Nephrotoxicity of continuous amphotericin B in critically ill patients with abdominal sepsis: a retrospective analysis with propensity score matching.

BACKGROUND: Continuous infusion of conventional amphotericin B (CCAB) is used in ICUs for pre-emptive treatment of invasive fungal infections. Amphotericin B has previously been associated with nephrotoxicity. OBJECTIVES: To investigate if CCAB with therapeutic drug monitoring (TDM) results in renal impairment over time in critically ill patients with abdominal sepsis. PATIENTS AND METHODS: The study was conducted at mixed medical-surgical ICUs of two large teaching hospitals in the Netherlands. Consecutive patients who were treated on the ICUs between 2006 and 2019 for abdominal sepsis, with or without CCAB, were included. CCAB dosing was guided by TDM. Serum creatinine concentrations and renal failure scores of patients with CCAB treatment were compared with those without CCAB treatment. Excluded were: (i) patients treated with CCAB for less than 72 h; and (ii) patients with renal replacement therapy. RESULTS: A total of 319 patients were included (185 treated with CCAB and 134 controls). A multiple linear regression model showed that the serum creatinine concentration was independent of CCAB treatment (ß = -0.023; 95% CI = -12.2 to 7.2; P = 0.615). Propensity score matching resulted in 134 pairs of CCAB-treated and non-treated patients. Again, the analysis of these pairs showed that the cumulative CCAB dose was not associated with serum creatinine concentration during intensive care treatment (ß = 0.299; 95% CI = -0.38 to 0.98; P = 0.388). CONCLUSIONS: CCAB with TDM did not result in renal impairment over time in critically ill patients with abdominal sepsis.

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.

Impact of joint consultation by a clinical pharmacist and a clinical geriatrician to improve inappropriate prescribing for elderly patients.

OBJECTIVE: Appropriate prescribing is a key quality element in medication safety. It is unclear if therapeutic interventions resulting from medication review lead to clinically relevant improvements. The effect of medication review on prescribing appropriateness was evaluated in the setting of an outpatient consultation team, consisting of a clinical pharmacist and a clinical geriatrician, in a large non-academic teaching hospital in the Netherlands. METHOD: A group of 49 elderly patients with polypharmacy was included after referral by their general practitioner for drug related problems. After a regular assessment by a clinical geriatrician and medication record review by a clinical pharmacist, a treatment plan was implemented based on the recommended interventions. The main outcome measure was the change in the Medication Appropriateness Index (MAI) before and 3 months after primary consultation. RESULTS: Overall 82% of the recommended interventions of the pharmacist were implemented by the geriatrician of which 63% persisted up to the last visit. Per patient an average of 6.6 interventions were carried out. The interventions showed a reduction of the MAI per patient of 50%. The number of drugs per patient was reduced from 12.1 to 11.0. The number of medications listed on the Beers list decreased from 2.3 to 1.5 and the number of drugs listed on the Hospital Admissions Related to Medication (HARM) Trigger list decreased from 2.1 to 1.5. CONCLUSIONS: Interventions from a multidisciplinary outpatient consultation team were effective in improving appropriate prescribing in elderly outpatients with polypharmacy.

Pharmacokinetics of riluzole: evidence for glucuronidation as a major metabolic pathway not associated with UGT1A1 genotype.

Pharmacokinetic studies of riluzole show a large inter-individual variability of the drug's clearance and serum concentrations. Optimizing the individual dosage of riluzole may have the potential to improve the effect of riluzole treatment on survival of patients with amyotrophic lateral sclerosis (ALS). Limited data are available on the in vivo metabolic elimination of riluzole. From in vitro experiments, CYP1A2 seems to be mainly involved in riluzole clearance. However, in vitro studies suggest that formation of riluzole-glucuronide plays a role and may determine the drug's pharmacokinetic variability in patients to some extent. In the current study the formation of riluzole-glucuronide was examined in amyotrophic lateral sclerosis (ALS) patients. It also aimed at relating glucuronidation of riluzole to differential UGT1A1*28 genotypes. The formation of riluzole-glucuronide was confirmed in serum from a group of 14 ALS patients taking riluzole. Riluzole-glucuronide concentrations were positively associated with those of riluzole. In a separate group of 131 ALS patients taking riluzole, the UGT1A1*28 genotype was not associated with trough or peak serum concentrations of riluzole. This study provides evidence that the in vivo metabolic elimination of riluzole in ALS patients involves glucuronidation. The results do not indicate that glucuronidation of riluzole highly contributes to the drug's inter-individual pharmacokinetic variability.

