High-dose continuous oxacillin infusion results in achievement of pharmacokinetics targets in critically ill patients with deep sternal wound infections following cardiac surgery.

Knowledge regarding antimicrobial therapy strategies in deep sternal wound infections (DSWI) following cardiac surgery is limited. Therefore, we aimed to determine the steady-state plasma and mediastinal concentrations of oxacillin administered by continuous infusion in critically ill patients with DSWI and to compare these concentrations with the susceptibility of staphylococci recovered. A continuous infusion of oxacillin (150 to 200 mg/kg of body weight/24 h) was administered after a loading dose (50 mg/kg). Plasma and mediastinal concentrations of total and unbound oxacillin were determined 4 h after the loading dose (H4) and then at day 1 (H24) and day 2 (H48). Twelve patients were included. Nine patients exhibited bacteremia, 5 were in septic shock, 8 were positive for Staphylococcus aureus, and 4 were positive for coagulase-negative staphylococci. The median MIC (first to third interquartile range) was 0.25 (0.24 to 0.41) mg/liter. Median plasma concentrations of total and unbound oxacillin at H4, H24, and H48 were, respectively, 64.4 (41.4 to 78.5) and 20.4 (12.4 to 30.4) mg/liter, 56.9 (31.4 to 80.6) and 21.7 (6.5 to 27.3) mg/liter, and 57.5 (32.2 to 85.1) and 20 (14.3 to 35.7) mg/liter. The median mediastinal concentrations of total and unbound oxacillin at H4, H24, and H48 were, respectively, 2.3 (0.7 to 25.9) and 0.9 (<0.5 to 15) mg/liter, 29.1 (19.7 to 38.2) and 12.6 (5.9 to 19.8) mg/liter, and 31.6 (14.9 to 42.9) and 17.1 (6.7 to 26.7) mg/liter. High-dose oxacillin delivered by continuous infusion is a valuable strategy to achieve our pharmacokinetic target (4× MIC) at the site of action at H24. But concerns remain in cases of higher MICs, emphasizing the need for clinicians to obtain the MICs for the bacteria and to monitor oxacillin concentrations, especially the unbound forms, at the target site.

Complicated atazanavir-associated cholelithiasis: a report of 14 cases.

Fourteen human immunodeficiency virus (HIV)-infected patients receiving an atazanavir (ATV)-based antiretroviral regimen developed complicated cholelithiasis. ATV was found in biliary calculi in 8 of 11 cases: infrared spectrometry analysis of calculi revealed that ATV made up a median of 89% (range, 10%-100%) of the total calculus composition. Development and management of ATV-associated cholelithiasis are discussed.

[Therapeutic drug monitoring of stiripentol]. / Suivi thérapeutique pharmacologique du stiripentol.

Stiripentol is a third generation antiepileptic, marketed since 2007 under the name of Diacomit(®). It is indicated, always in combination, in the treatment of severe myoclonic epilepsy in infancy or Dravet syndrome. Its pharmacokinetics is not linear. It is a potent inhibitor of CYP3A4, 1A2 and 2C19 and increases the plasma concentrations of many other antiepileptic drugs. Without this being considered as a validated therapeutic range, the trough plasma concentrations at steady-state, corresponding to the usual doses are between 10 and 15 mg/L. The concentration-efficacy relationship is not established, but there is some evidence for a concentration-related toxicity. However, because of its non-linear kinetics, stiripentol should be a good candidate for therapeutic drug monitoring (TDM). Nonetheless, the current level of evidence for the advantage of TDM is "remains to be estimated".

[Therapeutic drug monitoring of rufinamide]. / Suivi thérapeutique pharmacologique du rufinamide.

Rufinamide is a third-generation antiepileptic drug, available since early 2010 in France. It is indicated in combination therapy in the Lennox-Gastaut syndrome from the age of 4. It has orphan drug status. The bioavailability of rufinamide is high, but decreases with the dose and increases with food intake. Rufinamide is not metabolized by cytochromes but hydrolyzed by a carboxylesterase in an inactive carboxylic derivative. Elimination is mainly renal. The half-life varies from 6 to 10h. Although established from relatively few studies, exposure efficacy and exposure toxicity relationships are argued. A plasma concentration of 15 mg/L, obtained with a standard regimen, reduces the number of seizures of 25%. Few factors of intrinsic variability are described. There are few clinically significant pharmacokinetic interactions and they concern combinations with other antiepileptic drugs, especially valproate. Although there is no validated therapeutic range, the level of evidence for this therapeutic drug monitoring has been estimated at "possibly useful".

