RESUMEN
The pharmacokinetic behaviours of amoxicillin (AMX) and clavulanic acid (CA) in swine were studied after either an intravenous or oral administration of AMX (10 mg/kg) and CA (2.5 mg/kg). The concentrations of these two medicines in swine plasma were determined using high-performance liquid chromatographic-tandem mass spectrometry, and the data were analysed using a noncompartmental model with the WinNonlin software. After intravenous administration, both substances were absorbed rapidly and reached their effective therapeutic concentration quickly. CA was eliminated more slowly compared with AMX. Moreover, the distribution volume of AMX was larger than that of CA, suggesting that AMX could penetrate tissues better. After oral administration of the granular formulation, no significant difference was observed in the mean elimination half-life value between AMX and CA. The mean maximal plasma concentrations of AMX and CA, reached after 1.14 and 1.32 hr, were 2.58 and 1.91 µg/m, respectively. The mean oral bioavailability of AMX and CA was 23.6% and 26.4%, respectively. After oral administration, the T>MIC50 for three common respiratory pathogens was over 6.12 hr. Therefore, oral administration could be more effective in the clinical therapy of pigs, especially when administered twice daily.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Antibacterianos/farmacocinética , Porcinos/sangre , Administración Oral , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Femenino , Semivida , Inyecciones Intravenosas/veterinaria , MasculinoRESUMEN
OBJECTIVES: The aims of this study were to determine the side effect frequency and serum and urine drug concentrations of amoxicillin-clavulanic acid in cats with and without azotemic chronic kidney disease (azCKD). METHODS: Owners whose cats had been prescribed amoxicillin-clavulanic acid completed a survey regarding the occurrence and type of side effects, and whether treatment was altered as a result. Cats were defined as azCKD (serum creatinine concentration >2.0 mg/dl, urine specific gravity [USG] <1.035 with a clinical diagnosis of chronic kidney disease) and without azCKD (serum creatinine concentration <2.0 mg/dl). Data were assessed with Fisher's exact test. Serum and urine samples were obtained from client-owned cats with azCKD (n = 6) and without azCKD (n = 6, serum creatinine concentration <1.8 mg/dl, USG >1.035) that were receiving amoxicillin-clavulanic acid. Amoxicillin and clavulanic acid were measured with liquid chromatography coupled to tandem mass spectrometry and compared between groups with a Mann-Whitney test. Correlation between serum creatinine and drug concentrations in urine and serum was determined using Spearman's rank test. RESULTS: Sixty-one surveys were returned (11 azCKD cats and 50 without azCKD cats). No significant difference in the presence of side effects or type of side effects was seen between groups; however, significantly more azCKD cats had more than one side effect (P = 0.02). More owners of azCKD cats reported that an alteration in treatment plan was necessitated by side effects (55% vs 12%; P = 0.008). Urine amoxicillin was significantly lower in cats with azCKD (P = 0.01) and serum amoxicillin trended toward significance (P = 0.07). Serum amoxicillin concentration was positively correlated with serum creatinine (P = 0.02; r = 0.62) and urine amoxicillin concentration was negatively correlated with serum creatinine (P = 0.01; r = -0.65). CONCLUSIONS AND RELEVANCE: The data suggest that cats with azCKD have altered pharmacokinetics of amoxicillin, which may contribute to an increased incidence of multiple side effects.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio , Antibacterianos , Azotemia/veterinaria , Enfermedades de los Gatos/tratamiento farmacológico , Combinación Amoxicilina-Clavulanato de Potasio/efectos adversos , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Combinación Amoxicilina-Clavulanato de Potasio/orina , Animales , Antibacterianos/efectos adversos , Antibacterianos/sangre , Antibacterianos/orina , Azotemia/tratamiento farmacológico , Gatos , Femenino , Masculino , Proyectos PilotoRESUMEN
