Pharmacokinetic/pharmacodynamic evaluation of the efficacy and safety of daptomycin against Staphylococcus aureus.

Int J Antimicrob Agents. 2013 May 14;

Authors: Soon RL, Turner SJ, Forrest A, Tsuji BT, Brown J

Abstract
Daptomycin is a novel lipopeptide exhibiting concentration-dependent bactericidal activity against multidrug-resistant Gram-positive pathogens, including MRSA. Approval of daptomycin is granted at 4-6mg/kg once daily, however off-label use of doses up to 12mg/kg daily has been utilised without evidence of significant toxicity. Our aim was to optimise daptomycin regimens by assessing the probability of bacteriological efficacy (pTA) and toxicity (pTOX) at various MICs using Monte Carlo simulation (MCS) techniques. Population pharmacokinetic, pharmacodynamic and toxicodynamic models were developed based on current literature. MCS was performed for 10000 patients, who were assigned true weight and creatinine clearances, and were infected with four Staphylococcus aureus strains at each MIC. Bacteriostatic and bactericidal %pTA was calculated following administration of 6, 8, 10 and 12mg/kg daptomycin; activity was deemed adequate at %pTA≥90%. Considerable pharmacodynamic variability was observed in derived AUC/MIC targets between strains. Bacteriostatic targets were adequately attained against all strains at MIC≤1mg/L with daptomycin >6mg/kg. However, bactericidal target attainment was only achieved against all strains at the lowest MIC of 0.5mg/L with daptomycin >8mg/kg. At MIC=2mg/kg, bactericidal target attainment was extremely poor even at the highest dose of 12mg/kg. pTOX increased from 3.31% to 17.7% following exposure to 6mg/kg to 12mg/kg daily, respectively. Formal benefit:risk analyses favoured doses of 10mg/kg against infections with MIC<2mg/L, whilst modest improvements in activity at 12mg/kg could not justify the marked increase in pTOX.

PMID: 23684388 [PubMed - as supplied by publisher]

Management of candidaemia and invasive candidiasis in critically ill patients.

Int J Antimicrob Agents. 2013 May 8;

Authors: Chahoud J, Kanafani ZA, Kanj SS

Abstract
Critically ill patients in the intensive care unit (ICU) are at increased risk of encountering bloodstream infections (BSIs) with Candida spp., associated with an elevated crude mortality rate. This supports the significance of early detection of infection and identification of the most effective management approach. A review of the various antifungal treatments and an evaluation of the diverse management approaches for invasive candidiasis in critically ill patients is necessary for guiding evidence-based decision-making. Different early detection schemes for invasive candidiasis are well documented in the literature. Other than the common use of blood cultures, new methods entail the use of risk prediction scores and biomarker tests. Regarding management strategies, different options are currently supported. These include prophylaxis, empirical therapy, pre-emptive therapy, and treatment of culture-documented infections. The choice of treatment is greatly dependent on several factors related to the patient and/or to the surrounding environment. Attention needs to be given to previous exposure to azoles, epidemiological data on dominant Candida spp. in local ICUs, severity of illness and associated morbidities. This paper summarises the most recent literature as well as the guidelines issued by the Infectious Diseases Society of America. The objective is to identify the best diagnosis and management approaches for serious Candida infections in critically ill patients. In addition, this article addresses an important aspect associated with managing candidaemia in critically ill patients pertaining to the decision for intravenous catheter removal.

PMID: 23664579 [PubMed - as supplied by publisher]

Controversies in the management of the critically ill: the role of probiotics.

Int J Antimicrob Agents. 2013 May 9;

Authors: Theodorakopoulou M, Perros E, Giamarellos-Bourboulis EJ, Dimopoulos G

Abstract
Probiotics are commercially available, viable, non-pathogenic micro-organisms that, when ingested in sufficient quantities, exert a health benefit to the host derived through modification of the gut flora, local release of antimicrobial factors, maintenance of integrity of the gut barrier, competition for epithelial adherence, prevention of bacterial translocation, and modulation of the local immune response. In critically ill patients, probiotics appear to lead to decreased susceptibility to antibiotic-associated diarrhoea, Clostridium difficile infections, ventilator-associated pneumonia, necrotising enterocolitis, acute severe pancreatitis, sepsis and multiple organ dysfunction syndrome as well as a shortened duration of infections. Current scientific evidence supporting the use of probiotics is not conclusive and is mainly derived from single-centre, not very well designed trials that are limited by many factors including small sample sizes, heterogeneity in the probiotic strains used, effectiveness of the combined strains, optimum dose regimens, frequency and duration of administration, and certainly incomplete knowledge of the mechanism of action of each strain. Probiotics appear to be well tolerated, whilst adverse events are very rare. The most commonly reported adverse events include bacteraemia, fungaemia and sepsis. At present, based on the available evidence and although helpful and relatively safe for certain disease conditions, routine use of probiotics in the critically ill is not recommended.

PMID: 23664676 [PubMed - as supplied by publisher]