Anti-TB drug concentrations and drug-associated toxicities among TB/HIV-coinfected patients.

Background: Toxicities due to anti-TB treatment frequently occur among TB/HIV-coinfected patients. Objectives: To determine the association between anti-TB drug concentrations and the occurrence of hepatotoxicity and peripheral neuropathy among TB/HIV-coinfected patients. Methods: TB/HIV-coinfected patients were started on standard dose anti-TB treatment according to WHO guidelines. Anti-TB drug concentrations were measured using HPLC 1, 2 and 4 h after drug intake at 2, 8 and 24 weeks following initiation of TB treatment. Participants were assessed for hepatotoxicity using Division of AIDS toxicity tables and for peripheral neuropathy using clinical assessment of tendon reflexes, vibration sensation or symptoms. Cox regression was used to determine the association between toxicities and drug concentrations. Results: Of the 268 patients enrolled, 58% were male with a median age of 34 years. Participants with no hepatotoxicity or mild, moderate and severe hepatotoxicity had a median C max of 6.57 (IQR 4.83-9.41) µg/mL, 7.39 (IQR 5.10-10.20) µg/mL, 7.00 (IQR 6.05-10.95) µg/mL and 3.86 (IQR 2.81-14.24) µg/mL, respectively. There was no difference in the median C max of rifampicin among those who had hepatotoxicity and those who did not ( P = 0.322). There was no difference in the isoniazid median C max among those who had peripheral neuropathy 2.34 (1.52-3.23) µg/mL and those who did not 2.21 (1.45-3.11) µg/mL ( P = 0.49). Conclusions: There was no association between rifampicin concentrations and hepatotoxicity or isoniazid concentrations and peripheral neuropathy among TB/HIV-coinfected patients.

Treatment of gout in a renal transplant patient leading to severe thrombocytopenia.

WHAT IS KNOWN AND OBJECTIVE: Allopurinol (AP) inhibits the xanthine oxidase, which may indirectly lead to myelotoxicity when used in combination with azathioprine (AZA). CASE SUMMARY: A 79-year-old female developed symptomatic thrombocytopenia after combination therapy with AZA (75 mg/day) and AP (100 mg/day) - after AP had been stopped. Concentrations of the myelotoxic 6-thioguanine-nucleotides metabolite of AZA were increased. Thrombocyte counts normalized within 8 days of discontinuation of AZA. WHAT IS NEW AND CONCLUSION: The effect of a drug interaction in a patient with decreased elimination capacity may take several weeks to become apparent and may in fact do so even after the drug has been stopped. Concurrent AZA and AP therapy demands cautious use.

[Antibiotic therapy: impact and resistance]. / Antibiotikatherapie: Wirkung und Resistenz.

BACKGROUND: Many achievements in modern medicine, such as in transplantation medicine, cancer therapy, surgery, and intensive care medicine would have been impossible without effective treatment of bacterial infections. Antibiotic resistance is on the rise; the reasons for this are complex and vary greatly. OBJECTIVE: Knowledge about the impact of antibiotics and mechanisms of antibiotic resistance, which are the cornerstones of calculated and targeted antibiotic therapy, is imperative. RESULTS: This review describes the pharmacodynamics of relevant antibiotics in emergency and intensive care medicine. Commonly resistant bacteria with clinical relevance and the respective mechanisms of resistance are highlighted. Furthermore, the use of antiinfectives for reserve treatment of severe infections is discussed. CONCLUSION: Understanding the mechanisms of resistance and effects of antibiotics are fundamental for efficient and successful treatment of bacterial infections and for the reduction of resistant species.

Experience with daptomycin daily dosing in ICU patients undergoing continuous renal replacement therapy.