The pharmacokinetic properties of amoxicillin (AMX) and clavulanic acid (CLV) were studied in healthy cats following single intravenous and oral dosage of 10 mg/kg of AMX and 2.5 mg/kg of CLV. The drug concentrations in plasma were determined by a high-performance liquid chromatographic-tandem mass spectrometry (LC-MS-MS) method validated for canine plasma and further subjected to noncompartmental analysis. After intravenous injection, no significant difference (p > 0.05) was found in the volume of distribution of these two compounds. In addition, AMX and CLV were both rapidly eliminated from plasma with a clearance of 0.453 and 0.921 L hr-1 kg-1 , respectively; however, a quicker elimination was observed for CLV (p < 0.01). After oral administration, both drugs were characterized by rapid absorption with an absorption half-life of 1.10 and 0.70 hr for AMX and CLV, respectively. Significant differences were observed between their absorption rates (p < 0.05). However, the oral bioavailabilities of AMX and CLV (75.57% and 98.15%, respectively) were not statistically different (p > 0.05). A total intravenous or oral dose at 12.5 mg/kg of AMX and CLV (4:1) is predicted to be effective for treating those bacterial species isolated from cats with a minimum inhibitory concentration (MIC) of ≤0.25 µg/ml for 12 hr, based on a time above the MIC (T > MIC) of 40%.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Antibacterianos/farmacocinética , Gatos/sangre , Administración Oral , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Área Bajo la Curva , Estudios Cruzados , Femenino , Semivida , Inyecciones Intravenosas , MasculinoRESUMEN
The use of human generic amoxicillin-clavulanic acid formulations in veterinary medicine is currently lacking supportive evidence. This pilot study was conducted to determine preliminary pharmacokinetic parameters and relative oral bioavailability of a human generic and veterinary proprietary 4:1 amoxicillin-clavulanic acid formulation in healthy dogs to evaluate whether drug exposure was similar and to determine if further comparative investigation is warranted. Each dog received a single oral dose of each formulation containing 500:125 mg of amoxicillin-clavulanic acid at two separate instances with a 2 wk washout period between product administration. Following drug administration, blood was collected at fixed times over 24 hr to measure plasma amoxicillin and clavulanic acid concentrations using liquid chromatography-mass spectrometry. There were no statistically significant differences between pharmacokinetic parameters of either formulation. Clavulanic acid showed greater between-dog variation in drug exposure between formulations compared with amoxicillin and was also observed to be more variable within the veterinary proprietary formulation. The average relative oral bioavailability was 98.2% (23.6% coefficient of variation) for amoxicillin and 152.6% (64.3% coefficient of variation) for clavulanic acid between formulations. This pilot investigation supports the need for further bioequivalence studies regarding these formulations before commenting on product interchangeability.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio , Antibacterianos , Perros , Inhibidores de beta-Lactamasas , Animales , Perros/sangre , Perros/metabolismo , Femenino , Masculino , Administración Oral , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Antibacterianos/farmacocinética , Área Bajo la Curva , Inhibidores de beta-Lactamasas/administración & dosificación , Inhibidores de beta-Lactamasas/sangre , Inhibidores de beta-Lactamasas/farmacocinética , Disponibilidad Biológica , Estudios Cruzados , Composición de Medicamentos , Medicamentos Genéricos , Semivida , Proyectos Piloto , Distribución AleatoriaRESUMEN
OBJECTIVES: To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens. METHODS: Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens. RESULTS: AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily). CONCLUSIONS: The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Absorción Fisiológica , Administración Oral , Adolescente , Adulto , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Antibacterianos/sangre , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Método de Montecarlo , Adulto JovenRESUMEN
We investigated the efficacies of cefotaxime (CTX) and amoxicillin (AMX)-clavulanate (CLA) (AMC) against extended-spectrum-ß-lactamase (ESBL)-producing Escherichia coli in vitro and in a murine model of urinary tract infection (UTI). MICs, the checkerboard dilution method, and time-kill curves were used to explore the in vitro synergism between cefotaxime and amoxicillin-clavulanate against two isogenic E. coli strains-CFT073-RR and its transconjugant, CFT073-RR Tc bla(CTX-M-15)-harboring a bla(CTX-M-15) plasmid and a bla(OXA-1) plasmid. For in vivo experiments, mice were separately infected with each strain and treated with cefotaxime, amoxicillin, and clavulanate, alone or in combination, or imipenem, using therapeutic regimens reproducing time of free-drug concentrations above the MIC (fT≥MIC) values close to that obtained in humans. MICs of amoxicillin, cefotaxime, and imipenem were 4/>1,024, 0.125/1,024, and 0.5/0.5 mg/liter, for CFT073-RR and CFT073-RR Tc bla(CTX-M-15), respectively. The addition of 2 mg/liter of clavulanate (CLA) restored the susceptibility of CFT073-RR Tc bla(CTX-M-15) to CTX (MICs of the CTX-CLA combination, 0.125 mg/liter). The checkerboard dilution method and time-kill curves confirmed an in vitro synergy between amoxicillin-clavulanate and cefotaxime against CFT073-RR Tc bla(CTX-M-15). In vivo, this antibiotic combination was similarly active against both strains and as effective as imipenem. In conclusion, the cefotaxime and amoxicillin-clavulanate combination appear to be an effective, easy, and already available alternative to carbapenems for the treatment of UTI due to CTX-M-producing E. coli strains.