Uwe Tröger

Decreased meropenem levels in Intensive Care Unit patients with augmented renal clearance: benefit of therapeutic drug monitoring

One of the first-line drugs for empirical antibiotic therapy in patients with hospital-acquired infections is meropenem. An often neglected problem in sepsis is that patients with a normal serum creatinine concentration (SCr) might display augmented renal clearance (ARC). Here we describe two cases of sepsis with subtherapeutic exposures with standard meropenem dosing in whom therapy could be optimised by therapeutic drug monitoring (TDM). A 37-year-old man with acute lymphatic leukaemia and sepsis had a normal SCr at the beginning of his Intensive Care Unit (ICU) stay but showed decreased SCr of between 30 μmol/L and 40 μmol/L during his stay. He failed to achieve effective plasma concentrations with the meropenem standard dose of 3 g/day. Estimated glomerular filtration rate revealed values between 120 mL/min and 160 mL/min. He required a high meropenem daily dosage of 12 g that was far above the approved maximum dose. A 66-year-old patient undergoing surgery of a pulmonary aspergilloma presented SCr persistently <50 μmol/L, indicating ARC between 120 mL/min and 150 mL/min. This patient required 8 g of meropenem to achieve effective plasma concentrations. TDM may represent an invaluable approach to optimising drug exposure of β-lactam antibiotics in patients with ARC in the ICU. Further trials are clearly needed to become better informed about empirical dosing regimens usable in the ICU setting with regard to the relevance of ARC. In the meantime, daily measurement of creatinine clearance as well as TDM can be used to identify patients who manifest ARC, thereby allowing drug therapy to achieve the therapeutic range.

Influence of endogenous and exogenous effectors on the pharmacokinetics of theophylline. Focus on biotransformation.

SummaryTheophylline has been widely used as a bronchodilatory drug for the treatment of neonatal apnoea in premature newborns and patients with obstructive airways disease. The development of analytical equipment and procedures to determine the systemic concentration of theophylline renders it possible to improve the effectiveness of theophylline therapy and reduce the incidence of toxic and adverse effects. Since the beginning of the 1970s, endogenous and exogenous factors (e.g. age, blood pH, concomitant diseases and drug therapy, meal preparation procedures, nutritional habits, pregnancy, gender, smoking and, to a lesser extent, biorhythms), influencing nearly all parameters of theophylline pharmacokinetics have been described.Drug absorption depends on galenic formulation, drug delivery, nutritional habits and the chemical derivatives used. The mean plasma protein binding rates depend on the method of plasma protein determination: acidic blood pH values and advanced age may result in reduced plasma proteins. The volume of distribution depends primarily on age; it is 2-fold greater in newborns than in adults. Furthermore, changes in blood pH values, the plasma protein content and the administration of concomitant drugs may vary this parameter.Biotransformation is the most clinically important pharmacokinetic parameter. Hepatic metabolism accounts for 90% of the metabolism of theophylline. Essentially, 2 microsomal isoenzymes of the cytochrome P450 system appear to be responsible for the N-methylation and 8-hydroxylation of the drug. Age and concomitant disease are the major endogenous effectors influencing biotransformation of theophylline, whereas biorhythms, gender and pregnancy are of lesser importance. Exogenous factors, such as concomitantly administered drugs, smoking and nutritional factors, affect biotransformation by inducing or inhibiting the metabolising enzymes.Because of intra- and interindividual variability in the pharmacokinetics of theophylline, which may be increased by the presence of endogenous and/or exogenous effectors, it is necessary to supervise theophylline therapy by therapeutic drug monitoring if target concentrations are to be achieved.

Adverse nondrug reactions: An update

Healthy volunteers are involved in stage I of clinical investigations. It appears to be necessary to characterize such subjects more closely. Representing an essential aspect are symptoms giving rise to complaints that are typical side effects of drugs but that often also occur as adverse nondrug reactions. Correlations are supposed to exist between personality, motivation, and emotion of subjects and the incidence of their complaints.

Intravenous colistin in a patient with serious burns and borderline syndrome: The benefits of therapeutic drug monitoring

Colistin is a decades-old drug that fell out of favour due to its nephrotoxicity. Today, colistin is experiencing a renaissance as a treatment against multiresistant Gram-negative bacteria such as Pseudomonas and Acinetobacter in critically ill patients. The optimal dosing of colistin for most infections is unknown. Here we present the intravenous dosing, optimised by therapeutic drug monitoring (TDM), of a borderline patient with severe burns and a consecutive transfemoral amputation. A 32-year-old woman with severe burns (35% total body surface area) and sepsis exhibited normal serum creatinine (SCr) concentrations at the beginning of her intensive care unit (ICU) stay, but over the course of her ICU stay her SCr increased to 100 μmol/L. With the colistin standard dose of 3 × 3 million units (MU) colistin/day after a loading dose of 9 MU, she failed to achieve effective plasma concentrations. The estimated glomerular filtration rate (eGFR) via CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) revealed GFRs between 180 mL/min and 63 mL/min after correcting for body surface. The patient required a high daily dosage of colistin (3 × 6 MU) that exceeded the approved maximum dose. Most clinicians rely heavily on SCr concentrations as the primary biochemical marker of GFR. At most, the CKD-EPI formula is helpful in determining creatinine clearance. The pharmacokinetics of colistin are currently poorly understood. TDM of colistin methanesulfonate and colistin may represent an invaluable approach to optimise colistin drug exposure in ICU patients with fluctuating renal clearance.

