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Background: Extracorporeal removal of drugs during therapeutic plasma exchange (TPE) can lead to decreased efficacy, as shown in several reports discussing altered pharmacokinetics (PKs) of antibiotics during TPE. In particular, drugs with a low volume of distribution or a high protein binding are susceptible to extracorporeal removal, as these drugs remain substantially within the intravascular space. No information is known about antifungal drug removal during TPE. We report the PKs of voriconazole in a critically ill patient undergoing TPE., Methods: A 61-year-old man, presenting with catastrophic antiphospholipid syndrome for which TPE was started, developed probable pulmonary invasive aspergillosis. Intravenous voriconazole was started. Blood samples were taken under steady state conditions to calculate PK parameters of voriconazole, both with and without TPE., Results: PK parameters (area under the curve, Cl, Vd, and t1/2) were equivalent on both days. Voriconazole has a distribution volume of 4.5 L/kg and a protein binding of 58%, suggesting that drug removal during TPE would not be clinically significant. Our data support this assumption., Conclusion: Based on our findings, it seems that TPE does not alter the PK behavior of voriconazole. Voriconazole dosages should not be adjusted during TPE.

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., (Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Case Description: A 85 year old woman with a history of severe depression treated with mirtazapine and venlafaxine was admitted to the hospital twice after progressive deterioration of her general condition evolving to unconsciousness. Clinicians diagnosed a metabolic encephalopathy caused by a urinary tract infection which was treated appropriately. Although mirtazapine was stopped during the first hospitalization, the patient's general practitioner restarted mirtazapine four days before readmission. During rehospitalization, she developed extreme restlessness, hyperreflexia and an increased tone in the lower limbs. She was hypertensive and tachycardic. Excessive sweating, elevated creatine kinase levels and bilateral mydriasis were noticed. Urinary analysis showed positive levels of mirtazapine and venlafaxine and both drugs were withdrawn. Symptoms resolved within 48 h after discontinuation of her antidepressants. Conclusion To our knowledge, this is the first case of the serotonin syndrome confirmed by a positive challenge, de-challenge and re-challenge.

Background: Augmented renal clearance in critically ill patients can result in underdosing of life-saving drugs, potentially leading to therapeutic failure. To detect this phenomenon, correct assessment of the kidney function is essential. Currently, little is known about the validity of mathematical formulas to estimate renal function in this subset of patients., Objective: To evaluate the validity of different methods to estimate kidney function in critically ill patients with augmented renal clearance by comparing measured renal clearance with estimated clearance using different formulas., Methods: An observational, retrospective, single-center study was conducted in a 34-bed surgical intensive care unit (SICU) of the University Hospitals Leuven, Leuven, Belgium. Adults admitted to the SICU in 2010 with a measured creatinine clearance (CrCl) of 120 mL/min or more (based on 24-hour urinary collection) were included. The measured clearance values were compared with estimated clearance values as calculated by the Cockcroft-Gault (CrCl(CG)) method and the reexpressed 4-variable Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR) formula. Spearman rank order correlation was performed to determine the relationship between measured and estimated clearances. Bland-Altman plots were evaluated to assess bias and limits of agreement between the 2 methods., Results: Records on 1317 patients were screened. Augmented renal clearance was present in 390 patients. Spearman correlation showed fair correlation between measured and estimated clearances (r(s) = 0.343; p < 0.001 [CrCl(CG)] and r(s) = 0.290; p < 0.001 [eGFR]). Bias was -11.2 mL/min with limits of agreement (-131.7; 109.3 mL/min [CrCl(CG)]) and -19.9 mL/min with limits of agreement (-170.4; 130.7 mL/min [eGFR])., Conclusions: Estimated renal clearances, such as the eGFR estimated by the MDRD formula or CrCl estimated by CG, showed poor agreement with measured CrCl values in our critically ill population displaying augmented renal clearance. Clinicians should be cautious when interpreting kidney function based on estimating equations in this subset of patients. Instead, measured CrCl using urinary collection is recommended in patients suspected of displaying augmented renal clearance.

We report the successful treatment of extensive cutaneous infection and onychomycosis caused by Scytalidium dimidiatum in a 30-year old Nigerian woman.

