Low prevalence of tissue detection of cefepime and daptomycin used as empirical treatment during revision for periprosthetic joint infections: results of a prospective multicenter study.

Data demonstrating that antibiotics administered intraoperatively in patients with surgical revision for periprosthetic joint infection achieve concentrations exceeding minimal inhibitory concentrations of the identified bacteria at the surgical site when the new implant is inserted are lacking. We prospectively included patients with periprosthetic joint infection operated with one- or two-stage replacement during which cefepime (2g)-daptomycin (10mg/kg) combination was administered intravenously as intraoperative empirical antibiotic treatment. Three biopsies (two bones and one synovial membrane) were taken from each patient just before the insertion of the new implant. Eighteen adults of median age 68 years were included. Knee was involved in 10 patients (55.6%) and surgery consisted in one-/two-stage replacement in 11/7 patients. A tourniquet was used during the intervention in the 10 patients with knee prosthesis. Among 54 tissue samples, cefepime and daptomycin were detected respectively in 35 (64.8%) and 21 (38.9%) cases (P=0.01). A total of 17 bacteria dominated by staphylococci (n=14) were identified in 10 patients; tissue inhibitory quotient calculated in 51 samples was >1 in 22 cases (43.1%) for cefepime and in 16 cases (31.4%) for daptomycin. The proportion of tissue samples with detectable antibiotic was significantly higher in hip versus knee prosthesis (P=0.03). The present study suggests that intraoperative empirical administration of cefepime-daptomycin combination during septic prosthetic joint replacement results in a high proportion of tissue samples in which at least one of the two antibiotics was not detected or at a low concentration despite satisfactory concomitant blood serum concentrations.

Chicken adaptive response to low energy diet: main role of the hypothalamic lipid metabolism revealed by a phenotypic and multi-tissue transcriptomic approach.

BACKGROUND: Production conditions of layer chicken can vary in terms of temperature or diet energy content compared to the controlled environment where pure-bred selection is undertaken. The aim of this study was to better understand the long-term effects of a 15%-energy depleted diet on egg-production, energy homeostasis and metabolism via a multi-tissue transcriptomic analysis. Study was designed to compare effects of the nutritional intervention in two layer chicken lines divergently selected for residual feed intake. RESULTS: Chicken adapted to the diet in terms of production by significantly increasing their feed intake and decreasing their body weight and body fat composition, while their egg production was unchanged. No significant interaction was observed between diet and line for the production traits. The low energy diet had no effect on adipose tissue and liver transcriptomes. By contrast, the nutritional challenge affected the blood transcriptome and, more severely, the hypothalamus transcriptome which displayed 2700 differentially expressed genes. In this tissue, the low-energy diet lead to an over-expression of genes related to endocannabinoid signaling (CN1R, NAPE-PLD) and to the complement system, a part of the immune system, both known to regulate feed intake. Both mechanisms are associated to genes related polyunsaturated fatty acids synthesis (FADS1, ELOVL5 and FADS2), like the arachidonic acid, a precursor of anandamide, a key endocannabinoid, and of prostaglandins, that mediate the regulatory effects of the complement system. A possible regulatory role of NR1H3 (alias LXRα) has been associated to these transcriptional changes. The low-energy diet further affected brain plasticity-related genes involved in the cholesterol synthesis and in the synaptic activity, revealing a link between nutrition and brain plasticity. It upregulated genes related to protein synthesis, mitochondrial oxidative phosphorylation and fatty acid oxidation in the hypothalamus, suggesting reorganization in nutrient utilization and biological synthesis in this brain area. CONCLUSIONS: We observed a complex transcriptome modulation in the hypothalamus of chicken in response to low-energy diet suggesting numerous changes in synaptic plasticity, endocannabinoid regulation, neurotransmission, lipid metabolism, mitochondrial activity and protein synthesis. This global transcriptomic reprogramming could explain the adaptive behavioral response (i.e. increase of feed intake) of the animals to the low-energy content of the diet.