An association study of riluzole serum concentration and survival and disease progression in patients with ALS.

Patients with amyotrophic lateral sclerosis (ALS) who are treated with the antiglutamatergic drug riluzole receive a fixed-dose regimen of 50 mg b.i.d. The drug has been shown to increase tracheostomy-free survival by 3-6 months. The pharmacokinetics of riluzole show a high interindividual variability. Riluzole serum concentrations are associated with side effects and ALS symptoms, but the effect of the actual blood level of riluzole on disease progression and survival is unknown. We measured trough and peak serum concentrations of riluzole in 160 patients with ALS, and estimated the area under the curve for one dosage interval (AUCi) using a Bayesian method. We then determined the association between riluzole AUCi and survival over a 5-year period, and between riluzole AUCi and disease progression, defined by the rates of decline of arm strength and vital lung capacity. No significant association was found between riluzole AUCi and survival or disease progression.

[Severe phenytoin intoxication in patients with hypoalbuminaemia]. / Ernstige fenytoïne-intoxicatie bij patiënten met hypoalbuminemie.

Two patients, a 35-year-old woman and a 60-year-old man, developed severe neurological side effects during treatment with phenytoin: disorientation, myoclonia, hallucinations and drowsiness in the first patient and a comatose state in the second. The woman had spina bifida, a ventriculoperitoneal drain because of hydrocephalus, recurrent urinary-tract infection, and a history of status epilepticus. The man suffered from diabetic ketoacidosis complicated by epileptic convulsions. In both patients, the total phenytoin concentration in the blood was within the therapeutic range of 8-20 mg/l. However, both had low serum albumin concentrations, below 25 g/l. Low serum albumin levels are associated with increased concentrations of the free fraction of phenytoin. Toxic levels of free phenytoin were found: 4 and 8 mg/l, respectively, while the therapeutic range is 0.5-2 mg/l. The first patient recovered after treatment with phenytoin was stopped, after which she was placed on a lower dosage; the second patient died. When prescribing phenytoin to patients with hypoalbuminaemia, one should be aware of the risk of intoxication due to a high level of free phenytoin and consequently an increased risk of severe neurological side effects.

Plasma concentrations of meperidine and normeperidine following continuous intrathecal meperidine in patients with neuropathic cancer pain.

BACKGROUND: Intrathecal administration of meperidine, an opioid with local anesthetic activity, can induce analgesia in patients with intractable cancer pain. However, continuous intrathecal administration may result in the accumulation of normeperidine, responsible for central nervous system toxicity. METHODS: Ten patients with neuropathic cancer pain, not responding to conventional opioid therapy, were treated with continuous intrathecal administration of meperidine. In all patients, plasma concentrations of meperidine and normeperidine were measured the first days after the start of treatment. Visual analog scale scores were recorded to evaluate pain relief. Quality of life was assessed before and 3 weeks following the start of intrathecal treatment. RESULTS: In three patients the plasma concentrations of meperidine and normeperidine increased rapidly. In one patient the plasma normeperidine concentration was higher than the meperidine concentration. One patient demonstrated transient symptoms suggestive for central nervous system excitation. Three weeks following the start of treatment, seven patients were available for evaluation of their quality of life. Pain relief and overall quality of life improved during the intrathecal treatment. CONCLUSION: We conclude that continuous intrathecal administration of meperidine alone, or in combination with clonidine, can provide significant pain relief in patients with poor pain control despite pharmacological treatment. However, accumulation of meperidine and normeperidine resulting in central nervous system toxicity may occur during this treatment.

Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis.