Background: Caspofungin is the first echinocandin approved for the treatment of invasive fungal infections (IFI). As it is also well tolerated in patients with liver cirrhosis, caspofungin is an alternative for azoles in the treatment of IFI in patients with hepatic insufficiency., Methods: We report, for the first time, the pharmacokinetics (PK) of caspofungin in a patient with Child A cirrhosis and a transjugular intrahepatic portosystemic shunt (TIPS) and compare values to previously published results., Results: Caspofungin plasma levels were determined on days 14 (before TIPS reduction) and 29 (after TIPS reduction) of treatment. Troughs and peaks were 3.55 and 3.34 mg/l on day 14 and 9.28 and 9.49 mg/l on day 29, resulting in, (1) PK parameters only slightly higher than previously reported results in healthy volunteers and patients with Child A liver cirrhosis without TIPS and (2) similar exposures before versus after TIPS reduction. This limited increase in exposure is not expected to be correlated to toxicity., Conclusion: Caspofungin is a safe alternative for azoles when treating patients with TIPS suffering from IFI., (Copyright © 2012 S. Karger AG, Basel.)

Osteoporosis is a highly prevalent and often undertreated disease in the elderly. Osteoporosis-related fractures are associated with significant morbidity and mortality. Anti-osteoporotic drugs are only reimbursed by the Belgian government if strict conditions are fulfilled. The aim of this paper was to create a practical tool to guide the physician and other health care professionals to make an appropriate choice. Two flowcharts, based on Belgian reimbursement criteria and literature review were developed. Both tools provide an overview of the reimbursed pharmacological agents in the management of osteoporosis in male and female subjects.

Background and Objective: Posaconazole (Noxafil®) is an extended-spectrum triazole antifungal agent for prevention and treatment of invasive fungal infections. An inadequate dietary intake and abnormal gastric pH levels are common in critically ill patients receiving antifungal treatment with posaconazole, resulting in unpredictable bioavailability and sub-therapeutic plasma concentrations. This study was carried out to elucidate the impact of pH on posaconazole absorption and to explore the underlying mechanisms of enhanced intestinal absorption when coadministering an acidic carbonated beverage. In contrast to previously published studies, in which only plasma concentrations were determined, we also explored the gastric and intestinal behaviour of posaconazole after a single oral dose., Methods: A crossover study was performed in five healthy subjects. A single dose (10 mL) of posaconazole suspension (40 mg/mL) was administered orally in four different conditions: with 330 mL of water (condition 1); with 330 mL of a cola beverage [Coca-Cola®] (condition 2); with 330 mL of water following intake of the proton pump inhibitor esomeprazole 40 mg once daily for 3 days (condition 3); or with 330 mL of Coca-Cola® following intake of esomeprazole 40 mg once daily for 3 days (condition 4). After administration, gastrointestinal fluid and plasma samples were collected at regular time points, and posaconazole concentrations were determined., Results: Compared with administration with water, coadministration of Coca-Cola® did not alter the pH of the intraluminal environment but did significantly increase posaconazole gastric concentrations (+102%; p < 0.001) and systemic exposure (+70%; p < 0.05). This enhancement could be attributed to improved posaconazole solubility in Coca-Cola® and prolonged gastric residence. Coadministration of esomeprazole led to an increased gastric pH, which was accompanied by decreased posaconazole absorption; the mean plasma and gastric area under the concentration-time curve (AUC) values decreased by 37% and 84%, respectively. Simultaneous intake of Coca-Cola® could not completely compensate for the increase in pH induced by esomeprazole; compared with the reference condition, the mean plasma and gastric AUC values were still decreased by 19% and 73%, respectively. A good correlation between plasma and gastric posaconazole concentrations was observed (r = 0.8165; p < 0.0001), indicating that dissolution in the stomach dictates absorption of posaconazole., Conclusions: These results demonstrate that coadministration of Coca-Cola® has a positive effect on posaconazole bioavailability in the fasted state. However, it can only be considered a partially efficient strategy to increase absorption in patients with inadequate food intake who exhibit abnormal gastric pH levels due to coadministration of acid-suppressive agents.

