Nebulized colistin provides rapid and efficient bacterial killing in ventilated piglets with inoculation pneumonia caused by Pseudomonas aeruginosa.

No abstract

The antibacterial activities of imipenem-cilastatin, meropenem-cilastatin, cefepime and ceftazidime against Enterobacter cloacae NOR-1, which produces the carbapenem-hydrolyzing ␤-lactamase NmcA and a cephalosporinase, and against one of its in vitro-obtained ceftazidime-resistant mutant were compared by using an experimental model of pneumonia with immunocompetent rats. The MICs of the ␤-lactams with an inoculum of 5 log 10 CFU/ml were as follows for E. cloacae NOR-1 and its ceftazidime-resistant mutant, respectively: imipenem, 16 and 128 g/ml, meropenem, 4 and 32 g/ml, cefepime, <0.03 and 1 g/ml, and ceftazidime, 1 and 512 g/ml. The chromosomally located cephalosporinase and carbapenem-hydrolyzing ␤-lactamase NmcA were inducible by cefoxitin and meropenem in E. cloacae NOR-1, and both were stably overproduced in the ceftazidime-resistant mutant. Renal impairment was induced (uranyl nitrate, 1 mg/kg of body weight) in rats to simulate the human pharmacokinetic parameters for the ␤-lactams studied. Animals were intratracheally inoculated with 8.5 log 10 CFU of E. cloacae, and therapy was initiated 3 h later. At that time, animal lungs showed bilateral pneumonia containing more than 6 log 10 CFU of E. cloacae per g of tissue. Despite the relative low MIC of meropenem for E. cloacae NOR-1, the carbapenem-treated rats had no decrease in bacterial counts in their lungs 60 h after therapy onset compared to the counts for the controls, regardless of whether E. cloacae NOR-1 or its ceftazidime-resistant mutant was inoculated. A significant decrease in bacterial titers was observed for the ceftazidime-treated rats infected with E. cloacae NOR-1 only. Cefepime was the only ␤-lactam tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.

Plasma and cervicovaginal secretion (CVS) samples were collected from 19 human immunodeficiency virus type 1-infected women on lopinavir-or indinavir-containing regimens. Lopinavir and indinavir were detectable in 29 and 93% of CVS samples, respectively, a finding that may be ascribed to these drugs' differences in protein binding and pK a . The relationship between lopinavir and indinavir pharmacodynamics and viral evolution in the female genital tract should be assessed over time.Differential viral load suppression and rate of emergence of drug resistance-associated viral mutations have been observed between blood and genital compartments, a fact which has possibly been related to inadequate penetration of antiretroviral drugs into sanctuaries (3,4,9,11,12,14,15). Numerous studies have evaluated the penetration of antiretrovirals into the male genital tract (7,8,16,17). In contrast, data on the diffusion of antiretrovirals in the female genital tract are scarce, but preliminary results evidenced major differences between drugs in terms of detection in cervicovaginal secretions (CVS) (8,14). Protease inhibitors (PIs) exhibit variable protein binding capacities and physicochemical properties, which might influence PI diffusion into the female genital tract. We thus decided to compare the pharmacokinetics of indinavir alone or combined with ritonavir and that of lopinavir-ritonavir in the plasma and genital secretions of human immunodeficiency virus type 1 (HIV-1)-infected women.HIV-1-infected women who were on a lopinavir-or indinavir-containing regimen for a minimum of 4 weeks were recruited between October 2001 and July 2002. They had no symptoms of genital infection and no genital bleeding during the 5 days preceding the visit and were asked to avoid sexual intercourse and intravaginal medications within 2 days before sample processing. To assess whether the patients were adherent to their treatment, they were asked to fill out a simple self-administered questionnaire regarding their drug intake during the 4 days preceding the study visit. After the introduction of a speculum, genital secretions were collected by a lavage performed with 3 ml of phosphate-buffered saline, pH 7.2, containing a 10 mM concentration of lithium chloride. Within 15 min after collection of the genital secretion, a blood sample was taken for the measurement of plasma lopinavir or indinavir concentration. None of the women had taken drugs susceptible to interaction with the metabolism of either indinavir or lopinavir. For each woman, samples were precisely collected just before and 3 to 4 h after intake of the last drug for measurements of 12-h trough and peak plasma concentrations simultaneously with that of drug levels in genital secretions. Both peak and trough concentrations were measured at two different visits separated by 1 to 3 months. The study protocol was approved by the Ethics Committee of the Pitié-Salpêtrière Hospital, Paris, France, and signed informed consent was obtained from all women. Measurements of antiretroviral d...

