of novel dosing software that utilise Bayesian forecasting and/or artificial intelligence. These programs utilise therapeutic drug monitoring results to further personalise antimicrobial therapy based on each patient’s clinical characteristics. Studies quantifying the clinical and cost benefits associated with dosing software are required before widespread use as a point-of-care system can be justified

Should β-lactam antibiotics be administered by continuous infusion in critically ill patients? A survey of Australia and New Zealand intensive care unit doctors and pharmacists

Although there is a biological precedent for administration of beta-lactam antibiotics by continuous or extended infusion, there is no definitive evidence of a survival benefit compared with intermittent administration. The aim of this study was to explore clinician uncertainty with regard to the administration of beta-lactam antibiotics by continuous infusion. Doctors and pharmacists in Australian and New Zealand intensive care units (ICUs) were surveyed to investigate current beta-lactam antibiotic administration practices as well as the degree of uncertainty regarding the benefit of continuous infusion of two commonly used broad-spectrum beta-lactams, namely meropenem and piperacillin/tazobactam (TZP). There were 111 respondents to the survey. Intermittent infusion was reported as standard practice for meropenem (73.9%) and TZP (82.0%). A greater proportion of pharmacists compared with doctors believed continuous infusion to be more effective than intermittent administration (85.4% vs. 34.3%, respectively; P < 0.001). Both groups reported uncertainty as to whether administration by continuous infusion resulted in better patient outcomes (65.9% and 74.6%, respectively; P = 0.85). Overall, 91.0% of respondents were prepared to enrol eligible patients into a definitive randomised controlled trial on beta-lactam antibiotic administration. In conclusion, there is equipoise among clinicians working in Australian and New Zealand ICUs as to whether administration by continuous infusion offers a survival benefit in critically ill patients. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved

Antibiotic exposure at the site of infection: principles and assessment of tissue penetration

Introduction: Since the majority of bacterial infections occur at sites outside the bloodstream, antibiotic tissue concentrations are of significant relevance to optimize treatment. The aim of this review is to aid the clinician in choosing optimal regimens for the treatment of extravascular infections. Areas covered: We discuss the principles of antibiotic tissue penetration and assess different approaches to obtain data on this subject. Finally, we present tissue penetration data for several relevant groups of antibiotic agents in a number of extravascular sites. Data were obtained from an extensive literature search in PubMed until February 2019. Expert opinion: There is still a long way to go before reliable information about tissue penetration of antibiotics is sufficiently available to serve as a basis for the design of optimal strategies for drug and dose selection. At this moment, there is a lack of robust data on tissue penetration, where both the sampling and measurement techniques as well as the relationship between tissue concentrations and clinical outcome of antibiotic treatment have to be better defined

Risk factors for multidrug-resistant Gram-negative infection in burn patients

Background: Infection with multidrug‐resistant (MDR) Gram‐negative organisms leads to poorer outcomes in the critically ill burn patient. The aim of this study was to identify the risk factors for MDR Gram‐negative pathogen infection in critically ill burn patients admitted to a major tertiary referral intensive care unit (ICU) in Australia. Methods: A retrospective case–control study of all adult burn patients admitted over a 7‐year period was conducted. Twenty‐one cases that cultured an MDR Gram‐negative organism were matched with 21 controls of similar age, gender, burn size and ICU stay. Multivariable conditional logistic regression was used to individually assess risk factors after adjusting for Acute Burn Severity Index. Adjusted odds ratios (ORs) were reported. P‐values

Attitudes towards antimicrobial stewardship: results from a large private hospital in Australia

Introduction An effective hospital-wide antimicrobial stewardship (AMS) program requires engagement with all healthcare professionals involved in antimicrobial use. It is therefore useful to consider attitudes and perceptions among clinical stakeholders in Australian private hospitals before introducing AMS in these facilities. The aim of this study was to describe perceptions and attitudes towards antimicrobial resistance, antimicrobial use, AMS interventions, and willingness to participate. Methods A 26-item attitudinal survey was distributed to visiting specialists, nurses and pharmacists at a large (500 bed) private hospital in Australia. Survey questions utilised 'Yes/No' responses and a 7-point Likert scale ranging from 'strongly agree' to 'strongly disagree'. Descriptive analyses were performed and Chi-squared tests conducted. Results There were a total of 331 respondents (80 physicians, 58 surgeons, 78 anaesthetists, 105 nurses and 10 pharmacists). The response rate was 42% among clinicians, 100% among pharmacists and 13% among nurses. Only half of the respondents were willing to participate in proposed AMS interventions. A larger proportion of respondents believed that antimicrobial resistance was more of a serious problem in other Australian hospitals compared with the surveyed hospital (62% v. 45%,

Modifiable risk factors for multidrug-resistant Gram-negative infection in critically ill burn patients: a systematic review and meta-analysis

Background: We conducted a systematic review and meta-analysis to identify potentially modifiable risk factors for multidrug-resistant Gram-negative colonization or infection in critically ill burn patients. Methods: A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science and Central (Cochrane). Risk factors including antibiotic use and hospital interventions were summarized in a random-effects meta-analysis. Risk of publication bias was assessed using the Grading of Recommendations Assessment, Development and Evaluation method and funnel plots. Results: A total of 11 studies met the inclusion criteria. We identified several potentially modifiable risk factors and were able to grade their importance based on effect size. Related to prior antibiotic exposure, extended-spectrum cephalosporins (pooled odds ratio (OR) 7.00, 95% confidence interval (CI) 2.77-17.67), carbapenems (pooled OR 6.65, 95% CI 3.49-12.69), anti-pseudomonal penicillins (pooled OR 4.23, 95% CI 1.23-14.61) and aminoglycosides (pooled OR 4.20, 95% CI 2.10-8.39) were most significant. Related to hospital intervention, urinary catheters (pooled OR 11.76, 95% CI 5.03-27.51), arterial catheters (pooled OR 8.99, 95% CI 3.84-21.04), mechanical ventilation (pooled OR 5.49, 95% CI 2.59-11.63), central venous catheters (pooled OR 4.26, 95% CI 1.03-17.59), transfusion or blood product administration (pooled OR 4.19, 95% CI 1.48-11.89) and hydrotherapy (pooled OR 3.29, 95% CI 1.64-6.63) were most significant. Conclusions: Prior exposure to extended-spectrum cephalosporins and carbapenems, as well as the use of urinary catheters and arterial catheters pose the greatest threat for infection or colonization with multidrug-resistant Gram-negative organisms in the critically ill burn patient population