The detection of 1,3-β-D-glucan serum levels may permit establishing the diagnosis of invasive fungal infections more early. We tested in six healthy volunteers whether the intake of a 1,3-β-D-glucan-containing nutritional supplement leads to false-positive 1,3-β-D-glucan levels. All levels were negative, even in two different dosing regimens., (© 2010 Blackwell Verlag GmbH.)

Background: Medication histories acquired upon admission are often incomplete. Using a standardized approach warrants more complete medication reconciliation, however, this is too time consuming to be performed. Other strategies guaranteeing complete medication histories should be explored. We developed a limited list of standardized questions and assessed its impact on completeness of medication histories., Methods: This prospective study enrolled adults presenting to a tertiary care emergency department. In the control group, medication histories were conducted by physicians of general internal medicine conform standard care. In the intervention group, the physicians were obliged to use, besides the standard care, the 'limited questions list' for medication history acquisition. The clinical pharmacist re-obtained medication histories of the patients in both groups using a standardized approach. The primary outcome was the impact of the use of a 'limited questions list' on the frequency of drug omissions in medication histories., Results: 260 consecutive patients were enrolled: 130 in the intervention group and 130 in the control group. There was a significant reduction of 49.3% in drug omissions in the intervention group. The omission rate per medication history was 1.1 for the control group, which was significantly lower (0.6) in the intervention group. Antithrombotics were most frequently forgotten in the control care group as opposed to dietary supplements in the intervention group., Conclusion: Drug omission rate in medication histories can be significantly reduced if a limited list of simple questions is used during anamnesis. Widespread use of this tool should be considered to be implemented., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Posaconazole is a recently developed broad-spectrum triazole antifungal with potential for long-term prophylaxis or therapy of invasive fungal infections. This case illustrates the additive value for therapeutic drug monitoring to guide clinical decision-making in high risk patients.

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.

To determine why incidence of mucormycosis infections was increasing in a large university hospital in Belgium, we examined case data from 2000-2009. We found the increase was not related to voriconazole use but most probably to an increase in high-risk patients, particularly those with underlying hematologic malignancies.

Purpose: Recovery of Candida from the respiratory tract is common. Large series on the incidence of histologically proven Candida pneumonia in intensive care unit (ICU) patients are lacking., Methods: A two-year prospective study of all autopsies performed on patients who died in the ICU was conducted. For autopsy-proven cases of Candida pneumonia, we required microscopic demonstration of yeast invasion in lung autopsy specimens that showed inflammation. We looked for differences in incidence in patients with and without respiratory samples positive for Candida species pre-mortem., Results: Of 1,587 patients admitted to the ICU, 301 (19%) died of whom 232 (77%) were autopsied. Of those, 135 patients (58%) had histopathological evidence of pneumonia. A total of 77 cases (57%) with pneumonia at autopsy had positive tracheal aspirate and/or BAL cultures for Candida spp. performed during the preceding two weeks. No cases of Candida pneumonia were identified amongst those 77 cases. In the other 58 patients with autopsy-proven pneumonia and no Candida isolation pre-mortem, no Candida pneumonia was observed either., Conclusions: Despite frequent isolation of Candida spp. from the airways, over a two-year period no single case of Candida pneumonia was found among the patients with evidence of pneumonia on autopsy. This study indicates that Candida pneumonia is an extremely rare occurrence in ICU patients and provides further evidence against the common use of antifungal therapy triggered by a microbiology report of Candida isolation from the respiratory tract.

Background: In 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., Discussion: This 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.

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.

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.

Rationale: Invasive aspergillosis (IA) is an important cause of mortality in patients with hematologic malignancies. However, IA appears to be gaining a foothold in the intensive care unit (ICU) in patients without classical risk factors. A recent study described 89 cases of IA in patients in a medical ICU without leukemia or cancer. The diagnosis of IA remains difficult and is often established too late. Galactomannan (GM) is an exo-antigen released from Aspergillus hyphae while they invade host tissue., Objectives: This prospective single-center study was conducted to investigate the role of GM in bronchoalveolar lavage (BAL) fluid as a tool for early diagnosis of IA in the ICU., Methods: All patients with risk factors identified in our earlier study were evaluated. BAL for culture and GM detection, serum GM levels, and computed tomography scan were obtained for all included patients with signs of pneumonia. Patients were classified as having proven, probable, or possible IA., Measurements and Main Results: A total of 110 patients out of 1,109 admissions were eligible. There were 26 proven IA cases. Using a cutoff index of 0.5, the sensitivity and specificity of GM detection in BAL fluid was 88 and 87%, respectively. The sensitivity of serum GM was only 42%. In 11 of 26 proven cases, BAL culture and serum GM remained negative, whereas GM in BAL was positive., Conclusions: IA is common in immunocompromised, critically ill patients. GM detection in BAL fluid seems to be useful in establishing or excluding the diagnosis of IA in the ICU.

