RESUMEN
The ability of trovafloxacin and ciprofloxacin to select efflux mutants in vivo was studied in a model of acute Pseudomonas aeruginosa pneumonia in rats. Twelve hours after intratracheal inoculation of 10(6) CFU of P. aeruginosa strain PAO1 enmeshed in agar beads, two groups of 12 rats were treated by three intraperitoneal injections of each antibiotic given every 5 h. Dosing regimens were chosen to obtain a comparable area under the concentration-time curve from 0 to infinity/MIC ratio of 27.9 min for trovafloxacin (75 mg/kg of body weight) and of 32.6 min for ciprofloxacin (12.5 mg/kg). Twelve rats were left untreated and served as controls. Rats were sacrificed 12 h after the last injection (34 h after infection) for lung bacteriological studies. Selection of resistant bacteria was determined by plating lung homogenates on Trypticase soy agar plates containing antibiotic. In untreated animals, the frequency of resistant colonies was 10-fold higher than in agar beads. Compared to controls, both treatment regimens resulted in a 2-log reduction of lung bacterial load. The frequency of resistant colonies was 10-fold less with trovafloxacin than with ciprofloxacin at twice the MIC (7.4 x 10(-5) versus 8.4 x 10(-4), respectively) (P < 0.05) and at four times the MIC (6.2 x 10(-4) versus 5.0 x 10(-5), respectively) (P < 0.05). A multidrug resistance phenotype typical of efflux mutants was observed in all 41 randomly tested colonies obtained from treated and untreated rats. In agreement with in vitro results, trovafloxacin and ciprofloxacin preferentially selected MexCD-OprJ and MexEF-OprN overproducers, respectively. These results demonstrate the differential ability of trovafloxacin and ciprofloxacin to select efflux mutants in vivo and highlight the rapid emergence of those mutants, even without treatment.
Asunto(s)
Antiinfecciosos/uso terapéutico , Ciprofloxacina/uso terapéutico , Resistencia a Múltiples Medicamentos/genética , Fluoroquinolonas , Naftiridinas/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Pseudomonas aeruginosa , Enfermedad Aguda , Animales , Antiinfecciosos/farmacocinética , Ciprofloxacina/farmacocinética , Farmacorresistencia Microbiana , Pulmón/microbiología , Pulmón/patología , Masculino , Mutación/genética , Naftiridinas/farmacocinética , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/patología , Ratas , Ratas Sprague-DawleyRESUMEN
1. Two in vivo models, in the rat, were used to investigate, in the presence of different substrates, the overall and net intestinal elimination of ciprofloxacin: an open-intestinal perfusion model and an intestinal loop model respectively. 2. In the presence of quinidine, verapamil and cyclosporin (substrates of the P-glycoprotein (P-gp)), plasma AUCs of ciprofloxacin were 1.5 - 2 fold increased, while biliary clearance (1.5 - 2 fold), intestinal overall and net clearances (2 - 4 fold and 1.5 - 8 fold respectively) decreased. The weak effect obtained with cyclosporin as compared to verapamil and especially quinidine, suggests, for ciprofloxacin, the existence of transport systems distinct from the P-gp, as the OCT1 transporter which could be inhibited by quinidine. 3. With cephalexin and azlocillin, two beta-lactam antibiotics, plasma AUCs of ciprofloxacin increased and biliary and intestinal overall clearances decreased in a similar fashion (1.3 - 2 fold), suggesting the involvement of organic anion and/or cation transporters. 4. In the presence of structural analogues, the effect was dependent on the compound administered: Sparfloxacin had no effect on intestinal clearance of ciprofloxacin. In contrast, with pefloxacin, overall intestinal clearance of ciprofloxacin was decreased and net intestinal clearance increased. 5. The specificity of ciprofloxacin intestinal transport appears to be different from P-gp as outlined by the lack of competition with sparfloxacin, a P-gp substrate. Ciprofloxacin intestinal elimination seems to be mediated by organic anion and/or cation transporters and a mechanism sensitive to quinidine and verapamil.