PURPOSE: For critically ill patients undergoing continuous renal replacement therapy (CRRT), daptomycin dosing recommendations are scarce. We, therefore, retrospectively assessed routinely measured daptomycin plasma concentrations, daptomycin dose administered and microbiological data in 11 critically ill patients with Gram-positive infections that had received daptomycin once daily. METHODS: The retrospective analysis included critically ill patients treated at the intensive care unit (ICU) who had daptomycin plasma concentrations measured. RESULTS: Daptomycin dose ranged from 3 to 8 mg/kg/q24 h in patients undergoing CRRT (n = 7) and 6 to 10 mg/kg/q24 h in patients without CRRT (n = 4). Peak and trough concentrations showed a high intra- and inter-patient variability in both groups, independent of the dosage per kg body weight. No drug accumulation was detected in CRRT patients with once-daily daptomycin dosing. Causative pathogens were Enterococcus faecium (n = 6), coagulase-negative Staphylococcus (n = 2), Staphylococcus aureus (n = 2) and unknown in one patient. Microbiological eradication was successful in 8 of 11 patients. Two of three patients with unsuccessful microbiological eradication and fatal outcome had an Enterococcus faecium infection. CONCLUSION: In critically ill patients undergoing CRRT, daptomycin exposure with once-daily dosing was similar to ICU patients with normal renal function, but lower compared to healthy volunteers. Our data suggest that daptomycin once-daily dosing is appropriate in patients undergoing CRRT.

[Clinically important food-drug interactions: what the practitioner needs to know]. / Alle Medikamente zum Frühstück?--Einfluss der Nahrung auf die Medikamentenwirkung.

Most medicines are taken with breakfast which is usually unproblematic and has the advantage of improving adherence through establishment of a daily routine. However, due to alterations in absorption from the gastrointestinal tract, there are a number of medicines that either lose (such as bisphosphonates) or gain (such as albendazole) efficacy if taken together with food. Food components can also affect drug-metabolising enzymes and even cause drug toxicity (alcohol and grapefruit juice are notable examples). Conversely, drugs such as monoamine oxidase inhibitors can inhibit the metabolism of tyramine in tyramine-rich foods and lead to adverse circulatory reactions. These and other examples of when the ingestion of medication together with food can cause clinically relevant problems are discussed in this article.

Pharmacokinetics and pharmacodynamics of cinacalcet in patients with hyperparathyroidism after renal transplantation.

Cinacalcet is a calcimimetic drug for the treatment of secondary hyperparathyroidism (HPT). In a sequential open-label study, ten patients with persistent HPT after renal transplantation received first 30 and then 60 mg oral cinacalcet once daily over 2 weeks each. Cinacalcet steady state oral clearance was 131.1 +/- 20.9 l/h and 92.8 +/- 9.5 l/h (mean +/- SE) after 30 and 60 mg, respectively. Cinacalcet and parathyroid hormone (PTH) concentrations showed an inverse correlation and were fitted to a simple E(max) model (E(max) = 80% reduction vs. baseline, EC(50) = 13 ng/mL). A once daily administration of cinacalcet lowered serum calcium over 24 h without fluctuations. The 8-h fractional urinary excretion of calcium was increased after 60 mg cinacalcet (baseline 0.85 +/- 0.17%, 30 mg 1.53 +/- 0.35%, 60 mg 1.92 +/- 0.37%). Renal function remained stable. Cinacalcet pharmacokinetics and pharmacodynamics showed a pronounced interindividual variability. We conclude that the once daily administration of cinacalcet in patients with secondary HPT after renal transplantation effectively reduced iPTH and serum calcium. The transient calciuria could potentially favor nephrocalcinosis and reduce bone mineral density, suggesting that higher doses of cinacalcet need to be used with caution in renal transplant recipients with severe persistent hyperparathyroidism.

[Neuroleptic malignant syndrome after 30 years treatment with clozapine: a rarely seen differential diagnosis on intensive care units]. / Malignes neuroleptisches Syndrom nach 30-jähriger Behandlung mit Clozapin: Eine seltene Differenzialdiagnose auf der Intensivstation.