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 proconvulsive 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.

Purpose: Two case reports of rapid decreases in valproic acid levels after initiation of meropenem in patients who developed new-onset seizure activity during treatment with cefepime are presented., Summary: A 60-year-old Caucasian woman with myelodysplasia was transferred to the medical intensive care unit (MICU) on day 11 of her hospitalization. Cefepime was given as empiric therapy for febrile neutropenia. Pulmonary invasive aspergillosis was diagnosed. On day 16 of hospitalization, epileptic activity was confirmed. Valproic acid was initiated. Cefepime was discontinued and meropenem was initiated for treatment of cefepime-resistant pneumonia. Serum valproic acid levels decreased to subtherapeutic levels within 24 hours. Meropenem was discontinued and ceftazidime was started on day 22; serum valproic acid levels gradually increased but never reached therapeutic levels again. The patient died of intractable invasive aspergillosis on day 33. A 54-year-old Caucasian man with myelodysplasia was admitted to the MICU for nonconvulsive status epilepticus. Ten days before admission, cefepime had been started empirically for the treatment of neutropenic fever. One day before MICU admission, valproic acid was initiated as treatment for status epilepticus. The next day, serum valproic acid levels were therapeutic; cefepime was switched to meropenem. Serum valproic acid levels decreased within 24 hours and phenytoin was added. On day 4, the patient's serum valproic acid levels decreased further and meropenem was discontinued. Although the valproic acid dosage was increased, valproic acid levels did not return to the therapeutic range. The patient died on day 11., Conclusion: Following cefepime therapy, a clinically important interaction between meropenem and valproic acid occurred in two critically ill patients with new-onset status epilepticus.

Objective: Sepsis remains a major cause of mortality in ICU patients, despite advances in therapy. Drotrecogin alpha (Drot AA), a recombinant human activated protein C with anti-inflammatory and anticoagulant properties, has proven to be successful in patients with at least one organ failure. Our goal was to evaluate the data in patients with sepsis and at least two organ dysfunctions in a large university hospital in Belgium., Setting: The study was conducted at the medical and surgical intensive care units of the 1850-bed university hospital of Leuven, Belgium., Methods: We retrospectively evaluated the use of Drot AA during a 2.5 year period. At baseline patients' demographics, type of infection, APACHE II (acute physiology and chronic health evaluation), SOFA (sequential organ failure assessment), DIC (diffuse intravascular coagulation) score and number of organ failures were obtained. Overall hospital mortality was defined as primary outcome measure. Special attention was paid to bleeding, the main side effect of Drot AA., Main Outcome Measure: Evalution of hospital and ICU mortality in patients treated with Drot AA for severe sepsis., Results: Drot AA was administered to 23 patients with sepsis and at least 2 organ dysfunctions; all patients started treatment within 24 h of onset of the second organ failure. Mean age was 59 years. Mean number of organ failures was 3. Overall hospital mortality rate was 47.8%. A 28-day mortality of 26% was found, comparable with the 28-day mortality rate of the PROWESS trial. Bleeding, requiring more than 3 units of blood, occurred in 1 patient. Although underlying co-morbidity was more pronounced in survivors, non-survivors had a slightly higher median APACHE II, higher SOFA score and higher DIC score. However, the number of organ failures was identical in both groups., Conclusions: Overall hospital mortality rate was similar as observed in the Belgian Registry and 28-day mortality was equal to the results of the PROWESS study. Due to the limited number of patients, it is not clear if patients should be selected based on APACHE II, DIC or number of organ failures. However, selection based on number of organ failures is more appropriate due to intrinsic problems of the APACHE II score.