Asunto(s)
Antiinfecciosos/farmacocinética , Ciprofloxacina/farmacocinética , Mucosa Intestinal/metabolismo , Animales , Área Bajo la Curva , Transporte Biológico Activo , Fenómenos Químicos , Química Física , Absorción Intestinal/fisiología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Following intravenous doses, ciprofloxacin pharmacokinetics in control and nephrectomized rats were studied. There were no differences between control and nephrectomized rats for area under the concentration-time curve in plasma or biliary clearance. The intestinal clearance of ciprofloxacin was increased in nephrectomized rats. Intestinal elimination seems to compensate partially for the decrease in urinary excretion of ciprofloxacin in nephrectomized rats.
Asunto(s)
Antiinfecciosos/farmacocinética , Ciprofloxacina/farmacocinética , Mucosa Intestinal/metabolismo , Insuficiencia Renal/metabolismo , Animales , Área Bajo la Curva , Bilis/metabolismo , Cromatografía Líquida de Alta Presión , Creatinina/sangre , Masculino , Nefrectomía , Perfusión , Ratas , Ratas Sprague-DawleyRESUMEN
The activity of LY333328 against Enterococcus faecalis JH2-2, which is susceptible to glycopeptides, and against its transconjugants E. faecalis BM4281 and BM4316, with VanB and VanA phenotypes, respectively, was investigated. LY333328 was active in vitro against the three strains, for which MICs were 2 microg/ml on agar and 0.25 microg/ml in broth. LY333328 was bactericidal in broth against E. faecalis JH2-2 and BM4281 at a concentration of 8 microg/ml and against BM4316 at a concentration of 30 microg/ml. The protein binding of LY333328 to rabbit serum was >99%, and the bactericidal activity of LY333328 in broth was reduced when it was tested in the presence of 90% rabbit serum. Autoradiographic studies performed in rabbits with enterococcal endocarditis showed that 14[C]LY333328 was distributed heterogeneously throughout cardiac vegetations. In rabbits with aortic endocarditis, a regimen of 20 mg of LY333328 per kg of body weight administered intramuscularly twice a day for 5 days after a loading dose of 40 mg/kg was active against the three strains in vivo (P < 0.01), whereas vancomycin was not active against the VanB-type strain and teicoplanin was not active against the VanA-type strain. We conclude that the activity of LY333328 is not significantly modified by acquired resistance to glycopeptides in E. faecalis either in vitro or in experimental endocarditis.
Asunto(s)
Antibacterianos/farmacología , Endocarditis Bacteriana/tratamiento farmacológico , Enterococcus faecalis , Vancomicina/farmacología , Animales , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Autorradiografía , Proteínas Bacterianas/genética , Proteínas Sanguíneas/metabolismo , Ligasas de Carbono-Oxígeno/genética , Medios de Cultivo , Farmacorresistencia Microbiana , Endocarditis Bacteriana/microbiología , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/genética , Femenino , Glicopéptidos , Lipoglucopéptidos , Pruebas de Sensibilidad Microbiana , Miocardio/metabolismo , Unión Proteica , ConejosRESUMEN
Prosthesis infections are difficult to cure. Infection with methicillin-resistant staphylococci is becoming more common in patients with orthopedic implants. Using a recently developed model of methicillin-resistant Staphylococcus aureus (MRSA) infection of a knee prosthesis, we compared the efficacies of teicoplanin and vancomycin. [14C]teicoplanin diffusion in this model was also studied by autoradiography. A partial knee replacement was performed with a silicone implant fitting into the intramedullary canal of the tibia, and 10(7) CFU of MRSA was injected into the knee. Treatment with teicoplanin or vancomycin (20 or 60 mg/kg of body weight, respectively, given intramuscularly twice daily) was started 7 days after inoculation and was continued for 7 days. The teicoplanin and vancomycin MICs for MRSA were 1 microg/ml. Mean peak and trough levels in serum were 39.1 and 23.5 microg/ml, respectively, for teicoplanin and 34.4 and 18.5 microg/ml, respectively, for vancomycin. Fifteen days after the end of therapy, the animals were killed and their tibias were removed, pulverized, and quantitatively cultured. Teicoplanin and vancomycin significantly reduced (P < 0. 