[Therapeutic drug monitoring of lacosamide]. / Suivi thérapeutique pharmacologique du lacosamide.

Lacosamide is a third generation antiepileptic drug, available in France since 2008. It is indicated in combination therapy for the treatment of inadequately controlled focal seizures, from the age of 16. The bioavailability of lacosamide is 100% and is unaffected by food intake; protein binding is low; it is metabolized by CYP2C19 into inactive O-desmethyl lacosamide. It does not inhibit or induce cytochromes; the elimination is renal with a half-life of approximately 13 h. The relationship between dose and plasma concentration is established, but there does not appear to be any clear relationship between concentration and efficacy. However, the main side effects are concentration dependent. The potential for drug-drug interaction of lacosamide is low and variability between individuals is minimal. Accordingly, the level of evidence for the therapeutic drug monitoring has been estimated at "probably of no use".

[Therapeutic drug monitoring of primidone and phenobarbital]. / Suivi thérapeutique pharmacologique de la primidone et du phénobarbital.

Primidone is a minor first-generation antiepileptic drug, little currently prescribed for this indication, but except marketing authorization, remains a first-line treatment of essential tremor. Although it is metabolized in phenyl-ethyl-malondamide and phenobarbital, active metabolites that contribute also to its action, primidone is not a prodrug and is active by itself. The rate of conversion of primidone to phenobarbital is highly variable according to the subject. Generally accepted therapeutic range for primidone is between 5 and 10 mg/L (23-46 mmol/L). The therapeutic drug monitoring (TDM) of primidone must be accompanied by the determination of phenobarbital concentrations. The level of proof of the interest of the TDM primidone was estimated to be "probably useless". Phenobarbital, a very ancient anticonvulsant, is much less used today, for the benefit of other more recent compounds. It remains prescribed in neonatology and is one of the compounds used in status epilepticus. It is a molecule with a long half-life, metabolized in p-hydroxy-phenobarbital. It is a potent inducer of CYP3A4. Several side effects, especially drowsiness, are concentration-dependent. Generally accepted therapeutic range for phenobarbital is between 10 and 40 mg/L (43 - 172 mmol/L), without considering the type of crise. The level of proof of the interest of TDM of phenobarbital was evaluated as "recommended".

[Therapeutic drug monitoring of ethosuximide]. / Suivi thérapeutique pharmacologique de l'éthosuximide.

Ethosuximide is a minor antiepileptic drug, available in France since 1965, indicated in the epilepsy absence, whose interest was reassessed from recent clinical trials, showing that it was the first choice, in term of risk benefit relationship, in this indication. It is a chiral molecule that presents a high bioavailability, a lack of protein binding, hepatic metabolism and urinary excretion. Its elimination half-life is long, between 40 and 60 h in adults, 30 and 40 h in children. The therapeutic range is established at 40-100 mg/L (283-708 µmol/L), but the upper limit is probably underestimated. The clinical studies of relation exposure effects, although ancient (from the 1970s) and realized with methodologies that do not meet current criteria, show concentration-efficacy and -toxicity relationship and the risk of drug interactions is proven. It is a drug preponderantly prescribed in children, a vulnerable population with physiological change with age. To benefit at best of its effectiveness, it is necessary to have relatively high plasma concentrations. Despite these arguments and due to the lack of studies providing a sufficient level of evidence, the recommendation can only be "potentially useful", assessment probably underestimated.

[Level of evidence for therapeutic drug monitoring of ceftriaxone]. / Niveau de preuve du suivi thérapeutique pharmacologique de la ceftriaxone.

Ceftriaxone is a third generation cephalosporin with an original pharmacokinetics based on a long elimination half-life among cephalosporins, a high protein binding and a dual renal and biliary elimination. Also the pharmacokinetic parameters of ceftriaxone are highly variable in clinical situations such as severe renal insufficiency, liver and renal insufficiency, the elderly, the neonates less than 1 week of age and critically ill patients. In these clinical situations associated or not with high minimal inhibitory concentration (MIC) level, the relationship concentration-clinical outcome based on the ratio between trough plasma concentration and MIC can allow a dose adjustment. Consequently, therapeutic drug monitoring (TDM) of ceftriaxone could be possibly useful in these situations, whereas the necessity of TDM has still to be demonstrated to monitor toxicity.