[Comparative study of Vitek-2™ AIX versus Vitek-2™ PC: phenotypic resistance of enterobacteriaceae to ß-lactams]. / Comparaison du Vitek-2™ AIX versus Vitek-2™ PC par l'étude des phénotypes de résistance des entérobactéries aux ß-lactamines.

AIM OF THE STUDY: Vitek-2™ AIX versus Vitek-2™ PC have different rules for phenotypic interpretation. The aim of this study is to ensure that the raw results determined by these two versions of Vitek-2™ allow biologists to conclude to the same resistance phenotype, but also to evaluate their own phenotypic interpretation system (advanced expert system). MATERIAL AND METHODS: A total of 251 strains of Enterobacteriaceae of different groups and phenotypes was tested. Each strain was studied simultaneously on both types of Vitek-2™ from the same calibrated inoculum. We then compared their resistance phenotype to beta-lactams. RESULTS: For strains not producing ESBL or CHN, the biologist concluded in 99.3% of cases to the same resistance phenotype by interpreting the raw results of Vitek-2™ AIX versus PC. The phenotypic interpretation of biologist is different from the Vitek-2™ in respectively 40% versus 43% of cases for AIX and PC versions. For multi-resistant strains, the biologist concluded in 100% of cases to the same resistance phenotype by interpreting the raw results of Vitek-2™ AIX versus PC. In 51.5% of cases the biologist use the disk diffusion method (DD). The results of this technique put forward 29% discrepancy with the two types of Vitek-2™. Finally, when Vitek-2™ claims the presence of an ESBL alone, this result is routinely confirmed by DD. CONCLUSION: The switch from Vitek-2™ AIX to Vitek-2™ PC does not alter the results of the phenotypic interpretation of biologist.

[Microbial description of bacteriuria in long-term care facilities: a prospective study in the French Teaching Hospital of Strasbourg]. / Description de la flore bactérienne responsable des bactériuries symptomatiques en unité de soins de longue durée: étude prospective au CHRU de Strasbourg.

OBJECTIVE: The authors had for aim to assess, the incidence of symptomatic bacteriuria and the level of antibiotic resistance in bacteria identified in long-term care facilities (LTC). DESIGN: Symptomatic bacteriuria cases were prospectively collected, during 9 months in the two LTC of the Strasbourg French Teaching Hospital (196 beds). RESULTS: One hundred and eleven bacteriuria cases were included. They concerned 67 of the 274 residents (cumulative incidence: 2.07/1,000 patients-day). A gram-negative bacillus was identified in 85% of the symptomatic bacteriuria cases, and Escherichia coli in 40%. Sixty percent of the identified bacterial strain was resistant to amoxicillin (Amx-R) and 42% to the clavulanic acid combination (AmC-R). Third generation cephalosporins (3GC) were effective in 90% of Urinary tract infections (UTIs) and fluoroquinolones in 65% (Fq). Four bacterias with broad beta-lactamase spectrum were identified (0.04%) including 3 Enterobacter aerogenes. No yeast infection was diagnosed. E. coli strains were 65% Amx-R and 50% AmC-R. Concerning the Fq-R strains (15%), 50% were cotrimoxazole resistant (Stx-R) and 70% Amx-R; 3GC remained effective (82%). CONCLUSION: In LTC, multi-drug resistance bacteria are rare and 3GCs seem to be the best first line treatment. Nevertheless, Fq-R is increasing (15 vs 8%), and attention must be paid to the antibiotic therapy used.

Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography.