05) the bacterial density (2.7 +/- 1.3 and 3.3 +/- 1.6 log10 CFU/g of bone, respectively) compared to those for the controls (5.04 +/- 1.4 log10 CFU/g of bone). The bacterial covents of teicoplanin- and vancomycin-treated rabbits were comparable. The [14C]teicoplanin autoradiographic diffusion patterns in rabbits with prostheses, two of which were uninfected and two of which were infected, were studied 15 days after inoculation. Sixty minutes after the end of an infusion of 250 microCi of [14C]teicoplanin, autoradiography showed that in the infected animals, the highest levels of radioactivity were located around the prosthesis and in the periosteum, bone marrow, and trabecular bone. Radioactivity was less intense in epiphyseal disk cartilage, femoral cartilage, articular ligaments, and muscles and was weak in compact bone. A similar distribution pattern was seen in uninfected rabbits. Thus, teicoplanin may represent an effective alternative therapy for the treatment of these infections.
Asunto(s)
Antibacterianos/uso terapéutico , Artroplastia de Reemplazo/efectos adversos , Infecciones Estafilocócicas/tratamiento farmacológico , Teicoplanina/uso terapéutico , Animales , Autorradiografía , Radioisótopos de Carbono , Difusión , Conejos , Infecciones Estafilocócicas/metabolismo , Teicoplanina/farmacocinética , Teicoplanina/farmacologíaRESUMEN
Ciprofloxacin pharmacokinetics have been shown to be modified in patients with renal failure (e.g., the intestinal secretion of ciprofloxacin is increased). This study investigated the influence of renal failure on the pharmacokinetics of ciprofloxacin following oral and parenteral administration to rats of a dose of 50 mg/kg of body weight. After parenteral administration, only renal clearance (CLR) was reduced in nephrectomized rats (5.3+/-1.4 versus 17.8+/-4.7 ml/min/kg, P < 0.01, nephrectomized versus control rats). However, nonrenal clearance was increased in nephrectomized rats (32+/-4 versus 15+/-5 ml/min/kg, P < 0.01, nephrectomized versus control rats), suggesting compensatory mechanisms for reduced renal function. After oral administration, apparent total clearance and CLR were reduced (P < 0.01) in nephrectomized rats (117+/-25 and 6.8+/-4.4 ml/min/kg, respectively) compared with the values for control rats (185+/-9 and 22.6+/-5.3 ml/min/kg, respectively) and the area under the concentration-time curve was higher (P < 0.01) for nephrectomized rats (436.3+/-90.5 mg. min/liter) than for control rats (271.3+/-14.3 mg.min/liter). Terminal elimination half lives in the two groups remained constant after oral and parenteral administration. These results suggest an increased bioavailability of ciprofloxacin in nephrectomized rats, which was confirmed by a nonlinear mixed-effect model.
Asunto(s)
Antiinfecciosos/farmacocinética , Ciprofloxacina/farmacocinética , Riñón/efectos de los fármacos , Insuficiencia Renal/metabolismo , Administración Oral , Animales , Antiinfecciosos/administración & dosificación , Antiinfecciosos/efectos adversos , Ciprofloxacina/administración & dosificación , Ciprofloxacina/efectos adversos , Infusiones Parenterales , Riñón/cirugía , Masculino , Tasa de Depuración Metabólica , Nefrectomía , Ratas , Ratas Sprague-DawleyRESUMEN
The synergy between amoxicillin and cefotaxime against two strains of Enterococcus faecalis (JH2-2 and 6370) in vitro and in rabbit endocarditis was investigated. In vitro synergy was obtained only when amoxicillin concentrations were below the MBC and when cefotaxime concentrations were above 1 microg/ml. No synergy was observed in vivo, because of the short period of time during which these pharmacologic requirements were achieved.