Simultaneous determination of 12 beta-lactam antibiotics in human plasma by high-performance liquid chromatography with UV detection: application to therapeutic drug monitoring.

A rapid and specific high-performance liquid chromatography method with UV detection (HPLC-UV) for the simultaneous determination of 12 beta-lactam antibiotics (amoxicillin, cefepime, cefotaxime, ceftazidime, ceftriaxone, cloxacillin, imipenem, meropenem, oxacillin, penicillin G, piperacillin, and ticarcillin) in small samples of human plasma is described. Extraction consisted of protein precipitation by acetonitrile. An Atlantis T3 analytical column with a linear gradient of acetonitrile and a pH 2 phosphoric acid solution was used for separation. Wavelength photodiode array detection was set either at 210 nm, 230 nm, or 298 nm according to the compound. This method is accurate and reproducible (coefficient of variation [CV] < 8%), allowing quantification of beta-lactam plasma levels from 5 to 250 µg/ml without interference with other common drugs. This technique is easy to use in routine therapeutic drug monitoring of beta-lactam antibiotics.

Determination of daptomycin in human plasma by liquid chromatography-tandem mass spectrometry. Clinical application.

BACKGROUND: Daptomycin is a recently developed cyclic lipopeptide antibiotic active against most Gram-positive pathogens including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. To optimize treatment efficacy and safety, especially in patients undergoing multiple drug regimens and/or co-morbidities, a specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of daptomycin in plasma. METHODS: A C18 column was used for separation, with a mobile phase initially consisting of 0.1% formic acid, water, and acetonitrile (ACN) in a linear gradient from 20% to 70%. After protein precipitation with ACN, the clear upper layer was diluted in water:ACN (50:50, v/v) before injection. Detection was performed using an electrospray ionization technique. MS/MS transitions, monitored in the positive ion mode were m/z 811.1 → m/z 313.1 for daptomycin, and m/z 609.4 → m/z 194.9 for reserpine, used as internal standard. RESULTS: Elution of daptomycin and reserpine occurred at 4.5 and 3.9 min, respectively. The method was validated over a range of concentrations from 1 mg/L to 120 mg/L. The assay met recommended acceptance criteria: coefficients of variation were <6.3% and <7.4%, and accuracies were between -5.9% and +11.2% and between -3.5% and +3.7%, for intra- and inter-day validations, respectively. CONCLUSIONS: This method appears well-adapted to routine hospital practice for therapeutic drug monitoring of daptomycin considering its time of analysis, range of concentrations measured, precision and accuracy.

[Therapeutic drug monitoring of quinine]. / Suivi thérapeutique pharmacologique de la quinine.

Quinine is an antimalarial agent whose main mechanism of action on Plasmodium is to inhibit the transformation of toxic haem to polymeric non-toxic haemozoin. After oral and intramuscular administration, quinine is well absorbed, with peak plasma concentration reached in 1 to 3 hours. The pharmacokinetic of quinine differs depending on the severity of the disease: the volume of distribution and the clearance decrease proportionally to the infection, while the half-life increases. Plasma concentrations are approximately 50% higher in patients in the acute phase than in convalescence. Quinine is metabolized primarily by CYP3A4, implying changing the dosage when combined with inhibitors or inducers of CYP. The efficacy of quinine has been proved for residual concentrations above 5 mg/L (15 µmol/L) throughout the duration of treatment. Some side effects are concentration-dependent and a concentration of 20 mg/L (60 µmol/L) is considered as the threshold for toxicity. The 2007 consensus conference of the French Language Infectious Diseases Society calls for daily monitoring of plasma concentrations during the first 3 days of treatment targeting a trough concentration between 10 and 12 mg/L (30-36 µmol/L). For this compound, the level of evidence of the interest of therapeutic drug monitoring has been evaluated and the latter is recommended.

[Level of evidence for therapeutic drug monitoring of low dose methotrexate in inflammatory diseases]. / Suivi thérapeutique pharmacologique du méthotrexate à faible dose dans les maladies inflammatoires.

