[Non-parametric estimation of pharmacokinetic parameters of amikacin in patients with non-insulin-dependent diabetes mellitus]. / Estimation non paramétrique des paramètres pharmacocinétiques de l'amikacine chez des patients diabétiques non insulino-dépendants.

To establish a reference for MAP Bayesian adaptive control of amikacin therapy in non-insulin-dependent diabetic patients, 30 patients (age: 63.5 +/- 10.1 years) were studied. Weight (84.2 +/- 15.4 kg) and body mass index (28.0 +/- 4.3 kg/m2 for males and 30.5 +/- 6.4 kg/m2 for females) were stable during treatment. Creatinine clearance (CCr) was 70.3 +/- 27.2 ml/min/1.73 m2 before treatment and 69.6 +/- 24.3 ml/min/1.73 m2 (NS) at the end of treatment (2 to 15 days). 129 serum concentrations were drawn (4.8 +/- 2.6 levels per patient). The one-compartment model was parameterized as having Vs (l.kg-1) and Kslope (min/ml.h) for each unit of CCr (Kel = Kintercept + Kslope x CCr). The non-renal Kintercept was fixed at 0.00693 h-1. The NPEM computes the joint probability densities. The mean, median, and SD were respectively: Vs = 0.3574, 0.3654, 0.0825 l.kg-1; Kslope = 0.0026, 0.0027, 0.0007 min/ml.h. For the a priori first doses determination, precision is higher with the new population. No difference in adaptive control was observed. In additive, the full joint density probability should be used to develop stochastic multiple model linear quadratic (MMLQ) adaptive control strategies.

Computation of drug concentrations in endocardial vegetations in patients during antibiotic therapy.

The treatment of endocarditis often requires prolonged antibiotic therapy. Individualized drug dosage regimens have made such therapy possible even in patients with impaired renal function. However, the problem of efficacy remains. Especially for aminoglycosides, it would be a useful guide to have at least an approximate idea of the concentration of an antibiotic within an endocardial vegetation. This study was designed to develop software to model the drug concentrations at different layers within spherical vegetations to provide a guide during clinical therapy of patients with endocarditis. A general model describing the diffusion of antibiotics in spheres has now been developed and interfaced with the USC*PACK PC Clinical Programs in order to compute and plot concentrations, within the vegetation, based on the regimen given to the patient and the diffusitivity of the antibiotic into the vegetation. Some preliminary results of this research, which are still in progress, are presented. Diffusion into simulated spherical vegetations has been computed for different treatment regimens for endocarditis: amikacin or netilmicin and vancomycin were given to three elderly patients (3 women, 74, 75 and 92 years old, with initial estimated creatinine clearances of 51, 36, and 31 ml/min/1.73 m2, respectively). Although Amikacin has a low diffusivity, the concentrations, even in the center of the vegetation, appear to be effective. The effects of various regimens, including a 'once-a-day' aminoglycoside regimen, are presented.

[Adaptive control of therapeutics using amikacin in very old patients: retrospective analysis of efficacy and toxicity]. / Contrôle adaptatif des thérapeutiques par l'amikacine chez des patients très âgés: analyse rétrospective de l'efficacité et de la toxicité.

UNLABELLED: The authors previously showed the precision of adaptive control of amikacin therapy in elderly patients. The present retrospective study evaluated the effects of such therapy on outcomes. 48 patients, aged 80 +/- 5 years, with estimated creatinine clearance (eCCR) of 48 +/- 15 ml/mn, received amikacin initial dosage of 13.3 +/- 3.5 mg/kg/d, alone or with other drugs. Efficacy outcomes were: E1 = changes in dosage during therapy; E2 = fever reduction within 3 days after therapy; E3 = eradication of infection by culture data; E4 = reduction of white blood cell count (WCB) to normal; E5 = overall recovery. Toxicity outcomes were: T1 = subjective ototoxicity; T2 = nephrotoxicity, variation of serum creatinine low (between 18 et 44 mumol/l) or high (over 0.5 mg/dl). RESULTS: E1: final dose = 11.8 +/- 5.1 mg/kg/d (NS), 57% reduced, 33% increased, during 15.1 +/- 9.3 days in therapy, with 88% having effective peaks over 15 micrograms/ml. E2: fever reduced within 3 days 16/37; after 12/37; no change, 9/37. E3: cultures became negative, 13/28. E4: WBC fell early, 10/21; late, 7/21; no change, 2/21. E5: recovery 36; death, 8; change in therapy, 3. T1: no clinical signs of ototoxicity. T2: low(+), 9/51; low(-), 11/51; high(-), 7/51. final eCCR: 48 +/- 14 ml/mn (NS); no nephrotoxicity. These results suggest that adaptive control of amikacin regimens yields good efficacy and avoid toxicity in the Elderly. However, prospective controlled clinical trials should be done for confirmation.

[Aminoglycoside determinations calculated in endocarditis vegetations. Relations with clinical practices during infectious endocarditis treatment with amikacin]. / Concentrations calculées en aminoside dans des végétations d'endocardites. Relations avec les pratiques cliniques lors du traitement d'endocardites infectieuses par l'amikacine.

Using a new computer program SPHERE, amikacin concentrations have been computed at various layers of simulated endocardial vegetations. Inputs are the computed serum (central compartment) concentrations of either population pharmacokinetic models or of individualized patient-specific models utilizing Bayesian fitting to data of doses given and measured serum levels, using the USC*PACK PC Clinical Programs. The vegetation is modeled as an isotropic homogeneous sphere. Fick's second law of radial diffusion was applied to compute the in situ antibiotic concentrations. Examination of factors affecting concentrations in vegetations shows that in situ peak concentrations are less when the vegetation is larger, and when the antibiotic dose, serum concentrations and diffusivity are all less. The results show that early and aggressive treatment of infectious endocarditis is required with high doses of concentration-dependent antibiotics, such as aminoglycosides, to achieve the desired high peak serum levels and to reach effective concentrations deep inside the vegetations.