The pharmacokinetics and metabolism of Navelbine (NVB) were investigated in 20 patients by a specific high performance liquid chromatographic methodology allowing the monitoring of NVB, deacetyl-NVB, and N-oxide NVB. After the i.v. (15 min) administration of 30 mg/m2 of drug, blood and urine samples were collected for, respectively, 144 and 48 h. NVB is characterized by a three compartmental kinetics, with a Cmax of 1130 +/- 139 (SEM) ng/ml. The total body clearance and apparent volume of distribution, as defined by high performance liquid chromatography, are 1.26 +/- 0.09 liter/h/kg (48.6 +/- 4.1 liters/h/m2) and 75.6 +/- 9.2 liters/kg (2918.4 +/- 307.2 liters/m2). No metabolite could be detected in serum; the urinary excretion of NVB represented 11% of the administered dose. Deacetyl-NVB could be identified as a minor urinary metabolite when no N-oxide NVB appeared in the urine samples. Two additional peaks appeared in most of urinary chromatograms as trace amounts. Thus, the major pathway of NVB, as for other Vinca alkaloids, should be hepatic clearance, as biliary elimination and/or hepatic biotransformation.

[Use of linezolid for the treatment of lung infections in adults with cystic fibrosis]. / Utilisation du linézolide dans le traitement des infections broncho-pulmonaires du patient adulte atteint par la mucoviscidose.

INTRODUCTION: Linezolid, a new antistaphylococcal agent for oral or intravenous administration is active against Staphylococcus aureus with limited sensitivity to glycopeptides. The purpose of the present work was to compare data in the literature with practical clinical experience with the use of linezolid for lung infections in adult cystic fibrosis patients with the objective of developing local guidelines for use. MATERIAL AND METHODS: This retrospective clinical study was conducted in the adult pneumology department of a university hospital. RESULTS: The main clinical signs leading to prescription of linezolid were aggravating cough, bronchial obstruction, and exercise-induced fatigue. Among 42 cystic fibrosis patients, six aged 24+/-3 years were given 22 treatments of linezolid. Two patients were given the drug once and the others 2, 4, 5, and 9 times, 600 mg b.i.d. Mean duration of treatment with linezolid was 16+/-5 days. Among the six patients, two presented meti-R S. aureus infection. For twelve cases, clinical improvement was observed; and in two others the situation worsened leading to interruption of linezolid. CONCLUSIONS: There are few reports in the literature on use of linezolid in cystic fibrosis patients. Writing internal guidelines for our department has enabled standardized use: 600 mg b.i.d. p.o. for 14 days as second-line treatment for bronchial exacerbation of S. aureus infection.

Amoxicillin intestinal absorption reduction by amiloride: possible role of the Na(+) -H+ exchanger.

Intestinal absorption of beta-lactam antibiotics has been shown to use the dipeptide carrier system. In vitro experiments have established that the efficiency of uptake by enterocytes depends on an inwardly directed proton gradient--dipeptides and beta-lactam antibiotics being cotransported along with hydrogen ion. This gradient is thought to result from the sodium-hydrogen (Na(+)-H+) exchanger located on the brush-border membrane. The aim of the present study was to assess the in vivo relevance of these data in humans by examining the effect of amiloride, a well-known inhibitor of the Na(+) -H+ exchanger, on the bioavailability of amoxicillin in eight healthy volunteers. The results show that amiloride reduces significantly amoxicillin absorption rate (mean time to maximum concentration increases from 1.0 to 1.6 hours, p < 0.05) and absolute bioavailability (by 27%, p < 0.01) and that amiloride-induced inhibition of the intestinal Na(+) -H+ exchange could be associated with an additional inhibitory effect on (Na/K)-ATPase activity. The present data seem to confirm the role of Na(+) -H+ exchange in the uptake of beta-lactams by the intestine and to support the indirect sodium dependence of this carrier system in vivo.

Role of intrahepatic protein binding in the hepatobiliary extraction profile of cefixime in humans.