Methotrexate is prescribed to low-dose, ranging from 7.5 mg to 15 mg and until 25 mg if necessary, pulse once a week, in inflammatory pathologies, in particular in rheumatoid arthritis and psoriasis. The therapeutic answer and the frequency of adverse reactions are very variable from a patient to the other one, consequences of a large interindividual variability of the pharmacokinetic parameters of methotrexate, in particular bioavailability, suggesting a genetic support. Numerous polymorphisms being involved (carriers of influx and efflux, enzymes of the metabolism and of the mechanism of action of methotrexate), their determination with the aim of an individualized prescription does not seem realistic at the moment. On the other hand, an exposure-effect relationship, not so much by considering the plasma concentrations of methotrexate, but those of its polyglutamate derivatives in red blood cells, was described. Their determination should be able to contribute to a faster adaptation of dosages, or to a well-argued change of molecule in case of non clinical response. Although other studies are necessary to specify which markers would be the most relevant, which would be the best moment for their determination and to refine the therapeutic range, this approach seems promising. But currently, the level of proof of the therapeutic drug monitoring of low dose methotrexate in inflammatory disease was classified "remaining to evaluate".

Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock.

BACKGROUND: Severe sepsis results in a sustained deleterious immune dysregulation. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism, plays a pivotal role in immune tolerance and is induced during various inflammatory conditions. METHODS: Plasma samples obtained from patients with septic shock (n = 38), severe sepsis (n = 35), or sepsis (n = 10) and from healthy donors (n = 26) were analyzed for IDO activity by high-performance liquid chromatography. Lymphocyte, monocyte, and regulatory T cell counts as well as monocytic human leukocyte antigen DR (HLA-DR) expression were quantified by flow cytometry. Peripheral blood mononuclear cells and purified CD14(+) and CD14(-) fractions were assayed in vitro for spontaneous and inducible IDO expression and activity. RESULTS: IDO activity gradually increased according to sepsis severity, and septic patients who died had higher IDO activity on admission than did survivors (P = .013). Monocytes were a major source of active IDO in normal peripheral blood. The percentage and absolute number of circulating CD14(+) cells were increased in septic patients, and their monocytes remained fully able to produce functional IDO after NF-kappaB-independent interferon gamma stimulation but not through NF-kappaB-dependent Toll-like receptor engagement. CONCLUSIONS: IDO activity is increased during severe sepsis and septic shock and is associated with mortality. IDO production could be used to better characterize monocyte reprogramming in sepsis.

Liquid chromatography-tandem mass spectrometry method for simultaneous quantification of four triazole antifungal agents in human plasma.

BACKGROUND: Invasive fungal infections are an increasing cause of morbidity and mortality. Triazole antifungal agents are recommended for the prevention and treatment of such infections. Their broad inter- and intra-individual pharmacokinetic variability and the high probability of drug-drug interactions justify therapeutic drug monitoring (TDM). We developed a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of four triazole antifungal agents (fluconazole, itraconazole, posaconazole, voriconazole) and one of their metabolites (hydroxy-itraconazole) in human plasma. METHODS: After protein precipitation with acetonitrile (ACN), a C18 column was used for separation with a mobile phase consisting of 0.1% formic acid, water and ACN in a linear gradient from 20% to 70%, over 10 min. Detection was performed by electrospray ionization and quantification was performed using selected reaction monitoring transitions. RESULTS: Total run time was 15 min. The method was validated for a range of 0.1-12 µg/mL. Coefficients of variation were <9.5% and <13.8%, and accuracies were between -5.4% and +7.7% and between -10.8% and +10.4%, for intra- and inter-day validations, respectively. CONCLUSIONS: This method appears to be well suited to routine hospital practice for the TDM of triazole antifungal agents considering its time of analysis, range of concentrations measured, precision and accuracy.

[Therapeutic drug monitoring of valproate]. / Suivi thérapeutique pharmacologique du valproate.

Valproic acid is an anticonvulsant drug available in France since 1967. It is a broad spectrum molecule indicated in various forms of epilepsy of the adult and the child, but it is also prescribed in the treatment of different other pathologies of nervous system. The divalproate sodium is indicated in the treatment of bipolar disorders. The valproic acid is marketed under various pharmaceutical forms, with different corresponding tmax values. But, whatever the administered preparation, the circulating active molecule is the ion valproate. Elimination half-life is from 11 to 20 h. Metabolization of valproate is important and represents its main route of elimination. Valpromide is comparable to a prodrug which metabolizes in valproate. The inter and intraindividual variability of the plasma concentrations are important. Several studies show a concentration-effect relationship, but two interventional trials ended in the lack of interest of the Therapeutic Drug Monitoring (TDM), although it is of current practice. However, numerous drug interactions may modify the plasma concentrations of valproate. The therapeutic range is from 50 to 100 mg/L (346-693 micromol/L). The level of proof of the interest of the TDM for this molecule was estimated in: recommended.