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Antibacterianos/farmacología , Cefotaxima/farmacología , Pielonefritis/tratamiento farmacológico , Infecciones Urinarias/tratamiento farmacológico , Escherichia coli Uropatógena/efectos de los fármacos , beta-Lactamasas/genética , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Animales , Antibacterianos/sangre , Antibacterianos/farmacocinética , Cefotaxima/sangre , Cefotaxima/farmacocinética , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Expresión Génica , Humanos , Imipenem/farmacología , Ratones , Ratones Endogámicos CBA , Pruebas de Sensibilidad Microbiana , Plásmidos/química , Plásmidos/metabolismo , Pielonefritis/sangre , Pielonefritis/microbiología , Pielonefritis/patología , Infecciones Urinarias/sangre , Infecciones Urinarias/microbiología , Infecciones Urinarias/patología , Escherichia coli Uropatógena/enzimología , Escherichia coli Uropatógena/genética , Resistencia betalactámica/genética , beta-Lactamasas/metabolismoRESUMEN
INTRODUCTION: Acute otitis media is the most common respiratory tract infection in infancy and early childhood that is managed with antimicrobial agents. Ninety-three per cent of the cases diagnosed in Spain are treated with antibiotics, and Streptococcus pneumoniae and untypeable Haemophilus influenzae are the most frequently isolated pathogens. The aim of this work was to evaluate the usefulness of amoxicillin, amoxicillin/clavulanate and ceftriaxone for the empirical treatment of acute otitis media, looking at the pharmacokinetic variability and the antimicrobial susceptibility of paediatric strains of the two main pathogens responsible for AOM in Spain, Streptococcus pneumoniae and Haemophilus influenzae. METHODS: Free-drug plasma concentrations were simulated and the probability of target attainment at each minimum inhibitory concentration and the cumulative fraction of response (CFR) were determined. Microbiological susceptibility information was extracted from SAUCE 3 surveillance. RESULTS: CFR with amoxicillin varied from 83% to 96% against S. pneumoniae and from 78% to 86% against H. influenzae. CFR was always >85% with amoxicillin/clavulanate. With the 3-day ceftriaxone regimen, the probability of achieving free concentrations above MIC at 72 hours significantly increased compared to the single dose, with which CFR ranged from 70% to 84%. CONCLUSIONS: High-dose amoxicillin (at least 80 mg/kg/day) should be the first-line therapy in uncomplicated infections, whereas amoxicillin/clavulanate (40 mg/kg/day) should be the choice when additional coverage for H. influenzae is desired. Administration of 3 daily doses of ceftriaxone increases bacteriological eradication probability when compared with one-day regimen, although additional clinical evaluations are necessary to establish the best target attainment with ceftriaxone.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Amoxicilina/farmacocinética , Ceftriaxona/farmacocinética , Simulación por Computador , Infecciones por Haemophilus/tratamiento farmacológico , Método de Montecarlo , Otitis Media/tratamiento farmacológico , Infecciones Neumocócicas/tratamiento farmacológico , Amoxicilina/sangre , Amoxicilina/farmacología , Amoxicilina/uso terapéutico , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Ceftriaxona/sangre , Ceftriaxona/farmacología , Ceftriaxona/uso terapéutico , Niño , Relación Dosis-Respuesta a Droga , Infecciones por Haemophilus/microbiología , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/enzimología , Haemophilus influenzae/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones Neumocócicas/microbiología , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/enzimología , Streptococcus pneumoniae/aislamiento & purificación , Resistencia betalactámicaAsunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Antibacterianos/farmacocinética , Administración Oral , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Disponibilidad Biológica , Pollos/metabolismo , Femenino , Inyecciones Intravenosas/veterinariaRESUMEN