Asunto(s)
Amoxicilina/uso terapéutico , Cefotaxima/uso terapéutico , Quimioterapia Combinada/uso terapéutico , Endocarditis Bacteriana/tratamiento farmacológico , Enterococcus faecalis/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Amoxicilina/farmacocinética , Animales , Cefotaxima/farmacocinética , Sinergismo Farmacológico , Quimioterapia Combinada/farmacocinética , ConejosRESUMEN
Ofloxacin, a chiral fluoroquinolone, possesses two optical isomers. The antibacterial activity of S-(-)-ofloxacin is 8 to 128 times higher than that of R-(+)-ofloxacin. In the rat, a saturable absorption process has been described for racemic ofloxacin. In the present study we investigated the mechanism underlying the in vivo intestinal absorption of ofloxacin enantiomers in the rat. Blood samples were collected from the portal vein. Our results show that the intestinal absorption of ofloxacin isomers is pH dependent, both enantiomers being best absorbed at neutral pH. S-(-)-Ofloxacin seems to have a greater affinity for the intestinal transporter (initial concentrations at 5 min [C(init)] are 0.17 +/- 0.04 and 0.12 +/- 0.03 microg/ml for S-(-)- and R-(+)-ofloxacin, respectively). Dipeptides fail to modify ofloxacin absorption, but amino acids reduce both isomers' absorption (C(init) is reduced by 53 and 33% with glycine for S-(-)- and R-(+)-ofloxacin, respectively, and by 59 and 42% with L-leucine). Gamma amino butyric acid interferes with the absorption of ofloxacin isomers, but less seriously than do amino acids. Furthermore, ofloxacin competes with other fluoroquinolones or P-glycoprotein substrates for a common secretory pathway, resulting in an increased rate of absorption for both ofloxacin isomers; this is probably an indirect result of their reduced efflux from the apical side of intestinal cells.
Asunto(s)
Antiinfecciosos/farmacocinética , Absorción Intestinal/fisiología , Intestino Delgado/metabolismo , Ofloxacino/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Aminoácidos/farmacología , Animales , Área Bajo la Curva , Disponibilidad Biológica , Dipéptidos/farmacología , Absorción Intestinal/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
To understand the mechanism of hepatic glycogen depletion found in uremia and under sucrose feeding, we examined net hepatic glycogenolysis-associated active enzymes and metabolites during fasting. Liver was taken 2, 7, and 18 h after food removal in uremic and pair-fed control rats fed either a sucrose or cornstarch diet for 21 days. Other uremic and control rats fasted for 18 h were refed a sucrose meal to measure glycogen increment. Glycogen storage in uremia was normal, suggesting effective glycogen synthesis. During a short fast, sucrose feeding and uremia enhanced net glycogenolysis through different but additive mechanisms. Under sucrose feeding, there were high phosphorylase alpha levels associated with hepatic insulin resistance. In uremia, phosphorylase alpha levels were low, but the enzyme was probably activated in vivo by a fall of inhibitors (ATP, alpha-glycerophosphate, fructose-1,6-diphosphate, and glucose) and a rise of Pi, as verified in vitro. Enhanced gluconeogenesis was also suggested, but excessive hepatic glucose production was unlikely in uremia. During fasting, hypoglycemia occurred in uremia due to reduced glycogenolysis, inefficient hepatic gluconeogenesis, and impaired renal gluconeogenesis. This may be relevant to poor fasting tolerance in uremia, which could be aggravated under excessive sucrose intake.
