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The net state of immunosuppression, the occurrence of infections, drug-drug interactions, and toxicity can compromise the outcome of liver transplant recipients with multiple comorbidities. We present a 67-year-old man who developed early posttransplant severe chronic obstructive pulmonary disease exacerbation, pulmonary aspergillosis, and cytomegalovirus reactivation. Drug-drug interactions between azoles and cyclosporine, along with renal and liver toxicity, required adjustments in dosage. Interferon-gamma production from antigen-stimulated T cells was recorded. Early diagnosis and treatment, along with therapeutic drug monitoring and recovery of T-cell immunity, were key factors for a positive outcome.

Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of comedications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough level (Cmin). Voriconazole Cmin was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed-effect regression analyses were performed to identify the independent predictors of normalized Cmin. Of the 83 included patients, 35 had comedications with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median Cmin value (n = 199) was 2.4 mg/L with a wide range of distribution (5.5 mg/L (OR: 23.22, 95% CI: 3.01-179.09, p = 0.003). No significant association emerged when CYP inhibitors were coadministered with CYP inducers (OR: 3.53, 95% CI: 0.36-34.95, p = 0.280). The amount of expected Cmin increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are cotreated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously.

Objectives To report on linezolid exposure in a paediatric population who routinely underwent therapeutic drug monitoring (TDM) for dosage optimization and to assess the factors affecting interpatient variability. Methods We performed a retrospective study of patients whose plasma C(min) and Cmax levels were measured during linezolid treatment. Adequate exposure was defined as a C(min) of 2-7 mg/L and/or an estimated AUC24 of 160-300 mg · h/L. Patients were divided into two subgroups (Group 1, 2-11 years; Group 2, 12-18 years). Monte Carlo simulation was performed to investigate whether or not the currently recommended dosages might enable a high probability of target attainment (PTA) of two thresholds for linezolid efficacy (AUC24/MIC ≥ 80 or ≥ 100). Data on demographic characteristics, disease, microbiology and haematochemical parameters and outcomes were collected. Results A total of 23 patients were included. Standard dosages were suboptimal in 50.0% and 44.4% of patients in Group 1 and Group 2, respectively. Among those who underwent multiple instances of TDM, the dosages were increased in 33.3% of cases in both groups, and decreased in 6.6% and 9.5% of cases in Group 1 and Group 2, respectively. Co-treatment with phenobarbital, proton pump inhibitors and amiodarone accounted for most of the variability in C(min) (adjusted R(2) of 0.692). Simulations showed a PTA of ≥ 90% with the current dosing regimens in both groups only for pathogens with an MIC ≤ 1 mg/L. Conclusions Higher dosages of linezolid may be needed, especially in Group 1 when in the presence of pathogens with an MIC >1 mg/L. The role of TDM should be encouraged for optimization of linezolid exposure in the paediatric setting in the presence of infections caused by pathogens with borderline susceptibility and/or for patients co-treated with drugs that may alter linezolid exposure.

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OBJECTIVES To investigate the relationship between isoniazid plasma exposure and the likelihood of elevation of ALT (≥51 IU/L) among adult patients with TB. METHODS A retrospective observational study was conducted in patients who underwent periodic monitoring of hepatic function and in whom pharmacokinetic data were collected. Monte Carlo simulation was performed with the intent of identifying the probability of achieving an AUC24 greater than the identified threshold of hepatotoxicity with different dosing regimens (2.5, 5.0 and 7.5 mg/kg/day). RESULTS Forty-one out of 185 evaluable patients (22.2%) had an ALT elevation. A mild correlation between isoniazid AUC0-24 and ALT increase was observed (Spearman's ρ = 0.34, P

