[Rhinocerebral Mucormycosis]. / Rhinocerebrale Mucormykose.

Mucormycosis is a rare but serious type of fungal infection, which can progress rapidly especially in immunsupressed patients.We report about a 47 year old female patient with ptosis on the left eye. The ophthalmological report offered no further pathologic findings. Diabetes mellitus was known and the blood sugar value was very high.A computed tomography of the paranasal sinuses showed a shadow in the ethmoid bone and in an additonally performed MRI-scan, an increase of orbital fat and an extension of the ocular muscle were visible.As the patient lost her ability o look above, an operation of the paranasal sinus was done.The microbial results revealed a Mucormycosis (Lichtheimia). As the patient went blind in the further course, indication for orbital exenteration on the left side and revision of the paranasal sinus was given. High doses of Liposomal Ampthotericin B and Posaconazol were given and blood sugar was monitored very strictly. MRI-scans revealed a further progression of the infection and required additional surgeries and a dura resection accompanied by complications like recurrent septical episodes, renal insufficiency, a bifrontal epidural hematoma and multiple cerebral microinfarcts that impeded the recovery of our patient in the further course. After 8 months she was able to leave the hospital, an epithesis was adjusted and she is without a relapse for 24 month since the diagnosis.

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.

Stability of ceftolozane in human plasma and dried blood spots: Implications for transport and storage.

Ceftolozane is a newer ß-lactam antibiotic drug effective against gram-negative pathogens. Its pharmacokinetic parameters are dominated by the patients' kidney function. Consequently, in patients with impaired kidney function or those who are treated with different forms of renal replacement therapy, therapeutic drug monitoring (TDM) of ceftolozane is strongly recommended to enhance safety and efficiency of the antibiotic treatment. Various methods for the quantification of ceftolozane in plasma samples have been described utilizing HPLC-UV or LC-MS/MS. However, all these methods are impaired by the instability of ceftolozane in plasma samples. In this work, we have determined the stability of ceftolozane in human plasma at temperatures of 40 °C, 23 °C, 6 °C and - 20 °C. At 6 °C and - 20 °C, ceftolozane was stable in human plasma over the observed time range of 7 days. At 23 °C and 40 °C, plasma samples were of acceptable (i.e. less than 15% decay) stability over time ranges of 71.2 h and 5.6 h, requiring expedited sample transport to the laboratory. Dried blood spots (DBS) were reported in the literature as matrix with beneficial properties regarding stabilities of ß-lactam antibiotics. However, in this study we found that ceftolozane was of inferior stability in this matrix in comparison to plasma. Thus, DBS cannot be recommended as matrix for ceftolozane in TDM.

Stability of meropenem in plasma versus dried blood spots (DBS).

Meropenem, a beta-lactam antibiotic belonging to the group of carbapenems, is widely used in the treatment of serious and complicated infections. Therapeutic drug monitoring (TDM) is strongly recommended to achieve therapeutic success, but the limited stability of the drug in plasma makes transport between clinic and laboratory difficult. The aim of this study was to investigate whether the stability of meropenem was improved in dried blood spots (DBS) and whether sample transport between clinic and laboratory could be simplified by using this medium. Meropenem was quantified in DBS punch-out discs after extraction into acetonitrile - water (70:30 v:v) containing the internal standard D6-meropenem. The extracts were analyzed by hydrophilic interaction liquid chromatography (HILIC) coupled to tandem mass spectrometry (MS/MS). The calibration function was linear in the range of 0.5-50 µg/mL. Intra-day coefficients of variation were better than 12% with accuracies better than 5%. The corresponding inter-day values were better than 7% and 6%, respectively. Meropenem was stable for at least 7 days on DBS at -20 °C and 6 °C, whereas in plasma at 6 °C, meropenem showed a decay of <15% in 4 d. Stored at 23 °C, loss of <15% were observed during 11 h in plasma and about 48 h in DBS, allowing for DBS sample transport by mail. A pilot study with intensive care patients receiving meropenem (n = 33) showed that, after correction for hematocrit, plasma concentrations can be successfully calculated from the DBS quantification results, making DBS potentially applicable for TDM purposes.

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.

Determination of ornithine in human plasma by hydrophilic interaction chromatography-tandem mass spectrometry.

The amino acid ornithine (Orn) acts as a vital part in the physiologically fundamental urea cycle. As such, it is a main intermediate in the catabolic breakdown as well as in the synthesis of arginine and is involved in many other metabolic pathways with potential clinical implications. We here describe a LC-MS-MS method for the detection of Orn in human plasma which is fast, easy and precise. The sample preparation comprises only protein precipitation and the addition of the isotopic labeled I.S. The analytes are separated by hydrophilic interaction chromatography (HILIC) in less than 4min on a silica column with an isocratic mobile phase consisting of 0.1% trifluoroacetic acid in water and acetonitrile in the ratio of 25:75. Orn and its I.S. are detected and quantified by APCI tandem mass spectrometry. The calibration function is linear from 7.5 to 205 micromol/l and covers the range of concentrations found in patients undergoing different clinical interventions. The quantification results are independent with regard to the biological matrix analyzed. The intra-day and inter-day relative standard deviations are 1.1% and 3.5%, respectively. As an application of the described method in clinical investigations, we report arginine and ornithine plasma concentration results from an arginine supplementation study enrolling healthy volunteers and patients suffering from hypercholesterolemia. After oral dosing of 110 mg/kg arginine, ornithine plasma concentrations rose from 54 to 148 micromol/l after 2h and were back to baseline after 24h. However, arginine to ornithine ratios kept constant during the complete observation time.

Enantioselective quantification of omeprazole and its main metabolites in human serum by chiral HPLC-atmospheric pressure photoionization tandem mass spectrometry.

Omeprazole is a proton pump inhibitor drug in widespread use for the reduction of gastric acid production. It is also proposed as a test substance for the phenotyping of cytochrome CYP3A4 and CYP2C19 enzyme activities. For this purpose, it is necessary to quantify, additionally to omeprazole, the two main metabolites 5-hydroxyomeprazole and omeprazole-sulfon in human plasma. Since omeprazole is a racemic mixture of two enantiomers and its enzymatic decomposition depends in part on its chiral configuration, full information about its metabolic breakdown can only be gained by enantioselective quantification of the drug and its metabolites. We introduce a new LC-MS/MS method that is capable to simultaneously quantify omeprazole and its two main metabolites enantioselectively in human serum. The method features solid-phase extraction, normal phase chiral HPLC separation and atmospheric pressure photoionization tandem mass spectrometry. As internal standards serve stable isotope labeled omeprazole and 5-hydroxyomeprazole. The calibration functions are linear in the range of 5-750 ng/ml for the omeprazole enantiomers and omeprazole-sulfon, and 2.5-375 ng/ml for the 5-hydroxyomeprazole enantiomers, respectively. Intra- and inter-day relative standard deviations are <7% for omeprazole and 5-hydroxyomeprazole enantiomers, and <9% for omeprazole-sulfon, respectively.

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.

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.

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 ß-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.

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.