The neuroleptic malignant syndrome (NMS) is a rare, but potentially lethal side effect of conventional and atypical antipsychotic drugs. We present a 62 years old male patient who was admitted to our institution because of sudden onset of mild hyperthermia, muscle rigidity, stupor, leucocytosis and massive rhabdomyolysis after 30 years uneventful treatment with clozapine. The medication with clozapine was suspended because of the suspicion of NMS. When the acute symptoms were abated, the treatment with clozapine was resumed again after 14 days. The very next day, the patient suffered again from raised body core temperature, leucocytosis, elevated serum creatine kinase and new catatonia. The therapy with clozapine was stopped definitively and benzodiazepines were administered assuming a relapse of an alleviated, probably reconvening NMS. Under the treatment with benzodiazepines the patient was free of symptoms even after 1 month. To our knowledge, the latency of 30 years between the beginning of the treatment with clozapine and the onset of NMS is the longest period in the literature. According to our case, the differential diagnosis of NMS is not always trivial and is therefore discussed.

Mutagenesis of 16S rRNA C1409-G1491 base-pair differentiates between 6'OH and 6'NH3+ aminoglycosides.

Using a single rRNA allelic Gram-positive model system, we systematically mutagenized 16S rRNA positions 1409 and 1491 to probe the functional relevance of structural interactions between aminoglycoside antibiotics and the A-site rRNA that were suggested by X-ray crystallography. At the structural level, the interaction of the 2-deoxystreptamine aminoglycosides with the rRNA base-pair C1409-G1491 has been suggested to involve the following features: (i) ring I of the disubstituted 2-deoxystreptamines stacks upon G1491 and H-bonds to the Watson-Crick edge of A1408; (ii) ring III of the 4,5-disubstituted aminoglycosides shows hydrogen bonding to G1491. However, we found that mutants with altered 16S rRNA bases 1409 and 1491 discriminated poorly between 4,5-disubstituted and 4,6-disubstituted 2-deoxystreptamines, but differentially affected aminoglycosides with a hydroxyl group versus an ammonium group at position 6' of ring I, e.g. G1491U conferred high-level drug resistance to paromomycin and geneticin, but not to neomycin, tobramycin or gentamicin.

Fosfomycin for the initial treatment of acute haematogenous osteomyelitis.

BACKGROUND AND AIMS: At our institution there has been a dichotomous antimicrobial treatment behaviour for acute haematogenous osteomyelitis (AHOM) since 1984. The surgical department favoured fosfomycin as initial choice and the medical department beta lactams. We aimed to compare the performance of both strategies. METHODS: Data from patients discharged with the diagnosis of AHOM between January 1984 and January 1998 were gathered from the charts by means of a questionnaire. Patients receiving fosfomycin treatment (FT) were compared with those receiving fosfomycin plus other antimicrobials (FT+) and those receiving no fosfomycin treatment (NFT). RESULTS: A total of 103 patients aged 0.1-15.5 years (mean 6.5, median 6.9) with AHOM received no surgical treatment initially. In 23 (22.3%) FT was instilled initially, in 47 (45.6%) FT+, and in 33 (32.0%) NFT. The pathogen was established in 30%, 36%, and 42% of FT, FT+, and NFT patients, respectively, Staphylococcus aureus being the predominant isolate. Mean C reactive protein levels and erythrocyte sedimentation rates normalised in all treatment groups after two and four weeks, respectively. The mean duration of intravenous antimicrobial treatment in FT patients was 2.5 weeks, in FT+ patients 3.1 weeks, and in NFT patients 3.8 weeks (p < 0.05), whereas the mean duration of intravenous plus oral treatment was comparable (7.1 v 6.8 v 6.5 weeks). CONCLUSIONS: The leucocyte penetrating fosfomycin performed similarly to extracellular beta lactams in the treatment of AHOM. Intravenous treatment for longer than 2.5 weeks offered no advantage.