Background: Several authors have documented the role of low-molecular-weight heparin injection techniques in bruising. However, few researchers have measured the influence of injection duration on the occurrence and extent of bruising. Purpose: The aim of this study was to evaluate the influence of different durations of subcutaneous heparin injection on the occurrence and extent of bruising. Methods: A quasi-experimental case-crossover study design was adopted in 2010. A consecutive series of patients admitted to 2 orthopedic units in a large (600 beds) teaching hospital located in northern Italy were eligible for enrolment. Injections were administered following a standard procedure. The manipulated variable was the duration of the injection, 10 seconds (treatment A) and 30 seconds (treatment B). The evaluation of bruise occurrence and extension performed after 48 hours and data analysis were conducted in a blinded fashion. Results: A total of 150 patients receiving their first and second subcutaneous heparin injections (300 injections) were enrolled. Eighty-seven bruises were observed out of 300 injections (29%): 57 of 150 (38%) after injections lasting 10 seconds and 30 of 150 (20%) after injections lasting 30 seconds (relative risk, 1.50; 95% confidence interval, 1.21-1.86; P = .00). Of the 87 bruises that occurred, 69 (79.3%) were small (2-5 mm) and 18 (20.6%) were large (>5 mm), with no difference in size between 10-and 30-second injections (relative risk, 0.91; 95% confidence interval, 0.39-2.12; P = .83). Conclusions: Low-molecular-weight heparin injection should be administered over 30 seconds to decrease bruising. Clinical Implications: There is a need to reflect on the feasibility of such a practice because injecting low-molecular-weight heparin at 30 seconds requires accuracy, a steady hand, the absence of tremor, a calm environment, and the ability to administer an infinitesimally small amount of liquid (eg, 0.4 mL) per second. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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Background: the present study aims to assess the efficiency and effectiveness of the organizational system of a Clinical Pharmacological Service of an Italian tertiary care teaching hospital in providing advices (CPAs) to clinicians within timeframes useful for the personalization of antimicrobial dosing regimens in different patients' populations according to the clinical benefit for patient care. METHODs: the frequency per week of the various typologies of CPA was defined on the basis of prior evaluations aimed at estimating the clinical benefit for patient care (high priority level, for antimicrobials used to treat acute infections in the critically ill patients; moderate priority level, for those used to treat cytomegalovirus infections in solid organ transplant recipients; mild priority level, for those used to treat chronic infections). The CPAs provided between December 2011 and June 2012 represented the starting database. The measured turnaround time (TAT) of each CPA typology was used as an indicator of the performance of the organizational system according to a predefined scale (high, when within agreed timeframe; acceptable, when 1-2 days overdue; low, when > 2 days overdue). RESULTS: 6601 CPAs were provided (77.4% for AOUD and 22.6% for other hospitals), mainly for antimicrobials with high priority. The mean TAT was of < 24 hours for the CPAs provided 3 to 5 times per week, of < 48 hours for those provided 2 times per week, and of < 6 days for those provided once weekly every other week. Overall, the performance was high, the percentage of overdue advices always less than 5%, irrespective of the CPA type. CONCLUSIONS: our study confirms the suitability of the organizational system of our Service to provide a thousand per month TDM-based CPAs within timeframes clinically useful for the individualization of the dosing regimens of several antimicrobials.

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Hallucinations during voriconazole therapy

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One of the pivotal principles of the mamagement of HAP is tha early appropriate antibiotic therapy is associated with more favourable oputcome. The concept of appropriate is not exclusivey based on the pattwern of microbiological coverage but must regard the infezxion site, the PK/PD behavior of drugs and the patient condition.

Continuous renal replacement therapy (CRRT), particularly continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltration (CVVHDF), are gaining increasing relevance in routine clinical management of intensive care unit patients. The application of CRRT, by leading to extracorporeal clearance (CL(CRRT)), may significantly alter the pharmacokinetic behaviour of some drugs. This may be of particular interest in critically ill patients presenting with life-threatening infections, since the risk of underdosing with antimicrobial agents during this procedure may lead to both therapeutic failure and the spread of breakthrough resistance. The intent of this review is to discuss the pharmacokinetic principles of CL(CRRT) of antimicrobial agents during the application of CVVH and CVVHDF and to summarise the most recent findings on this topic (from 1996 to December 2006) in order to understand the basis for optimal dosage adjustments of different antimicrobial agents. Removal of solutes from the blood through semi-permeable membranes during RRT may occur by means of two different physicochemical processes, namely, diffusion or convection. Whereas intermittent haemodialysis (IHD) is essentially a diffusive technique and CVVH is a convective technique, CVVHDF is a combination of both. As a general rule, the efficiency of drug removal by the different techniques is expected to be CVVHDF > CVVH > IHD, but indeed CL(CRRT) may vary greatly depending mainly on the peculiar physicochemical properties of each single compound and the CRRT device's characteristics and operating conditions. Considering that RRT substitutes for renal function in clearing plasma, CL(CRRT) is expected to be clinically relevant for drugs with dominant renal clearance, especially when presenting a limited volume of distribution and poor plasma protein binding. Consistently, CL(CRRT) should be clinically relevant particularly for most hydrophilic antimicrobial agents (e.g. beta-lactams, aminoglycosides, glycopeptides), whereas it should assume much lower relevance for lipophilic compounds (e.g. fluoroquinolones, oxazolidinones), which generally are nonrenally cleared. However, there are some notable exceptions: ceftriaxone and oxacillin, although hydrophilics, are characterised by primary biliary elimination; levofloxacin and ciprofloxacin, although lipophilics, are renally cleared. As far as CRRT characteristics are concerned, the extent of drug removal is expected to be directly proportional to the device's surface area and to be dependent on the mode of replacement fluid administration (predilution or postdilution) and on the ultrafiltration and/or dialysate flow rates applied.Conversely, drug removal by means of CVVH or CVVHDF is unaffected by the drug size, considering that almost all antimicrobial agents have molecular weights significantly lower (

In the present research, levels of gentamicin (GM) in serum and carrageenan pleural exudate from the rat have been compared, using three evaluation methods: microbiological assay (MA), enzyme-immunoassay (EMIT) and fluorescence-immunoassay (TDX). In a first study, the evaluations carried out by MA and EMIT have furnished comparable data in serum, while statistically significant differences were verified at all times in pleural exudate. On the contrary, in a second study, while the evaluations carried out by MA and EMIT, at all times and in both biological fluids, have produced similar data, the evaluation carried out by TDX consistently supplied higher results, with statistically significant differences at some times (5 min and 60 min for serum, 30 min and 60 min for exudate). Some possible interpretations of these results are discussed.