The hepatobiliary extraction profile of cefixime, a dianionic cephalosporin antibiotic, was studied in 10 patients, each of whom was provided with T-tube drainage of his or her common bile duct after cholecystectomy. After a single 200 mg oral dose, cefixime biliary clearance proved to be nonlinear, mostly in its initial phase, which is consistent with a concentrative uptake and intracellular protein binding for the drug. The latter process appears to be saturable and to operate at a rate that correlates with the total amount of cefixime recovered in the 24-hour bile drainage. Such findings seem to confirm the significant role played in vivo by hepatic ligandin in the hepatobiliary extraction of organic anions. The data also show that a single 200 mg oral dose of cefixime yields drug levels in bile substantially higher than the minimal inhibitory concentrations for the most frequent Enterobacteriaceae in biliary tract infections. Accordingly, this cephalosporin could be an interesting alternative in both prophylaxis and treatment of biliary tract infections.

Clinical pharmacokinetics of vinorelbine.

Vinorelbine (5'-noranhydrovinblastine) is a recently developed semisynthetic anticancer drug which belongs to the Catharanthus alkaloid family. Its mechanism of action is only partially known but it is assumed that it acts, like vinblastine and vincristine, as an antimicrotubule agent arresting cell division in mitosis. Clinically, vinorelbine has mainly shown activity in the treatment of advanced non-small-cell lung cancer and the treatment of metastatic breast cancer. Early pharmacokinetic data were obtained with radioactive assays (radio-immunoassay or 3H-labelled vinorelbine), then with more selective high performance liquid chromatographic techniques. Vinorelbine is usually administered intravenously but there has also been some experimentation with an oral formulation. The bioavailability of a liquid filled gelatin capsule ranges between 12 and 59% with a mean value of 27% [standard deviation (SD) 12%]. Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. In vitro, vinorelbine is mainly distributed into the blood cells, especially platelets (78%) and lymphocytes (4.8%) The unbound blood fraction is around 2%. In lung tissue vinorelbine concentrations are much higher than in serum, by up to 300-fold 3 hours after administration. Little is known about the biotransformation of vinorelbine. Desacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25% of the injected dose. Urinary excretion of vinorelbine is low, accounting for less than 20% of the dose. Faecal elimination has been demonstrated in 2 patients who were administered 3H-labelled vinorelbine; the amount of radioactivity recovered in the faeces was 33.9 and 58.4% for the 2 patients, respectively. The pharmacokinetic profile of vinorelbine is often described as a 3-compartment model characterised by a long terminal half-life (t1/2) that varies between 20 and 40 hours and a large apparent volume of distribution (Vd) of around 70 L/kg. Systemic clearance ranges between 72.54 and 89.46 L/h (1209 and 1491 ml/min) when determined by high performance liquid chromatography and is higher than that reported by radioimmunoassay [46.2 L/h (770 ml/min)]. This could be due to the greater specificity of the chromatographic method. Vinorelbine has been administered by continuous intravenous infusion over 4 days. Steady-state was reached and the concentrations obtained were above the in vitro IC50 (concentration of drug causing 50% inhibition). The effect of liver disease on vinorelbine pharmacokinetics has been studied in patients with breast cancer. Patients with massive secondary liver disease had a lower systemic clearance than those who have no liver disease or a lesser invasion. In children, vinorelbine seems to display a shorter t1/2 (14.7 hours) than that found in adults. In addition, the systemic clearance is highly variable [from 12 to 93.96 L/h/m2 (200 to 1566 ml/min/m2)]. Vinorelbine is often co-administered with cisplatin in the treatment of advanced non-small-cell lung cancer. The disposition of the alkaloid is not altered by concurrent administration of cisplatin.

Clinical pharmacokinetics of cefotiam.

Cefotiam, a semisynthetic parenteral cephalosporin of the aminothiazole group, exhibits interesting properties: stability against hepatic metabolism and excellent solubility, accounting for an apparent volume of distribution 2 to 3 times higher than that of most other cephalosporins. Its degree of protein binding is about 40%. High concentrations of cefotiam are observed in several tissues (kidney, heart, ear, prostate and genital tract) as well as in fluids and secretions (bile, ascitic fluid). In healthy subjects, the serum elimination half-life is about 1 hour. The pharmacokinetics are linear only for doses lower than 1g. Cefotiam is mostly (and rapidly) eliminated in unchanged form in urine; 50 to 70% of the dose is recovered during the 12 hours following administration, and only severe renal failure, with creatinine clearance less than 5 ml/min, significantly alters the elimination half-life. Although the drug has no proven nephrotoxicity in man, a reduction of the dose is recommended when creatinine clearance is less than 30 ml/min.