AIMS: Riluzole is used in a fixed dosing schedule of 50 mg twice daily to treat patients with amyotropic lateral sclerosis (ALS), one form of motor neurone disease. The large variability in the pharmacokinetics of riluzole may be a factor contributing to its limited therapeutic benefit. Riluzole is assumed to be mainly metabolized by the cytochrome P450 enzyme 1A2 (CYP1A2). The aim of the study was to investigate the relationship between CYP1A2 activity and riluzole clearance with a view to optimize drug treatment. METHODS: A group of 30 ALS patients participated in the study. In each patient the CYP1A2 activity was determined using caffeine as a metabolic probe. Riluzole clearance was estimated from serum drug concentration measurements followed by Bayesian fitting. RESULTS: Riluzole clearance and the serum paraxanthine : caffeine (P/C) ratio showed a positive correlation (r = 0.693; P = 0.0002). Linear regression analysis identified the P/C ratio (beta: 1.16) and height (beta: 0.027) as independent predictors of riluzole clearance (adjusted r2 = 0.369). CONCLUSIONS: The P/C ratio, used as measure of CYP1A2 activity, significantly correlated with the riluzole clearance, although only 37% of the observed variability could be explained.

A validated HPLC assay to monitor riluzole plasma or serum concentrations in patients with amyotrophic lateral sclerosis.

A specific, accurate and precise high-performance liquid chromatographic assay was developed for the determination of riluzole, a drug used to treat patients with amyotrophic lateral sclerosis. Samples were treated by extraction with dichloromethane followed by reversed-phase chromatography with ultraviolet detection at 260 nm. Preset validation criteria were met from 20 to 2000 ng/mL with a linear response curve. Extraction recovery of riluzole was 65-76%. The accuracy of the method was 102-103%. Intra- and inter-day coefficients of variation were in the ranges 2.8-4.9% and 1.8-9.7%. A detection limit of 5 ng/mL was found. Determination of concentrations in serum and plasma resulted in similar results below 500 ng/mL. At higher values a matrix effect cannot be excluded. This presented method can be used to monitor plasma or serum levels in ALS patients treated with riluzole.

High mortality among patients with bacterial meningitis in a rural hospital in Tanzania.

Although the disease is an important cause of mortality in the region, most published reports on bacterial meningitis in East Africa are from urban referral hospitals. Poor laboratory facilities make diagnosis difficult in the area and treatment is limited to inexpensive antibiotics. The case-fatality 'rate' in one rural hospital in Tanzania, the Ndala Mission Hospital (NMH), appears to have increased dramatically over recent years, perhaps as the result of increasing resistance to ampicillin and chloramphenicol. The aim of the present study, which was partially retrospective and partially prospective, was to review the number, characteristics and outcome of children admitted to this hospital with bacterial meningitis and to investigate possible resistance of the causative micro-organisms to the antibiotics used. Data from the 181 children who were admitted with bacterial meningitis [confirmed by the examination of Gram-stained smears of cerebrospinal fluid (CSF)] between 1999 and 2002 were retrospectively reviewed. The overall mortality among these children was 51%. No seasonal pattern was observed in the number of cases. In a 2-month prospective study in 2002, CSF samples from 19 consecutive cases were collected in Trans-Isolate medium and shipped to the Academic Medical Center in Amsterdam for culture and analysis of antibiotic susceptibility. For only eight (42%) of the cases was there agreement between the species of bacterium identified, by Gram-staining, in Tanzania and that identified, by culture, in The Netherlands. As there was no evidence of resistance to ampicillin and the antibiotics used in the NMH were found to be of good quality, the cause of the high mortality in the NMH remains uncertain. Poor laboratory testing, long doctor-patient delays and/or poor drug administration on the wards may all be contributory factors. Attempts will now be made to address each of these problems.

Relative bioavailability of three newly developed albendazole formulations: a randomized crossover study with healthy volunteers.

This study of healthy volunteers shows that the relative bioavailability of albendazole formulations that use arachis oil-polysorbate 80 or hydroxypropyl-beta-cyclodextrin as an excipient was enhanced 4.3- and 9.7-fold compared to the results seen with commercial tablets. Administration of macrogol suppositories did not result in measurable plasma concentrations of albendazole sulfoxide.

Riluzole serum concentrations in patients with ALS: associations with side effects and symptoms.

Riluzole exerts a dose-dependent effect on survival of patients with ALS and, although serum levels show a high interindividual variability, is usually prescribed in a fixed dose. In this study, riluzole serum levels and area under the curve per kilogram of body weight (AUC/kg) of 169 patients with ALS showed a high interindividual variability. Patients with high serum levels and AUC/kg more often had diarrhea but less often had fasciculations and muscle stiffness. It may therefore be advantageous to raise the riluzole dose in patients with low riluzole serum concentrations without the risk of serious side effects.

