A pilot study of 220 mg/m2 melphalan followed by autologous stem cell transplantation in patients with advanced haematological malignancies: pharmacokinetics and toxicity

We studied the pharmacokinetics and toxicity of 220 mg/m² melphalan (HDM 220) followed by autologous stem cell transplantation in 16 patients with advanced haematological malignancies. Pharmacokinetic parameters (mean values of steady-state volume of distribution 14.6 l/m², total body clearance 313 ml/min/m², elimination half-life 46 min) were the same as those of 140 or 200 mg/m² melphalan in previous reports. HDM 220 was feasible. Extramedullary toxicity was mainly W.H.O. grade 4 mucositis (13/16 patients). The median duration of 41 d (10, not reached) of thrombocytopenia <25 × 10⁹/l was long. In multiple myeloma the response rate was 89% in heavily pretreated patients, suggesting that HDM 220 could be considered earlier in the course of the disease as an alternative consolidation therapy.     

Population pharmacokinetics of imipenem in burn patients

The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a population pharmacokinetic approach, and (ii) to test the influence of factors on pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n = 47,118 samples) and analysed by a nonlinear mixed effect modelling method. Among the tested covariates (age, gender, body weight, height, size of burn and creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic parameters substantially. The best fit is obtained with a two-compartment model integrating a linear-inverse relationship between imipenem clearance and creatinine plasma level. The estimates of imipenem clearance (16.37 +/- 0.204 L/h) and of the distribution volume of the central compartment (0.376 +/- 0.039 L/kg) are higher in the population of burn patients than the estimates in healthy subjects. This result is connected with high values of glomerule filtration rate and confirms the interest of therapeutic drug monitoring of imipenem in burn patients and particularly for patients with extreme values of creatinine clearance.     

In vitro and in vivo synergistic activities of linezolid combined with subinhibitory concentrations of imipenem against methicillin-resistant Staphylococcus aureus

Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.     

Constant rate infusion of vancomycin in premature neonates: a new dosage schedule

Aims Since vancomycin's bactericidal action has been shown to be time-dependent, a constant rate infusion over 24  h might result in a better bactericidal efficacy. The purpose of this study was to define a new dosage schedule in prematures.
Methods Two vancomycin 24  h constant rate infusion schedules were tested in two groups of neonates. Postconceptional age (PCA) was 27 to 41 weeks in group 1 ( n =24) and 28 to 51.5 weeks in group 2 ( n =29). Group 1 neonates received continuous infusion of 10 to 30  mg  kg⁻¹ day⁻¹, adjusted for PCA and weight. Group 2 was designed to take into account the significant relationship observed in group 1 between vancomycin clearance standardized on weight and PCA and consisted of a constant loading dose of 7  mg  kg⁻¹ followed by continuous infusion of 10 to 40  mg  kg⁻¹ day⁻¹ adjusted for PCA and weight.
Results Mean vancomycin serum concentration at steady state was 11±3.1  mg  l⁻¹ in group 1 and 15.4±6.2  mg  l⁻¹ in group 2. Fifty-six percent of group 1 values vs 88% of group 2 values were between 10 and 30  mg  l⁻¹ at steady state ( P <0.01). Both regimens were well tolerated.
Conclusion A loading dose of vancomycin followed by constant rate infusion of the appropriate dose adjusted for PCA and weight might improve vancomycin concentrations in neonates.     

Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model.

Adaptive resistance following the first exposure to aminoglycosides is a recently described in vitro phenomenon in Pseudomonas aeruginosa and other aerobic gram-negative bacilli. We investigated the in vivo relevance of adaptive resistance in P. aeruginosa following a single dose of amikacin in the experimental rabbit endocarditis model. Rabbits with P. aeruginosa endocarditis received either no therapy (control) or a single intravenous (i.v.) dose of amikacin (80 mg/kg of body weight) at 24 h postinfection, after which they were sacrificed at 5, 8, 12, 16, or 24 h postdose. Excised aortic vegetations were subsequently exposed ex vivo to amikacin at 2.5, 5, 10 or 20 times the MIC for 90 min. In vivo adaptive resistance was identified when amikacin-induced pseudomonal killing within excised aortic vegetations was less in animals receiving single-dose amikacin in vivo than in vegetations from control animals not receiving amikacin in vivo. Maximal adaptive resistance occurred between 8 and 16 h after the in vivo amikacin dose, with complete refractoriness to ex vivo killing by amikacin seen at 12 h postdose. By 24 h postdose, bacteria within excised vegetations had partially recovered their initial amikacin susceptibility. In a parallel treatment study, we demonstrated that amikacin given once daily (but not twice daily) at a total dose of 80 mg/kg i.v. for 1-day treatment significantly reduced pseudomonal densities within aortic vegetations versus those in untreated controls. When therapy was continued for 3 days with the same total daily dose (80 mg/kg/day), amikacin given once or twice daily significantly reduced intravegetation pseudomonal densities versus those in controls. However, amikacin given once daily was still more effective than the twice-daily regimen. These data confirm the induction of aminoglycoside adaptive resistance in vivo and further support the advantages of once-daily aminoglycoside dosing regimens in the treatment of serious pseudomonal infections.     

