Beta-lactam allergy in adults with cystic fibrosis

Background: Allergic reactions to one or more beta-lactam antibiotic can pose a management problem in patients with cystic fibrosis (CF), and may limit antibiotic choice. Method: The aim of this study was to assess the prevalence of allergy to anti-pseudomonal beta-lactam antibiotics in an adult CF centre and to assess variables, which may contribute to the development of allergic reactions. A questionnaire-based interview and a review of medical records were performed. Results: Of the 150 patients, 54 (36%) had allergic reactions to one or more beta-lactam antibiotics and 20 (19%) had allergic reactions to multiple beta-lactam antibiotics. The proportion of patients allergic to specific beta-lactam antibiotics varied from 10% to 26%. Rates of reactions were highest for penicillins and cephalosporins, intermediate for carbepenems and lowest for aztreonam. Of all reactions, 40% occurred within 24 h of the commencement of an individual antibiotic course. Patients with one or more beta-lactam allergic reactions had received greater cumulative exposure (p < 0.0001), were older (p=0.016) and had lower lung function (p=0.037) than patients without a history of beta-lactam allergy. Cystic Fibrosis transmembrane regulator (CFTR) status, gender, peripheral blood eosinophil count and total IgE concentrations were not different in patients with allergic reactions. Conclusions: This study demonstrates that the prevalence of allergic reactions to beta-lactam antibiotics is high in adults with CF. Increasing age; cumulative exposure and decreasing FEV1 were associated with the development of allergy. (C) 2006 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Cefepime versus cefpirome: The importance of creatinine clearance

Standard dosage recommendations for beta-lactam antibiotics can result in very low drug levels in intensive care (IC) patients without renal dysfunction. We compared the pharmacokinetics of two fourth-generation cephalosporins, cefepime and cefpirome, and examined the relationship of drug clearance (CL) to creatinine clearance (CLCR). Two separate but similar pharmacokinetic studies (which used 2 g twice daily for each antibiotic) were conducted. Blood was sampled after an initial and a subsequent antibiotic dose. Drug plasma concentrations were measured, and pharmacokinetic analyses were conducted and compared. The pharmacokinetics of cefepime and cefpirome are similar in IC patients. Any differences in drug CL can largely be attributed to differences in CLCR. Despite normal plasma creatinine concentrations, 54% of patients' antibiotic concentrations were less than the minimum inhibitory concentration (MIC) (4 mg/L) for >20% of the dosing interval. Thirty-four percent of patients had CLCR >144 mL/min (20% higher than the expected maximum of 120 mL/min). Only CLCR was an independent predictor of antibiotic CL. Time above MIC was predicted only by CLCR. Some IC patients have a very large CLCR which results in very low levels of studied antibiotics. Either shortening the dosage interval or using continuous infusions would prevent low levels and keep troughs above the MIC for longer periods. In view of the lack of bedside measurement of cephalosporin levels, we suggest that more frequent use be made of CLCR to allow prediction of small concentrations clinically.

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics

Continuous infusion (CI) ticarcillin-clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of beta-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin-clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3-12.4 g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home Cl of ticarcillin-clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting. (c) 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Gymnoascolides A-C: Aromatic butenolides from an Australian isolate of the soil ascomycete Gymnoascus reessii

Three new aromatic butenolides, gymnoascolides A-C (1-3), have been isolated from the Australian soil ascomycete Gymnoascus reessii and assigned structures on the basis of detailed spectroscopic analysis. The absolute configurations of gymnoascolides B (2) and C (3) at C-5 were solved using a combination of chemical derivatization and quantum chemical simulations.

Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis

Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis. Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to 'third-spacing', both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance. Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (V-d) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (C-max)/minimum inhibitory concentration ratio is recommended. beta-Lactams and carbapenems are time-dependent antibacterials. An increase in Vd and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required. Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased V-d and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung). Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The V-d of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs. In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes. In conclusion, certain antibacterials can have a very high V-d, therefore leading to a low C-max and if a high peak is needed, then this would lead to underdosing. The Vd of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing. Copyright © 2010 Elsevier Inc. All rights reserved.