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We describe the case of an intravenous drug user affected by life-threatening Staphylococcus aureus-complicated skin and soft tissue infection with associated bacteraemia who, while on replacement therapy with methadone, required 11 mg/kg/day daptomycin to achieve trough (Cmin) and peak (Cmax) plasma levels similar to those observed with the standard dosage of 6 mg/kg in healthy volunteers (mean ± standard deviation: Cmin 12.35 ± 0.80 mg/L, C max 63.90 ± 8.71 mg/L). Clinical pharmacological advice based on real time therapeutic drug monitoring may be helpful for optimizing daptomycin exposure in these patients. Physicians should take into account that dosages much higher than the standard ones may be needed, probably as a consequence of augmented drug clearance. © Springer-Verlag 2013.

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.

Community-acquired pneumonia (CAP) represents one of the most common reasons for hospitalization in elderly people. Because older persons are the fastest growing segment of the population, a further increase of the incidence of CAP is expected in the next few years. Due to the high frequency, the different epidemiology, the atypical clinical presentation and the age-related modifications in drug metabolism that complicate the treatment, infections in the elderly people represent a major challenge for physicians. Despite the peculiarity of the management of CAP in the elderly people, no specific recommendations for antimicrobial treatment are provided in the international guidelines. The aim of this review is to give an update of the current antibiotic options for CAP in the elderly people reporting available data on the CAP etiology and risk factors, and tolerability, toxicity and pharmacokinetics/pharmacodynamic of antimicrobial agents used for elderly patients.

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

This study aimed to assess the influence of dose frequency and the presence or absence of cotreatment with proton pump inhibitors (PPIs) on the time to a target trough concentration ( C min ) of >700 ng/ml with posaconazole in the first 8 days of antifungal prophylaxis in hematological patients. This was a retrospective, observational study performed with 42 adult patients with acute myeloid leukemia who underwent posaconazole prophylaxis with 200 mg every 8 h (q8h) or 200 mg q6h after receiving induction chemotherapy and who had at least three subsequent therapeutic drug monitoring assessments during the first 8 days of treatment. The cohort was split into four groups (group 1, 200 mg q8h without PPI; group 2, 200 mg q8h with PPI; group 3, 200 mg q6h without PPI; group 4, 200 mg q6h with PPI). Rapid attainment of the target C min was obtained only in group 3 ( P < 0.01) (median C min on day 4 of 935.5 ng/ml [interquartile range, 760.0 to 1,270.0 ng/ml] in group 3, versus 567.0 ng/ml [346 to 906 ng/ml] in group 1, 420.0 ng/ml [326.2 to 527.2 ng/ml] in group 2, and 514.0 ng/ml [403.7 to 564.7 ng/ml] in group 4). A linear accumulation of posaconazole over time was observed among patients in groups 1 and 3, regardless of the total daily dosage, differently from what occurred among those receiving PPI cotreatment (groups 2 and 4). Dose intensification (200 mg q6h) coupled with avoidance of PPI coadministration may represent a very powerful strategy to rapidly achieve effective concentrations with posaconazole in neutropenic hematological patients.

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