The pharmacokinetics of orally administered amoxicillin were investigated in 12 healthy volunteers in a crossover design. They received either a placebo or a saline-polyethylene glycol solution (SPG) for 4 d, the last dose being given simultaneously with 1 g amoxicillin; blood samples were drawn for the next 12 h. Amoxicillin kinetics were similar in the two treatments but small differences in some pharmacokinetic parameters reached significance. The mean +/- SD area under the curve was lower with SPG (43.8 +/- 6.8 against 47.8 +/- 8.2 mg h L-1, p < 0.05) but the treatments were equivalent according to Westlake's test (95% confidence interval = 14.95%). Analysis of SPG against placebo amoxicillin absorption kinetics after fitting the data to a Weibull model revealed a longer duration of the absorption, a slower rate of absorption, and a different shape of the curve. No clinical consequences are expected from these minor variations but possible mechanisms could be relevant to other drugs.

The efficacy of antimicrobial agents against pulmonary infections depends on their local concentrations in the lung. The aims of the present study were to: 1) compare technetium-99m diethylenetriaminepenta-acetic acid ( 99m Tc-DTPA) and urea as markers of epithelial lining fluid (ELF) dilution for measuring ELF concentrations of pharmaceuticals; 2) quantify ELF cefepime concentrations in normal and injured lung; and 3) measure the increase in permeability to cefepime following oleic acid-induced acute lung injury.A modified bronchoalveolar lavage technique, based on equilibration of infused 99mTc-DTPA, was used to measure ELF volume. Cefepime was administered intravenously at steady plasma levels. Six serial bronchoalveolar lavages were performed 5 h after the beginning of infusion.ELF to plasma cefepime concentration ratios were 95¡17 and 100¡14.5% in normal and injured lung respectively. When urea was used as marker, cefepime concentration ratios were underestimated at 16.4¡2.7 and 73.9¡8.4% respectively. Cefepime blood/ airspace clearance increased from 3.8¡0.7 mL?min -1 in controls to 39.8¡4.9 mL?min -1 in acute lung injury. It was concluded that: 1) cefepime concentrations in epithelial lining fluid were in equilibrium with those in plasma in both normal and injured lung after 5 h at steady plasma concentrations; 2) epithelial lining fluid cefepime concentration by the urea method was much less underestimated in injured versus normal lung; and 3) acute lung injury induces a 10-fold elevation of cefepime blood/airspace clearance. Eur Respir J 2004; 24: 150-156.

The pharmacokinetics of diacetylrhein following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups of 8 patients with mild or severe renal insufficiency. Statistical analysis using a Kruskal-Wallis rank sum test showed a significant difference between the three groups for the following parameters. In severely uraemic patients, median AUC0-infinity was multiplied by a factor of about 2: 40.5 mg.h/l versus 21.3 mg.h/l in healthy subjects, P = 0.04; and t1/2 was prolonged by the same factor: 9.6 h versus 4.3 h in the control group, P = 0.003. Apparent drug availability and renal clearance assessed through urinary data decreased with renal failure, respectively: 14.5% and 0.045 l/h versus 35.4% (P = 0.01) and 0.13 l/h (P = 0.008) in healthy subjects. Amounts of glucuro- and sulpho-conjugates in urine were lower in severely uraemic patients. Intermediate values were observed for mildly uraemic patients. Other parameters: lag time, Cmax, tmax, Vss/F, urinary glucuro- to sulpho-conjugate ratios did not change significantly. Apparent total clearance of rhein was poorly correlated with creatinine clearance and this was related to a decrease of non-renal clearance of rhein in renal insufficiency. It was concluded that, from a pharmacokinetic point of view, a reduction (50%) in the initial dosage of diacerein should be considered in severe renal failure.

The pharmacokinetics of diacerein following a single oral dose of 50 mg was studied in 12 healthy volunteers, 10 patients with a mild liver cirrhosis (Child Pugh's grade A), and 6 patients with a more severe liver cirrhosis (Child Pugh's grade B to C). Statistical analysis using a Kruskal-Wallis test showed no significant differences between the three groups for the following parameters: median Cmax was 3.9 mg l-1 for the cirrhotic patients group I (CPI) and 3.2 mg l-1 for the cirrhotic patients group II (CPII) versus 3.2 mg l-1 for the healthy volunteers (HV); median t1/2 was 4.9 h for CPI and 4.3 h for CPII versus 4.3 h for HV; median Cl/F was 2.1 l h-1 for CPI and 2.5 l h-1 for CPII versus 1.6 l h-1 for HV; median Vdss/F was 12.6 l for CPI and 14.0 l for CPII versus 13.21 for HV. The urinary parameters were comparable. It was concluded that, from a pharmacokinetic point of view, no reduction in the initial dosage of diacerein need be proposed in liver cirrhosis.