Contribution of high-performance liquid chromatography to the identification of some Corynebacterium species by comparison of their corynomycolic acid patterns.

Reverse-phase high-performance liquid chromatography of corynomycolic acids provided a specific pattern for each Corynebacterium species studied. These data suggest that a fast and reproducible procedure is now available for bacteriological identification at the genus and at the species level of corynomycolic-acid-containing bacteria. Mass spectrometry analysis of post-column collected fractions provided the order of elution of some corynomycolic acids and isomers and showed the high specificity of the chromatographic assay which could be used for the routine bacteriological identification of some species belonging to the genus Corynebacterium.

Corynebacterium group D2 ("Corynebacterium urealyticum") constitutes a new genomic species.

Twenty-one Corynebacterium group D2 ("C. urealyticum") strains were found to constitute a tight DNA hybridization group distinct from named Corynebacterium species. The strains of Corynebacterium group D2 had cell wall component type IV, short chain mycolic acids and G+C content of DNA of 65-66 mol %. Corynebacterium group D2 constitutes a genomic species which can be identified by phenotypic tests.

Penetration of roxithromycin into gingival tissue.

Roxithromycin is a new macrolide with an antibacterial spectrum similar to that of erythromycin. Absorption is rapid and complete, resulting in high serum levels and a long half-life. Tissue distribution is extensive and sustained, as shown by the high concentrations measured in the lung, prostate, ovaries, liver, kidney, and skin. In this study, we measured the penetration of roxithromycin into gingival tissue at steady state in 30 patients treated orally with 150 mg every 12 hr for 5 days. Tissue specimens were sampled at 2, 4, 6, 8, or 12 hr (n = 6 each time) after dose 10, and blood samples were taken simultaneously. Serum and tissue concentrations of roxithromycin were measured by high-performance liquid chromatography. The peak serum level, reached 4 hr after dosing, was 6.60 +/- 1.15 micrograms/ml. The peak tissue level was 4.63 +/- 1.84 micrograms/g and was reached after 8 hr. From 4 to 10 hr after dosing, tissue concentrations were greater than 2 micrograms/g, that is, higher than the MIC90 of roxithromycin against most oral pathogens. These data support the use of roxithromycin in the treatment of oral infections.

Clinical pharmacokinetics of vinorelbine alone and combined with cisplatin.

Vinorelbine (NVB) is a new anticancer drug belonging to the vinca alkaloid family that shows activity as a single-agent treatment in advanced non-small cell lung cancer (NSCLC). Preliminary results show a better response rate with a combination of cisplatin (CDDP) and NVB than with NVB alone. To assess whether this increased activity is secondary to a pharmacokinetic interaction, the authors compared the pharmacokinetic profiles of NVB alone and combined with CDDP in previously untreated inoperable NSCLC patients. Five patients received NVB (30 mg/m2) by short intravenous infusion, and four patients received CDDP (80 mg/m2) 1 hour after the NVB infusion (30 mg/m2). Serum NVB was assayed using a specific high-performance liquid chromatography method. The mean serum concentrations in both groups were similar. In addition, the areas under the curve calculated from 1 hour (beginning of CDDP administration) to 72 hours were 414 ng.hour/mL (standard deviation [SD]: 94) (group NVB alone) and 407.1 ng.hour/mL (SD: 32.9) (group NVB + CDDP). In conclusion, the increased activity observed with the combination NVB + CDDP is not the result of a pharmacokinetic interaction.