Inter- and intraindividual variability of riluzole serum concentrations in patients with ALS.

All patients with amyotrophic lateral sclerosis (ALS) are treated with the same dose of riluzole: 50 mg twice daily. Reasonably large interindividual differences in clearance of the drug have been reported. The relatively small group of patients with high blood concentrations of riluzole has probably primarily influenced the efficacy and the incidence of side-effects in the previously conducted clinical trials with riluzole. Individual dosing of the drug may, in the case of large interindividual differences in serum concentrations of the drug, be necessary in the future. Exact data concerning the plasma and serum concentrations of riluzole in patients with ALS, after standardized intake of the drug, diet and blood sampling are unknown so far. In this study, inter- and intraindividual variability of serum and plasma levels of riluzole in 21 patients with "probable" or "definite" ALS were determined. The interindividual variability of peak serum levels (coefficient of variation=74%) was significantly larger than intraindividual variability (p<0.001). Serum levels were not correlated with age or smoking status. The determination of a correlation between riluzole serum concentrations and survival of patients with ALS will be the aim of further studies.

Hydroquinine pharmacokinetics after oral administration in adult patients with muscle cramps.

OBJECTIVE: This study was conducted to determine the pharmacokinetic properties of hydroquinine after oral administration in adult patients with muscle cramps. The main reason for this study was the poor availability of pharmacokinetic data, hindering the design of studies to explore the possible relationship between hydroquinine concentrations and effects. METHODS: Sixteen adult patients with a clinical history of muscle cramps were given once-daily oral doses of 300 mg hydroquinine hydrobromide for 4 days. Serum and saliva samples were taken following a predefined schedule until 24 h after the last dose. Urine was collected during the study period. Hydroquinine concentrations were measured, and calculations were made of pharmacokinetic parameters using non-linear curve fitting. RESULTS: Pharmacokinetics of hydroquinine could be best described using a one-compartment open model. After oral administration, hydroquinine was rapidly absorbed (mean +/- SD: maximum concentration 2.43+/-0.68 mg/ 1; time to maximum concentration 1.4+/-1.2 h; lag time 0.54+/-0.50 h). With an elimination half-life of 10.9+/-6.1 h, steady-state was reached in several days. The distribution volume was 1.24+/-0.29 l/kg, total clearance was 6.7+/-3.2 l/h. The measured unbound hydroquinine fraction was 8.6+/-3.0%. No correlation was found between saliva and serum concentrations. Cumulative urinary excretion of unchanged hydroquinine 24 h after the first dose was 35.5+/-9.2 mg. CONCLUSION: Pharmacokinetic properties of hydroquinine are roughly similar to those of quinine. The unchanged fraction of hydroquinine excreted in urine is higher than that reported for quinine. Saliva hydroquinine concentrations could not be related to serum values. Steady-state trough or other fixed-time serum concentrations may prove useful for further optimisation of hydroquinine dosage.

Tetracaine versus lidocaine-prilocaine for preventing venipuncture-induced pain in children.

The efficacy of tetracaine cream versus that of lidocaine-prilocaine cream for the prevention of pain in children undergoing venipuncture was studied. Hospital inpatients 1-15 years of age received, on the back of each hand, a 30-minute application of tetracaine 4% cream or a 60-minute application of lidocaine-prilocaine cream (EMLA, Astra) before undergoing scheduled venipuncture. The phlebotomists in this open, randomized trial evaluated the efficacy of the cream at the moment of venipuncture as adequate, inadequate, or inconclusive. Blood samples were taken immediately after venipuncture from 10 patients one to five years of age to measure the serum concentrations of tetracaine and its metabolite, N-butyl-p-aminobenzoic acid. Lidocaine-prilocaine cream was significantly more efficacious in preventing pain than tetracaine 4% cream (97% of the former group [n = 32] had adequate pain relief, compared with 76% of the latter [n = 34]. The only adverse effects observed were mild local erythema in the tetracaine group and local skin blanching in the lidocaine-prilocaine group. No tetracaine could be detected in serum, and the serum concentrations of N-butyl-p-aminobenzoic acid ranged from 0 to 1.8 mg/l. Statistically, lidocaine-prilocaine cream was more efficacious than tetracaine 4% cream, but the difference is of minor clinical significance and is outweighed by the practical advantages of tetracaine 4% cream, namely the shorter application time, vasodilation and lower cost.