Ludo Willems

Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics

Itraconazole is a triazole antifungal agent with a broad spectrum of activity. It is well tolerated and highly efficacious, particularly because its main metabolite, hydroxy‐itraconazole, also has considerable antifungal activity. Two new formulations of itraconazole, an oral solution and an intravenous formulation, have recently been developed, which combine lipophilic itraconazole with cyclodextrin. These formulations have improved the solubility of itraconazole, leading to enhanced absorption and bioavailability compared with the original capsule formulation, without having an impact on the tolerability profile of itraconazole. The oral solution and intravenous formulations of itraconazole produce consistent plasma concentrations and are ideal for the treatment of systemic fungal infections in a wide range of patient populations. The additional flexibility offered by the different routes of administration means that itraconazole treatment can be specifically tailored for use in all patients, including children and those requiring intensive care.

Pharmacist- versus physician-acquired medication history: a prospective study at the emergency department

Background Recent literature revealed that medication histories obtained by physicians and nurses are often incomplete. However, the number of patients included was often low. Study objective In this study, the authors compare medication histories obtained in the Emergency Department (ED) by pharmacists versus physicians and identify characteristics contributing to discrepancies. Methods Medication histories were acquired by the pharmacist from patients admitted to the ED, planned to be hospitalised. A structured form was used to guide the pharmacist or technician to ensure a standardised approach. Discrepancies, defined as any difference between the pharmacist-acquired medication history and that obtained by the physician, were analysed. Results 3594 medication histories were acquired by pharmacy staff. 59% (95% CI 58.2% to 59.8%) of medication histories recorded by physicians were different from those obtained by the pharmacy staff. Within these inaccurate medication histories, 5963 discrepancies were identified. The most common type of error was omission of a drug (61%; 95% CI 60.4% to 61.6%), followed by omission of dose (18%; 95% CI 17.6% to 18.4%). Drugs belonging to the class of psycholeptics, acid suppressors and beta blocking agents were related to the highest discrepancy rate. Acetylsalicylic acid, omeprazole and zolpidem were most commonly forgotten. Conclusion This large prospective study demonstrates that medication history acquisition is very often incomplete in the ED. A structured form and a standardised method is necessary. Pharmacists are especially suited to acquire and supervise accurate medication histories, as they are educated and familiar with commonly used drugs.

Epidemiology of catheter-related infections in adult patients receiving home parenteral nutrition: A systematic review

BACKGROUND AND AIMS Catheter-related infection (CRI) is the most common and serious complication for adult patients receiving home parenteral nutrition (HPN). Our aim is to provide epidemiological data on infection incidence, infecting pathogens and contributing risk factors. METHODS Four electronic databases (Embase, Medline, IPA, CINAHL) were screened for eligible studies published between 1970 and March 2012. Methodological quality was evaluated and terminology/definitions were re-categorized. RESULTS Thirty-nine studies were included. Extensive variability was observed in terminology/definitions as well as in expression of CRI rate. After correct interpretation of definitions, overall catheter-related bloodstream infection rate (CRBSI) ranged between 0.38 and 4.58 episodes/1000 catheter days (median 1.31). Gram-positive bacteria of human skin flora caused more than half of infections. An analysis of the reported risk factors showed that the origin of a CRBSI is often multifactorial. The risk factors were related to the patient, the venous access device, the education, HPN therapy and follow-up. CONCLUSIONS This review on CRI in adult HPN patients revealed that included studies are of low quality and used poorly described risk factors and different definitions. The human skin flora caused most of infections; therefore, hand hygiene and training remain essential.

Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation

OBJECTIVES During extracorporeal membrane oxygenation (ECMO), drug disposition changes significantly. Plasma concentrations are altered due to an expanded circulating volume leading to a decreased elimination. In addition, adsorption and sequestration of drugs by the ECMO circuit components may further alter pharmacokinetics. Treating patients during the ECMO period with antifungals is difficult. Loss in the ECMO circuit can potentially result in sub-therapeutic levels. METHODS Two cases are presented in which caspofungin and voriconazole levels and pharmacokinetic parameters were determined during the ECMO period. RESULTS Mean caspofungin trough and peak levels were 3.73 and 11.95 microg/mL. These are comparable to previously reported ones. Also pharmacokinetic parameters were identical to those reported in the literature. It seems that caspofungin is not sequestrated by the ECMO circuit, which is expected based on its low log P value. During the first days of ECMO therapy, voriconazole trough and peak levels did not differ much from those determined prior to ECMO therapy. However, at the start of ECMO therapy, the voriconazole dose was increased from 280 to 400 mg twice daily as loss due to binding to the circuit was expected. This increase was not immediately reflected in higher voriconazole levels, which may be due to drug sequestration by the circuit. However, the voriconazole half-life was extended up to 20 h in our patient. Two days after the dose increase, levels reached troughs >10 microg/mL and peaks of around 15 microg/mL, exceeding the therapeutic interval for voriconazole. This can possibly be explained by the saturation of binding sites on the ECMO circuit. CONCLUSIONS Our results suggest that adequate caspofungin plasma levels are maintained during ECMO. In the case of voriconazole, it is recommended to monitor plasma levels to ensure efficacy and avoid toxicity.

Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases.

Background:The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ).Methods:Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk.Results:Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates.Conclusion:Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.

Interaction Between Valproate and Meropenem: A Retrospective Study:

Background: Valproate and meropenem are frequently used in the intensive care unit to treat seizures and serious infections, respectively. Several case reports have described a remarkable interaction between the drugs when administered concurrently. The interaction leads to a significant drop in plasma concentrations of valproate within 24 hours and relapse of seizures in some patients. Objective: To evaluate a consecutive population of hospitalized patients who were simultaneously treated with meropenem and valproate and assess the effect on epileptic activity. Methods: A retrospective study of an 18 month period was performed to assess the extent and clinical impact of this interaction. To assess the relevance of the interaction, the time-relationship between the drop in plasma concentrations and relapse in seizure activity and/or deterioration of electroencephalogram recordings was determined. We investigated other contributing preconvulsive cofactors and concomitant antiepileptic treatment. Drug interaction probability scale (DIPS) scores were calculated. Results: Thirty-nine patients were treated simultaneously with valproate and meropenem. The pharmacokinetic interaction was observed in all 39 patients, with an average drop in valproate plasma concentrations of 66%, The decrease occurred within 24 hours, as shown in 19 patients who had daily plasma concentration monitoring, The clinical impact of the interaction could not be assessed in 19 (49%) patients due to death (n = 13) or incomplete charts (n = 6). In the remaining 20 (51%) patients, DIPS scores were calculated and clinical relevance was assessed. The interaction was considered to be probable in 16 patients and possible in 4, as calculated by the DIPS. The interaction contributed to electroclinical deterioration in 11 patients. Conclusions: The pharmacokinetic interaction between valproate and meropenem was present in all patients and led to a drop of valproate concentrations with an average of 66% within 24 hours. This interaction was clinically relevant with electroclinical deterioration in 55% of patients. To avoid patients’ possible neurologic deterioration, meropenem and valproate should not be administered together.

Therapeutic Drug Monitoring of Phenytoin in Critically Ill Patients

Therapeutic drug monitoring of phenytoin is necessary to ensure therapeutic and nontoxic levels. Hypoalbuminemia, renal failure, and interactions with other highly protein‐bound drugs (e.g., valproic acid) alter protein binding of phenytoin. When these conditions are present, free serum concentrations, which represent the pharmacologically active entity, cannot be predicted from total serum concentrations. Besides general alterations in drug distribution and elimination, protein binding is often altered in critically ill patients. Case reports describe phenytoin toxicity secondary to inappropriate dosage adjustments based solely on total serum concentrations in patients with hypoalbuminemia. Free drug measurements and theoretical equations to facilitate the interpretation of total phenytoin serum levels have been introduced. However, they are not widely implemented in clinical practice because evidence of improvements in patient outcomes is limited. Knowledge of the pharmacokinetic properties of phenytoin is indispensable for correct interpretation of total serum concentrations when protein binding is altered. Free serum concentrations should be measured, or theoretically calculated if measurements are unavailable, to avoid misinterpretation of total serum levels and consequent inappropriate adjustments in the dosage of phenytoin in critically ill patients.

