Clinically relevant potential drug-drug interactions in intensive care patients: A large retrospective observational multicenter study.

PURPOSE: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. MATERIALS & METHODS: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. RESULTS: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when considering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. CONCLUSIONS: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients.

Development of diagnostic prediction tools for bacteraemia caused by third-generation cephalosporin-resistant enterobacteria in suspected bacterial infections: a nested case-control study.

OBJECTIVES: Current guidelines for the empirical antibiotic treatment predict the presence of third-generation cephalosporin-resistant enterobacterial bacteraemia (3GCR-E-Bac) in case of infection only poorly, thereby increasing unnecessary carbapenem use. We aimed to develop diagnostic scoring systems which can better predict the presence of 3GCR-E-Bac. METHODS: A retrospective nested case-control study was performed that included patients ≥18 years of age from eight Dutch hospitals in whom blood cultures were obtained and intravenous antibiotics were initiated. Each patient with 3GCR-E-Bac was matched to four control infection episodes within the same hospital, based on blood-culture date and onset location (community or hospital). Starting from 32 commonly described clinical risk factors at infection onset, selection strategies were used to derive scoring systems for the probability of community- and hospital-onset 3GCR-E-Bac. RESULTS: 3GCR-E-Bac occurred in 90 of 22 506 (0.4%) community-onset infections and in 82 of 8110 (1.0%) hospital-onset infections, and these cases were matched to 360 community-onset and 328 hospital-onset control episodes. The derived community-onset and hospital-onset scoring systems consisted of six and nine predictors, respectively. With selected score cut-offs, the models identified 3GCR-E-Bac with sensitivity equal to existing guidelines (community-onset: 54.3%; hospital-onset: 81.5%). However, they reduced the proportion of patients classified as at risk for 3GCR-E-Bac (i.e. eligible for empirical carbapenem therapy) with 40% (95%CI 21-56%) and 49% (95%CI 39-58%) in, respectively, community-onset and hospital-onset infections. CONCLUSIONS: These prediction scores for 3GCR-E-Bac, specifically geared towards the initiation of empirical antibiotic treatment, may improve the balance between inappropriate antibiotics and carbapenem overuse.

Severe neurological symptoms following synthetic cannabinoid intoxication.

Synthetic cannabinoids are becoming increasingly popular as substances of abuse. However, in the Netherlands synthetic cannabinoid intoxications are rare. We report a 16-year-old male who became deeply comatose and was admitted to the intensive care unit for invasive mechanical ventilation after a buse of aninitially unknown drug. Routine toxicology screening with an immunoassay only detected tetrahydrocannabinol, but additional tests with liquid chromatography mass spectrometry revealed synthetic cannabinoid use. This case underlines the challenging diagnosis of synthetic cannabinoid intoxications and the severe complications they can produce.

A tailored implementation strategy to reduce the duration of intravenous antibiotic treatment in community-acquired pneumonia: a controlled before-and-after study.

We previously showed that 40 % of clinically stable patients hospitalised for community-acquired pneumonia (CAP) are not switched to oral therapy in a timely fashion because of physicians' barriers. We aimed to decrease this proportion by implementing a novel protocol. In a multi-centre controlled before-and-after study, we evaluated the effect of an implementation strategy tailored to previously identified barriers to an early switch. In three Dutch hospitals, a protocol dictating a timely switch strategy was implemented using educational sessions, pocket reminders and active involvement of nursing staff. Primary outcomes were the proportion of patients switched timely and the duration of intravenous antibiotic therapy. Length of hospital stay (LOS), patient outcome, education effects 6 months after implementation and implementation costs were secondary outcomes. Statistical analysis was performed using mixed-effects models. Prior to implementation, 146 patients were included and, after implementation, 213 patients were included. The case mix was comparable. The implementation did not change the proportion of patients switched on time (66 %). The median duration of intravenous antibiotic administration decreased from 4 days [interquartile range (IQR) 2-5] to 3 days (IQR 2-4), a decrease of 21 % [95 % confidence interval (CI) 11 %; 30 %) in the multi-variable analysis. LOS and patient outcome were comparable before and after implementation. Forty-three percent (56/129) of physicians attended the educational sessions. After 6 months, 24 % (10/42) of the interviewed attendees remembered the protocol's main message. Cumulative implementation costs were 5,798 (20/reduced intravenous treatment day). An implementation strategy tailored to previously identified barriers reduced the duration of intravenous antibiotic administration in hospitalised CAP patients by 1 day, at minimal cost.