Taxonomy of Corynebacterium diphtheriae and related taxa, with recognition of Corynebacterium ulcerans sp. nov. nom. rev.

Levels of genomic DNA relatedness were determined using a S1 nuclease procedure for reference bacteria identified as biotypes of Corynebacterium diphtheriae, biovars of Corynebacterium pseudotuberculosis, and 'Corynebacterium ulcerans'. These results showed that the three species are separate taxa at the genomospecies level whereas biotypes and biovars are closely related genomically within each species. Phylogenetic analyses of small-subunit rDNA sequences revealed that 'Corynebacterium ulcerans' forms a tight cluster with Corynebacterium pseudotuberculosis within the robust branch that groups all Corynebacterium sequenced to date. Therefore, we propose that the species incertae sedis 'C. ulcerans' should be conclusively recognized as a distinct species within the genus Corynebacterium with strain CCUG 2708 = NCTC 7910 as type strain. This species is characterized by urease production and fermentation of glycogen.

Pulmonary distribution of vinorelbine in patients with non-small-cell lung cancer.

Vinorelbine (Navelbine, NVB) is a new semi-synthetic vinca alkaloid that is currently used in the treatment of advanced breast cancer and advanced non-small-cell lung cancer (NSCLC). In this study we investigated the tumoral and healthy pulmonary tissue concentrations of NVB in previously untreated NSCLC patients undergoing surgery. A total of 13 patients (mean age, 60 years; range, 42-70 years) were included and received NVB (20 mg/m2) at 1 h (mean, 1.1 h; SD, 0.2 h; n = 6 patients) and 3 h (mean, 3.0 h; SD, 0.6 h; n = 7 patients) before tumor resection. A tumoral and adjacent healthy lung-tissue specimen as well as simultaneously sampled serum were analyzed for NVB by high-performance liquid chromatography (HPLC). NVB levels were much higher in tissue than in serum (up to 300-fold). The tissue/serum ratio increased between the 1-h sampling time (range, 0.1-100) and the 3-h time point (range, 10-300). In all patients but two, NVB concentrations were lower in tumors than in healthy lung tissue. The tumor/healthy tissue ratio ranged from 0.06 to 1.3 (median, 0.09) at 1 h and from 0.18 to 1.1 (median, 0.55) at 3 h. This ratio increased between the 1-h sampling time and the 3-h time point as a consequence of increasing tumor levels (median, 50.4 ng/g at 1 h and 278 ng/g at 3 h). In four patients, concentrations could be measured in necrotic and peripheral tumor zones, showing lower values in necrotic areas. Thus, these data indicate that NVB is highly distributed in lung tissue, with the disposition rate being slower in tumor tissue than in healthy parenchyma during the first 3 h.

Biliary elimination and pharmacokinetics of vinorelbine in micropigs.

The biliary elimination and pharmacokinetics of vinorelbine (NVB) were investigated in five conscious micropigs provided with a double-terminal choledocal fistula allowing the collection and reinstillation of bile. After the i.v. administration of NVB (0.5 mg/kg), serum and bile samples were collected over a 48-h period. The concentrations of NVB were measured by high-performance liquid chromatography. The serum concentrations decreased rapidly from a maximal value of 208.6 ng/ml (SD, 111.7 ng/ml). The mean half-life was 10.9 h (SD, 8.6 h) and the mean AUC0-48 h was 292.8 ng ml-1 h (SD, 79.4 ng ml-1 h). The bile concentrations were high, amounting to 16.0 micrograms/ml (range, 5.4-27.7 micrograms/ml). The 0- to 48-h biliary excretion of unchanged NVB accounted for 25.8% (SD, 5.7%) of the injected dose, with 21.5% (SD, 4.0%) being eliminated during the 0- to 8-h period. Desacetyl-NVB was found in an inconstant manner and in very low amounts in bile samples. In addition, no glucuronide of NVB could be detected. Thus, in the micropig, biliary excretion represents an important route of elimination for NVB.