Mini-series: II. Clinical aspects. Clinically relevant CYP450-mediated drug interactions in the ICU

BackgroundIn the critically ill, multiple drug therapies for acute and chronic conditions are often used at the same time and adverse drug events occur frequently. Many pharmacological and disease-related factors, e.g. altered renal and hepatic function, catecholamine-related circulatory changes, altered drug volume of distribution, enteral versus parenteral feeding and morbid obesity, along with concomitant multiple drug regimens may account for the wide inter-individual variability in drug exposure and response in critically ill patients and for the high risk for drug–drug interactions to occur. The practicing intensivist must remain aware of the major mechanisms for drug–drug interactions, among which the drug-metabolizing enzyme inhibitory or induction potential of associated chemical entities are paramount. Metabolism-based drug–drug interactions are largely due to changes in levels of drug-metabolizing enzymes caused by one drug, leading to changes in the systemic exposure clearance of another. Among the numerous drug-metabolizing enzymes identified to date, the activity of cytochrome P450s (CYP450) is a critical determinant of drug clearance and appears to be involved in the mechanism of numerous clinically relevant drug–drug interactions observed in critically ill patients.DiscussionThis manuscript will cover a practical overview of clinically relevant CYP450-mediated drug–drug interactions. Medications frequently used in the intensive care unit such as benzodiazepines, immunosuppressive agents, opioid analgesics, certain anticonvulsants, the azoles and macrolides have the potential to interact with CYP450-mediated metabolism and may lead to toxicity or therapeutic failure.

Guidelines recommendations on care of adult patients receiving home parenteral nutrition: a systematic review of global practices.

BACKGROUND & AIMS Because home parenteral nutrition (HPN) in adult patients can give rise to a variety of complications, good guidance is necessary. To achieve this, clarity and consistency in guidelines are essential. The aim of this review is to identify and compare evidence-based guidelines, and to compile a list of main recommendations, according to their evidence-based grade. METHODS We searched Medline and the international guideline database for HPN guidelines, performed a content analysis of retrieved guidelines, and evaluated their quality. We then compiled a comparative table of guideline recommendations along with their assigned level of evidence. SUMMARY OF RESULTS Six systematically developed evidence-based guidelines and one expert opinion-based standard for home care were retrieved. Of these guidelines, two were exclusively devoted to HPN. Although the guidelines generally covered the same topics, most did not provide information on intravenous medication, bone metabolic disease, and indications in patients with malignant disease. Moreover, we found grading discrepancies among various guidelines, as identical recommendations were often labeled with different grades. CONCLUSION Our comparison of guidelines and standards for HPN revealed substantial differences among recommendations. Identification of these discrepancies and omissions should facilitate the development of more comprehensive and better justified guidelines in the future.

Dosing of piperacillin/tazobactam in a morbidly obese patient

The combination of piperacillin and tazobactam has been shown to be efficacious for the treatment of intra-abdominal infections, skin and soft tissue infections, bacteraemia and pneumonia. The pharmacokinetics (PK) of piperacillin/tazobactam have been extensively investigated in both healthy volunteers and in distinct patient settings. 1 Like other b-lactams, piperacillin/tazobactam displays time-dependent pharmacodynamics (PD), whereby duration of time that concentrations remain above the MIC correlates best with bacterial kill and efficacy. The PK/PD target associated with a high probability of therapeutic success is defined as free concentrations above the MIC for 50% of the dosing interval (50% fT .MIC). 2 In case of more severe infections or when poor penetration into infected tissues is expected, 30%‐ 40% fT . 4‐5 ×MIC should ideally be attained. 2 It is not clear whether these targets are reached in morbidly obese patients as published information on optimal dosing in this subset of patients is rare. A 33-year-old morbidly obese patient (220 kg, 1.9 m and body mass index 55 kg/m 2 ) was transferred to our orthopaedic ward with a surgical site infection following a transfemoral amputation of the left leg following a car accident. He has provided written, informed consent for the details given here to be published. The patient had been empirically started on amoxicillin/ clavulanic acid; however, despite 8 days of treatment, necrosis increased and markers of infection were still raised (C-reactive