Asunto(s)
Sacarosa en la Dieta/farmacología , Glucógeno Hepático/metabolismo , Hígado/metabolismo , Fosforilasa a/metabolismo , Uremia/metabolismo , Animales , Glucemia/metabolismo , Creatinina/sangre , Carbohidratos de la Dieta , Glucógeno Sintasa/metabolismo , Riñón/fisiología , Riñón/fisiopatología , Hígado/anatomía & histología , Hígado/efectos de los fármacos , Masculino , Tamaño de los Órganos , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Almidón , Factores de Tiempo , Urea/sangre , Aumento de PesoRESUMEN
The aim of this work was to examine the mechanism involved in intestinal elimination of the two optical isomers of ofloxacin in the rat. An intestinal segment was isolated in situ and perfused with saline, while drug solution was administered via the carotid artery. Blood samples and intestinal effluents were collected and analyzed by a high-performance liquid chromatography method. We observed saturable and stereoselective intestinal elimination of the ofloxacin enantiomers. The elimination process favored the R-(+) form of the molecule. After a parenteral dose of 20 mg of racemic ofloxacin per kg of body weight, intestinal clearances were 0.23 +/- 0.03 versus 0.30 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively. Ciprofloxacin and pefloxacin interfered with ofloxacin elimination and significantly reduced the intestinal clearance of S-(-)- and R-(+)-ofloxacin. With concomitant ciprofloxacin, intestinal clearances became 0.13 +/- 0.02 versus 0.17 +/- 0.03 ml/min and 0.14 +/- 0.01 versus 0.19 +/- 0.05 ml/min with pefloxacin for S-(-)- and R-(+)-ofloxacin, respectively. Those findings argue for the presence of a common transport system in the rat intestine with variable affinities for fluoroquinolones. In addition, verapamil and quinidine, two P-glycoprotein blockers, significantly reduced the intestinal elimination of both ofloxacin isomers (with concomitant verapamil, intestinal clearances were 0.12 +/- 0.02 versus 0.18 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively, while with concomitant quinidine, values were 0.18 +/- 0.01 versus 0.23 +/- 0.01 ml/min without modifying their areas under the concentration-time curve in serum. Similar results were found with another fluoroquinolone, ciprofloxacin, in previous work. P-glycoprotein appears to be involved in the intestinal elimination of fluoroquinolones in rats. The characterization of fluoroquinolone intestinal elimination has significant clinical relevance for the better evaluation of the influence of this secretory pathway on antibiotic efficacy and selection of resistant bacteria within the intestinal flora.
Asunto(s)
Antiinfecciosos/farmacocinética , Proteínas Portadoras/metabolismo , Mucosa Intestinal/metabolismo , Ofloxacino/farmacocinética , Animales , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Técnicas In Vitro , Masculino , Perfusión , Ratas , Ratas Sprague-Dawley , EstereoisomerismoRESUMEN
The intestinal elimination of ciprofloxacin in the large bowel was studied in a rabbit model. Segments from the cecum, colon, and sigmoid colon along with their intact blood vessels were isolated and perfused, and their contents were collected over a 90-min period following the administration of a single parenteral dose of 27 mg of ciprofloxacin per kg of body weight. The elimination rates of ciprofloxacin were 0.126 +/- 0.084 micrograms.min-1.cm-2 in the cecum and 0.264 +/- 0.126, 0.11 +/- 0.07, and 0.21 +/- 0.141 micrograms.min-1.cm-2 in the proximal colon, distal colon, and sigmoid colon, respectively. The calculated fraction of ciprofloxacin eliminated in the large bowel was 3% of the parenteral dose administered. The elimination pattern of ciprofloxacin in the large bowel may explain the unusual activity of this fluoroquinolone in modifying the colonic flora.