Determination of cerebrospinal fluid concentrations of arginine and dimethylarginines in patients with subarachnoid haemorrhage

Elevated cerebrospinal fluid (CSF) concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), are assumed to be related to delayed vasospasm after subarachnoid haemorrhage (SAH). However, data on CSF concentrations of L-arginine, ADMA and its structural isomer symmetric dimethylarginine (SDMA) are very sparse in humans. We here present a new hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS-MS) method for the precise determination of these substances in CSF. The method requires only minimal sample preparation and features isotope labeled internal standards. First data of patients with SAH showed that on the day of admission CSF concentration values of L-arginine and ADMA were not significantly different from controls, but increased markedly during the course of the hospital stay. The decrease of the L-arginine to ADMA ratio points to a progressive impairment of the NO production rate in the brain after SAH which is confirmed by a simultaneous decrease in nitrate and nitrite concentrations in CSF.

Esomeprazole-induced rhabdomyolysis in a patient with heart failure.

A 75-year-old male patient with chronic heart failure underwent aortic valve replacement and coronary artery bypass surgery and was transferred to our intensive care unit. He also suffered from renal failure and diabetes mellitus. He was sedated initially by propofol and sufentanil for mechanical ventilation. Other medications were insulin, heparin (800 IU/h), furosemide (40–120 mg/day), amiodarone (36 mg/h), meropenem (2 g/day), linezolid (1,200 mg/day) and catecholamines. Intravenous esomeprazole was administered (40–80 mg/day) for stress ulcer prophylaxis. Furthermore, the patient was treated with continuous veno-venous haemofiltration for 12 days. After the successful surgery procedure, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and the C-reactive protein (CRP) levels decreased, but myoglobin remained elevated. After excluding several clinical reasons, the most probable drugs known to cause rhabdomyolysis—propofol and amiodaron—were discontinued. Nevertheless, myoglobin continued to range between 1,000 and 2,000 lg/l (normal: \72 lg/l). This was accompanied by high temperature (about 38 C), slightly increased gamma-glutamyltransferase of 84 U/l (6–42 U/l), an increased LDH 402 U/ l (135–225 U/l) and CRP 220 mg/l (\5 mg/l), but normal levels of ALAT, ASAT and creatine kinase. Consequently, esomeprazole was suspected to be trigger of the adverse reaction. The drug was withdrawn, and serum levels were measured. One day after cessation of esomeprazole, myoglobin levels decreased persistently, and 8 days later the patient could be transferred to a rehabilitation centre. Rhabdomyolysis commonly occurs in response to trauma or excessive muscle activity, but non-traumatic rhabdomyolysis is often associated with seizures or toxic drug reactions [1]. We do not know why creatine kinase did not increase in our patient. However, a study in critically ill patients with rhabdomyolysis reported a 17% rate of isolated increased myoglobin in serum [2]. Although there is only limited evidence to support the use of proton pump inhibitors (PPI) for prophylactic treatment of stress ulcers in critical care medicine, these drugs are commonly used for this indication [3]. PPI have already been suspected of causing rhabdomyolysis [4]. However, this is the first report about a dose-related toxic rhabdomyolysis. The temporal relationship between esomeprazole administration and the onset of symptoms, as well as the clinical improvement following the discontinuation of the drug support our hypothesis. Moreover, the retrospective evaluation revealed a relation between the esomeprazole dose and the myoglobin serum concentration with a delay of some days (Fig. 1). In addition, the half-life of esomeprazole was clearly prolonged. The calculated elimination half-life was 4.81 h, almost four-fold compared to healthy Caucasians [5], and perhaps caused by reduced liver activity due to the patient’s decreased cardiac output (ejection fraction \30%). Moreover, the patient had no history of seizures and took no drugs known to cause rhabdomyolysis, such as statins. Rhabdomyolysis as a direct effect of the surgical procedures is also not probable, because of continued high levels of serum myoglobin. The exact mechanism of this adverse effect is unknown. One possibility, an idiosyncratic drug reaction resulting in some myopathies [6], could be neglected because the clear correlation between the esomeprazole dose and myoglobin values strongly

The effect of anxiety and personality on the pharmacokinetics of oral midazolam.