Evidence for a true post-beta-lactamase-inhibitor effect of clavulanic acid against Klebsiella pneumoniae and Haemophilus influenzae.

OBJECTIVE: The purpose of this study was to investigate and characterize in vitro the post-beta-lactamase inhibitor effect (PLIE) of clavulanic acid against two beta-lactamase-producing species of bacteria. METHODS: The PLIE was investigated against one strain of Klebsiella pneumoniae and one strain of Haemophilus influenzae. A stationary-phase inoculum of about 107 colony-forming units per mL of each bacterium was pre-exposed for 2 h to clavulanic acid, either alone or in combination with amoxicillin at various concentrations. After pre-exposure, the dilution required to remove the beta-lactamase inhibitor was 1:100 or 1:1000 according to the bacterial species and their susceptibilities to clavulanic acid. Bacteria were counted hourly after drug removal, on solid agar medium. RESULTS: Control cultures exposed to amoxicillin alone after dilution, showed a delay in growth, which may be inherent to the time required to synthesize sufficient beta-lactamase after the dilution steps. Control experiments clearly distinguished the post-antibiotic effect and the growth delay from the PLIE. CONCLUSION: The PLIE could be one of several factors explaining why beta-lactam/beta-lactamase inhibitor combinations remain effective throughout the dosing interval, even if a few hours after in vivo administration, serum concentrations of beta-lactamase inhibitor fall below levels that are active in vitro.

Gastric diffusion of antibiotics used against Helicobacter pylori.

Only a few pharmacological studies have been carried out on men and guinea pigs to determine the gastric diffusion of antibiotics, which are active against Helicobacter pylori. The results of these studies have been analysed in considering the physicochemical nature, the mode of administration, the way of gastric diffusion (topic and/or systemic) and the pharmacological interactions. The correlation of these pharmacokinetic results with those obtained in clinical trials is difficult because of the heterogeneity of the pharmacological and pharmacodynamic data. The absence of a convenient and suitable animal or in vitro study model renders further standardized pharmacokinetic studies in infected man and at steady state necessary.

Pharmacokinetics of three new beta-lactams in the Yucatan micropig model administered by intravenous bolus injection and continuous infusion.

The miniature pig is becoming a popular non-rodent animal model in biochemical research because of physiological similarities to humans. In addition, the micropig presents the advantages of large animal species for experimental pharmacokinetics. However, pharmacokinetics of antimicrobial agents are poorly documented in the pig and further work is needed to establish interspecies comparisons. This prompted us to investigate the disposition of three well documented beta-lactams (cefepime, cefpirome and meropenem) in this model and also to evaluate the potential to use it for pharmacodynamic studies. Each drug was given following a single dose both by direct intravenous injection (or short infusion for meropenem) and continuous infusion. Six animals were enrolled in each group. Blood samples were obtained over a 0-12 h period, using a catheter placed in the external jugular vein. All beta-lactams were assayed by high performance liquid chromatography (HPLC). Pharmacokinetics of cefepime and cefpirome given by bolus injection in the microswine were close to those in man receiving equivalent dosage (i.e. 2 g). The terminal half-lives are similar (human: 1.80 h, 1.80 h; pig: 1.46 h, 1.29 h) as is the case for clearance values (human: 1.82, 1.80; pig: 1.90, 1.74 ml/min per kg) for cefepime and cefpirome, respectively. The administration by continuous infusion does not influence the elimination rate of cefepime, cefpirome and meropenem. Meropenem kinetics in the micropig were also similar to those in man. The terminal half-lives are similar (human, 0.83 h; pig, 0.88 h) as in the case for clearance values (human, 4.0 h; pig, 4.90 ml/min per kg) after 30 min intravenous infusion of meropenem. We concluded that the micropig is an adequate model for the study of the pharmacokinetics and probably the pertinent model for ex-vivo pharmacodynamics investigations of cefepime, cefpirome and meropenem.