Dosing of carboplatin in a patient with amputated legs: A case report.

Carboplatin is a platinum derivative that is commonly used in combination chemotherapy for treatment of several malignancies, including small-cell lung carcinoma (SCLC). Because the estimated glomerular filtration rate, and therefore the carboplatin dose, is based on the serum creatinine level, dosing of carboplatin for amputees is a challenge. This case report describes how serum carboplatin levels were used to determine the most suitable carboplatin dose for an amputee. The patient received four cycles of etoposide in combination with carboplatin area under the curve = 5 mg·min/ml, with a dose reduction of 25% and concurrent radiotherapy. The measured area under the curve was found to be 3.41 mg·min/ml, while the target area under the curve was 3.75 mg·min/ml (75% of 5 mg·min/ml). Therefore, for the next cycles, the carboplatin dose was calculated using the Calvert formula. No recurrence of disease was seen within two years after completion of therapy. This case demonstrates that therapeutic drug monitoring can successfully be used to determine the carboplatin dose for an amputee.

[Acute delirium, probably precipitated by clarithromycin]. / Acuut delier, waarschijnlijk uitgelokt door claritromycine.

Clarithromycin is a relatively new antibiotic with many applications. Its frequent use explains why side-effects previously reported seldom now become clear. Two patients, a man aged 74 and a woman aged 56 years, developed delirium after treatment with clarithromycin as part of eradication treatment of Helicobacter pylori, presumably as a result of an ideosyncratic reaction to the clarithromycin. Preclinical and clinical investigations did not reveal side effects on the central nervous system. By now the appearance of a delirium presumably related to the use of clarithromycin has been described in several patients. Furthermore some patients had a positive rechallenge. Finally, 17 reports on psychiatric side effects, of which 7 were delirium, after the use of clarithromycin reached the Netherlands Pharmacovigilance Foundation (Lareb). This combination of facts makes a causal relationship probable.

Troglitazone. Is it all over?

In January 1997 a drug from a new pharmacological class, the thiazolidinediones, became available: troglitazone. Troglitazone indirectly enhances peripheral insulin sensitivity. In this way it lowers the levels of both glucose and insulin. Troglitazone also has a lowering effect on the levels of triglycerides. In clinical trials only mild side effects had been observed. Therefore, troglitazone seemed a promising drug. Recently, however, it became clear that troglitazone could cause liver dysfunction in some patients. Although this side effect is reversible in most cases, six deaths have been described due to liver damage. Troglitazone was to be introduced in Europe in 1998 but registration procedures and clinical trials have been stopped because of its side effects on the liver. In the United States and Japan troglitazone is still being used, albeit with extra precautions. Troglitazone is a valuable addition to the arsenal of antidiabetic drugs for type 2 diabetes. It can be particularly useful, both as an additive and as a replacement, in patients for whom metformin is not suitable because of contraindications or side effects. The risk of severe liver dysfunction is a reason to reserve troglitazone as a second-line drug.

Tissue concentrations after a single-dose, orally administered ofloxacin in patients with diabetic foot infections.

We studied the penetration of orally administered ofloxacin at the site of diabetes-related foot infections in patients with a planned debridement of the lesion. A total of nine patients received 800 mg of oral ofloxacin 120 to 150 minutes before surgery. During surgery, vital margin tissue and a serum sample were obtained. Serum and tissue concentrations of ofloxacin were measured. From seven patients sufficient amounts of tissue were obtained. Mean serum concentration was 7.0+/-3.5 mg/liter; mean tissue concentrations was 11.5+/-8.4 mg/kg. Mean serum and tissue concentrations exceed the minimal inhibitory concentration90 (MIC90) of commonly involved pathogens. This indicates that orally administered ofloxacin can be an effective treatment for infected diabetic foot lesions.