Cyclosporine monitoring in renal transplant recipients with induction therapy: C2 levels in patients monitored on C0

The aim of this retrospective study was to compare the cyclosporine C(2) blood levels in renal transplant recipients with induction therapy, monitored on C(0) levels during the early and long-term post-transplantation periods in different French transplantation centres, to the target values recommended by the International Consensus on Neoral and used in the Mo2art study. A retrospective study was conducted by the therapeutic drug monitoring (TDM) committee of the French Pharmacological Society. Cyclosporine C(0) and C(2) concentrations from 168 renal transplant recipients were collected at different post-transplantation periods by six TDM laboratories of transplantation centres from April 2001 to April 2002. Cyclosporine blood levels were determined by fluorescence polarization immunoassay (mFPIA, AxSYM, Abbott) or enzyme immunoassay (EMIT, Dade Behring). Most patients had C(0) values in the recommended target ranges, with C(2) levels below the targets used in the Mo2art study or proposed by the International Consensus Conference, both during the early and long-term post-transplantation periods. Sixty-eight per cent of patients had C(2) below 1,500 microg/L +/- 20% in the first 2 months post-transplantation and 55% had C(2) below 800 microg/L +/- 20% in the late post-transplantation period (>1 year). Cyclosporine dose should be increased by 40% on average during the first week post-transplantation period and by 50% during the maintenance period to achieve the C(2) targets. In France, most renal transplant recipients receiving induction agents monitored on C(0) had C(2) levels below the targets recommended by the International Consensus Conference. In clinical practice, the optimal therapeutic windows for CsA monitoring based on C(2) needs to be more precisely defined, both during the early and long-term post-transplantation periods in renal transplant recipients receiving induction agents.     

In vivo antibacterial effects of simulated human serum profiles of once-daily versus thrice-daily dosing of amikacin in a Serratia marcescens endocarditis experimental model.

Once-daily dosage of aminoglycosides is currently under consideration. The lower toxicity of this regimen has been clearly established, but there are conflicting experimental and clinical data concerning its efficacy. It is inadvisable to optimize human therapy by extrapolation from experimental studies since animal and human pharmacokinetics differ. The simulation of human pharmacokinetics in experimental infectious models would seem to offer a more rational approach. We used computer-controlled infusion of amikacin at a variable flow rate to simulate human pharmacokinetics in a Serratia marcescens rabbit endocarditis model and to compare two therapeutic regimens (once-daily versus thrice-daily doses). The doses corresponded to simulations of 15 and 30 mg/kg of body weight per day in humans, and antibacterial activity was measured in vegetations (Veg) after 24 h of treatment. The results show that the dose corresponding to 15 mg/kg/day failed to produce a significant reduction of CFU (6.8 +/- 0.9 and 6.4 +/- 0.8 log10 CFU/g of Veg, respectively, for once-daily and thrice-daily doses versus 7.6 +/- 1.0 for controls). A significant reduction was observed only for the dose corresponding to 30 mg/kg/day in humans (5.2 +/- 1.5 and 5.4 +/- 1.1 log10 CFU/g of Veg, respectively, for the two regimens). With this model, the efficacy of amikacin was similar for both regimens after 24 h of treatment simulating human pharmacokinetics.     

Thiopurine methyl transferase activity: new extraction conditions for high-performance liquid chromatographic assay.

A new liquid-liquid extraction is described for thiopurine methyl transferase (TPMT, EC 2.1.1.67) activity determination: the use of a pH 9.5 NH4Cl buffer solution, before adding the solvent mixture, allows more rapid extraction, avoiding a centrifugation step, and reduces the global cost of analysis. After the extraction step, 6-methylmercaptopurine, synthesised during the enzymatic reaction, is determined by a liquid chromatographic assay. Analytical performance of the assay was tested on spiked erythrocyte lysates. The linear concentration range was 5-250 ng ml(-1) (r> or =0.997, slope=1.497, intercept=-0.367). The recoveries were 82.8, 89.9 and 82.2% for 75, 125 and 225 ng ml(-1), respectively. The coefficients of variation were < or =6.1% for within-day assay (n=6) and < or =9.5% for between-day assay precision (n=6; 14 days). TPMT activity was determined in a French adult Caucasian population (7 =70). The results ranged from 7.8 to 27.8 nmol h(-1) ml(-1) packed red blood cells and the frequency distribution histogram is similar to that previously published.