We investigated the relationship between the pharmacokinetic variables of oral midazolam and patients’ state/trait anxiety and personality. Twenty-six patients received the standard 15-mg oral dose for anxiolysis on the evening before otorhinolaryngological surgery. Blood samples were taken over a 9-h period after the administration, and the samples were analyzed for concentrations of midazolam and its two main metabolites by using a gas chromatography-mass spectrometry procedure. The pharmacokinetic variables maximum concentration, time to reach the maximum concentration, the elimination half-life, and the area under the curve were calculated from these data. When the patients were divided into groups with respect to their anxiety and personality scores, no significant differences in the pharmacokinetic variables of midazolam could be found. Only small, insignificant changes in the maximum concentrations were found with respect to nervousness and emotionality. We conclude that personality traits and anxiety levels had no effect on the pharmacokinetic variables of midazolam.

Successful treatment of extensively drug-resistant Pseudomonas aeruginosa osteomyelitis using a colistin- and tobramycin-impregnated PMMA spacer

Discovered in 1949, the antibiotic colistin was initially used for therapeutic purposes. Parenteral use of colistin was gradually abandoned because of its side-effect profile, especially its nephrotoxicity and neurotoxicity. Despite the risk of these potentially serious adverse effects, increasing resistance of Gram-negative bacteria has led to a renaissance of intravenous use of colistin in the last few years. Local administration of colistin is an alternative method to minimise the risk of systemic toxicity. We present a case of extensively drug-resistant Pseudomonas aeruginosa osteomyelitis treated successfully with high-dose colistin- and tobramycin-impregnated bone cement as a drug delivery vehicle. For the first time, local colistin concentrations in drainage and synovial fluid were quantified in order to determine the optimal dose and to minimise serious side effects. Insertion of a bone cement spacer loaded with a high dose of tobramycin and colistin resulted in local colistin levels at the infection site that exceeded the minimum inhibitory concentration (MIC) of colistin against the isolated P. aeruginosa five-fold on Day 4. Thus, the treatment may be expected to exert a prolonged effect. Whereas systemic administration of colistin alone was not sufficient to treat the infection, combined local and parenteral therapy led to eradication of P. aeruginosa in this patient. Plasma colistin levels remained in the therapeutic range, which confirms the systemic safety of the method.

Omeprazole-induced cough in a patient with gastroesophageal reflux disease.

Persistent cough could be caused by various diseases such as postnasal drip syndrome, asthma and gastroesophageal reflux disease (GERD) or adverse event of drugs such as angiotensin-converting enzyme inhibitors. We report a case of persistent cough associated with high plasma levels of the proton pump inhibitor omeprazole in a patient with GERD. This case suggests cough as an adverse drug event to omeprazole, which is otherwise commonly prescribed for the management of GERD-related cough. Therefore, physicians should be aware of the onset or an exacerbation of cough during omeprazole therapy.

Pharmacokinetics and dose recommendations of Niaspan® in chronic kidney disease and dialysis patients

BACKGROUND Niaspan® is an extended-release formulation of nicotinic acid with improved tolerability compared with the immediate-release and sustained-release formulations. It is used to treat hypertriglyceridaemia with low high-density lipoprotein levels. This type of dyslipidaemia frequently appears in patients with chronic kidney disease (CKD). Dose recommendations for these patients are not available because pharmacokinetic data are missing. The present study was performed to analyse the pharmacokinetics of prolonged-release nicotinic acid in CKD and in dialysis patients to derive dose recommendations. METHODS Ten dialysis patients and eight patients with CKD were enrolled in a prospective, three-period, open-label pharmacokinetic study. They received in the first week 500 mg Niaspan® per day, in the second week 1000 mg/day and in the third week 1500 mg/day. On the fourth day of every treatment unit, 11 plasma samples were collected for 24 h post-dose and analysed for nicotinic acid (NA) and its metabolites nicotinamide and nicotinuric acid (NUA). RESULTS Median plasma NA concentrations in subjects with CKD were obviously higher than in dialysis patients, but not higher than reported in patients without renal impairment. t(max) of NA were on average 0.75 h in dialysis patients and 3.0 h in CKD patients and, therefore, especially for dialysis patients, clearly shorter than expected for extended-release formulations. It is particularly noticeable that the AUC, C(max) and t(1/2) of the metabolite NUA are significantly higher in dialysis patients in comparison to CKD patients. This may indicate that the dialysis was not effective in removing this metabolite. However, there was no correlation between the incidence of flush and the concentration of NUA. Another possibility could be a drug-drug interaction with omeprazole via CYP450 enzymes. CONCLUSIONS These data suggest that no dose adjustment of Niaspan® is necessary in patients with renal impairment. Despite an extended-release formulation of NA, we could not detect a delay in t(max) especially in dialysis patients. We found no correlation between the incidence of flush and the NUA concentration. Furthermore, there were hints of an interaction with omeprazole.