[Not Available]. / Suivi thérapeutique pharmacologique du topiramate.

Topiramate, a second generation anticonvulsant drug, is marketed in France since 1997. It is also indicated in the prophylaxis of headache and is used, except legal notices, in the treatment of neuropathic pains and bipolar disorders. The efficiency and the risk of adverse reactions are dose dependent. However, the good correlation between the dosage and the plasmatic concentrations, and the relatively low interindividual variability, when we take into account the age and the association with an enzyme inducer, are not in favour of the interest of a dosage. Furthermore, there is a covering range between the effective and not effective concentrations, and levels susceptible or not to facilitate the appearance of an adverse event. There is no validated therapeutic range, but to the usual dosages the plasma concentrations are included between 5 and 20 mg/L(15-60 |imo]/L), mostly in the low part of this interval. For this molecule, the level of proof of the interest of the TDM was estimated in: possibly useful.

[Not Available]. / Suivi thérapeutique pharmacologique du vigabatrin.

Vigabatrin is a second generation anticonvulsant drug available in France since 1995. It is an amino acid analogue of the GABA, marketed under the racemic form [R(-)/S(+)50/50], but only the S(+)-enantiomer is active. Neither the mechanism of action of vigabatrin, an irreversible enzymatic inhibition, nor its pharmacokinetic characteristics (no binding to plasma proteins, low metabolism, no interaction with CYP), are in favour of TDM. There is no validated therapeutic range, but to the recommended dosage of 1 to 3g a day correspond plasma concentrations ranging from 0,8 to 36 mg/L (6 - 279 µmol/L). For this molecule, the level of proof of the interest of the TDM was estimated in: to be useless.

Suivi thérapeutique pharmacologique du zonisamide.

Zonisamide is a second generation antiepileptic drug available in France since 2005. It provides a mechanism of action similar to those of phenytoin or carbamazepine. It is indicated in association in the treatment of partial epilepsy with or without secondary generalization. Zonisamide is well absorbed with maximum concentration achieved in 2 to 5h. It is partly metabolized by the CYP3A4. Its elimination half-life is very long, around 60h. Studies in adults and children show low concentration-efficacy and concentration-toxicity correlations, but a therapeutic range has been determined between 10 and 40 mg/L. Zonisamide is sensitive to the inductive molecules of CYP which will increase its clearance and decrease its half-life. A specific monitoring of patient is recommended in renal impairment. For this molecule, the interest of TDM has been evaluated: possibly useful.

Suivi thérapeutique pharmacologique de la lamotrigine.

Lamotrigine is a second generation anticonvulsant drug available in France since 1996. As other anticonvulsant drugs, lamotrigine is also used in type I bipolar disorders and except legal notices, in the treatment of neuropathic pains. It is mainly metabolized by the UDP-glucuronyltransferase in inactive metabolites. Its average half-life of elimination is of the order of 22 h, but it is reduced approximately at 14h if it is associated with enzymatic inductors and increased at 70h if lamotrigine is administered with sodium valproate. The pharmacokinetic parameters are modified at the young child's, but not in the old population. During the pregnancy, the plasmatic concentrations are lowered and re-increase strongly after the delivery, if dosages were adapted. The renal insufficiency does not require adaptation of dosage, on the other hand in case of severe hepatic insufficiency a decrease of the dose is to be considered. The correlation concentration-efficiency does not seem demonstrated, but there are not enough published studies and they included few patients. Furthermore, they were led with a methodology more pragmatic than rigorous. The correlation concentration-toxicity is better argued. The recommended therapeutic range is from 2.5 to 15 mg/L. For this molecule, the level of proof of the interest of the TDM was estimated in: possibly useful.

Suivi thérapeutique pharmacologique du felbamate.

Felbamate is a derivative of meprobamate used in second-line partial epilepsy and in the Lennox-Gastaut syndrome. Felbamate is well absorbed and has linear kinetics: Cmax and AUC increasing linearly with dose. The metabolism takes place in the liver. Metabolites represent 40 to 60% of excretion and are eliminated via the urine. The half-life is between 15 and 23 hours. Clearance is dependent on renal function. There is a concentration - efficacy and concentration - toxicity relationship. These arguments are in favour of a TDM but the therapeutic range is not clearly established. Potentially fatal side effects can be caused by felbamate (aplastic anemia, acute liver failure), which limits its use because they are dose-independant.