Asunto(s)
Antiinfecciosos/farmacocinética , Ciprofloxacina/farmacocinética , Intestino Grueso/metabolismo , Animales , Antiinfecciosos/administración & dosificación , Transporte Biológico , Ciego/metabolismo , Ciprofloxacina/administración & dosificación , Colon Sigmoide/metabolismo , Íleon/metabolismo , Yeyuno/metabolismo , Masculino , ConejosRESUMEN
The intestinal transepithelial elimination of sparfloxacin and fleroxacin was compared with that of ciprofloxacin in a rat model following a single parenteral administration of 25 mg of each of the antibiotics per kg of body weight. All three fluoroquinolones were eliminated through the small intestine. Ciprofloxacin was eliminated in the proximal jejunum at a rate of 1.97 +/- 0.70 micrograms/cm2, while the elimination rates of fleroxacin and sparfloxacin were 0.64 +/- 026 and 0.21 +/- 0.10 micrograms/cm2, respectively, over a 90-min collection period. In the ileum, the elimination rates of ciprofloxacin, fleroxacin, and sparfloxacin over the same period were 1.44 +/- 0.77, 1.00 +/- 0.33, and 0.41 +/- 0.26 micrograms/mc2, respectively. These data suggest that these fluoroquinolones undergo a transepithelial elimination process in the small intestine. This route of elimination may be important in the therapy of bacterial diarrhea.
Asunto(s)
Antiinfecciosos/farmacocinética , Ciprofloxacina/farmacocinética , Fleroxacino/farmacocinética , Fluoroquinolonas , Íleon/metabolismo , Yeyuno/metabolismo , Quinolonas/farmacocinética , Animales , Cromatografía Líquida de Alta Presión , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The intestinal transepithelial elimination of ciprofloxacin was studied in a rabbit model. Jejunal, ileal, and cecal segments along with their intact blood vessels were isolated and perfused, and their contents were collected over a 120-min period following administration of a single parenteral dose of 27 mg of ciprofloxacin per kg of body weight. The intestinal elimination rates of ciprofloxacin were 0.126 +/- 0.084, 0.235 +/- 0.22, and 0.11 +/- 0.084 micrograms.min-1.cm-2 for the jejunal, ileal, and cecal segments, respectively. The calculated fractions of ciprofloxacin eliminated were 3.3 mg from the jejunum and 13.8 mg from the ileum, representing 19% of the administered dose. Additional amounts of 2.5 to 3.7 mg or 4.9 to 7.3% of the administered dose were eliminated from the cecum. Elimination was probably not due to a passive diffusion process but rather due to an active transepithelial transport. This intestinal elimination pattern of ciprofloxacin may explain the unusual activity of the fluoroquinolones in modifying the intestinal flora.
Asunto(s)
Ciprofloxacina/farmacocinética , Mucosa Intestinal/metabolismo , Animales , Ciego/metabolismo , Ciprofloxacina/administración & dosificación , Íleon/metabolismo , Técnicas In Vitro , Inyecciones Intravenosas , Yeyuno/metabolismo , Masculino , ConejosRESUMEN
The transepithelial intestinal elimination of ciprofloxacin was studied in a rat model. Two jejunal and one ileal segment, along with their intact blood supplies, were isolated and continuously perfused. Following a single parenteral administration of 25 mg/kg ciprofloxacin, the drug in amounts of 1.97 +/- 0.70, 1.88 +/- 0.99, and 1.44 +/- 0.77 micrograms/cm2 of mucosal surface was recovered over 90 min from the proximal and distal jejunal loops and the ileal loop, respectively, reaching a calculated fraction of 6%-7% of the dose eliminated in the entire small intestine. The rate of intestinal elimination related linearly to the parenteral dose. In the proximal jejunum, however, doses > 25 mg/kg were not accompanied by a concomitant increase in the eliminated fraction, suggesting a saturable transport process. Parenterally administered probenecid, amoxicillin, and nifedipine and changes ranging from 6.0 to 8.5 in the pH of the perfusates did not alter transepithelial elimination. This pathway of elimination of ciprofloxacin may play an important role in curing intestinal infections.