The reliability of a silicone double-lumen catheter implanted into the external jugular vein and tunnelled towards the neck region was investigated in eight pigs. Surgery was uneventful without interference with the normal homoeostasis during 8 days. After injection of amoxicillin/clavulanic acid through the distal port of the catheter, analysis of drug components in the simultaneous blood samples obtained by the proximal port and a Venoject system were comparable in one pig. Histological control of the catheterized jugular veins pointed to an acceptable tissue reaction while bacteriological examination of the tip of the catheters was negative in only three animals. A moulding of the intestinal veins was made in a pig cadaver to determine the optimal length of insertion of a silicone portal catheter from the splenic vein towards the portal vein. Surgery was straightforward in four pigs whereby the catheter was exteriorized towards the back region. No complications were encountered during and after surgery for 9 days. The technique of a double-lumen catheter placed into the jugular vein and a transsplenic portal catheter is a useful tool for the study of the pharmacokinetics and also the first-pass effect of drugs in experimental pigs.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Antibacterianos/farmacocinética , Cateterismo/veterinaria , Venas Yugulares/cirugía , Vena Porta/cirugía , Porcinos/sangre , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Cateterismo/métodos , Catéteres de Permanencia/veterinaria , Cromatografía Liquida/veterinaria , Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Procedimientos Quirúrgicos del Sistema Digestivo/veterinaria , Femenino , Siliconas , Porcinos/metabolismo , Porcinos/cirugíaRESUMEN
INTRODUCTION: The objective of this study was to evaluate the efficacy of the most commonly used antimicrobial treatments in odontogenic infections in children and adolescents on the basis of pharmacokinetic/ pharmacodynamic (PK/PD) criteria. METHODS: Unbound drug plasma concentration-time curves were simulated with mean population pharmacokinetic parameters of amoxicillin, co-amoxiclav, cefuroxime axetil, spiramycin, clindamycin, azithromycin, and metronidazole. For drugs showing time-dependent antibacterial killing, the time above MIC90 of the pathogens studied was calculated (T>MIC). For drugs with concentration-dependent bactericidal activity, the area under the concentration-time curve (AUC)/MIC90 ratio was calculated. RESULTS: Adequate efficacy indexes (T>MIC>40%) against all the microorganisms examined with the exception of Veillonella spp. were obtained with co-amoxiclav (80 mg/kg/day). Clindamycin (40 mg/kg/day) obtained adequate PK/PD indexes except for Lactobacillus, Actinobacillus actinomycetemcomitans, penicillin-resistant Peptostreptococcus, and Eikenella corrodens. High-dose amoxicillin yielded unsatisfactory results against many bacterial species. Azithromycin and metronidazole showed inadequate efficacy indexes against the majority of pathogens studied (AUC/MIC90<25). CONCLUSION: When antibiotic therapy is needed for odontogenic infections in children and adolescents, the most active empirical therapeutic choice is co-amoxiclav with high doses of amoxicillin. Clindamycin can be used as an alternative option. These results should be confirmed in clinical trials, in which the PK/PD approach could be useful for the design and assessment of results.
Asunto(s)
Antibacterianos/uso terapéutico , Gingivitis/tratamiento farmacológico , Periodontitis/tratamiento farmacológico , Pulpitis/tratamiento farmacológico , Adolescente , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Antibacterianos/sangre , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Niño , Preescolar , Caries Dental/prevención & control , Relación Dosis-Respuesta a Droga , Femenino , Gingivitis/sangre , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Periodontitis/sangre , Pulpitis/sangre , Resultado del TratamientoRESUMEN
The aim of this study was to explore bactericidal activity of total and free serum simulated concentrations after the oral administration of cefditoren (400 mg, twice daily [bid]) versus the oral administration of amoxicillin-clavulanic acid extended release formulation (2,000/125 mg bid) against Haemophilus influenzae. A computerized pharmacodynamic simulation was performed, and colony counts and beta-lactamase activity were determined over 48 h. Three strains were used: ampicillin-susceptible, beta-lactamase-negative ampicillin-resistant (BLNAR) (also resistant to amoxicillin-clavulanic acid) and beta-lactamase-positive amoxicillin-clavulanic acid-resistant (BLPACR) strains, with cefditoren MICs of < or =0.12 microg/ml and amoxicillin-clavulanic acid MICs of 2, 8, and 8 microg/ml, respectively. Against the ampicillin-susceptible and BLNAR strains, bactericidal activity (> or =3 log(10) reduction) was obtained from 6 h on with either total and free cefditoren or amoxicillin-clavulanic acid. Against the BLPACR strain, free cefditoren showed bactericidal activity from 8 h on. In amoxicillin-clavulanic acid simulations the increase in colony counts from 4 h on occurred in parallel with the increase in beta-lactamase activity for the BLPACR strain. Since both BLNAR and BLPACR strains exhibited the same MIC, this was due to the significantly lower (P < or = 0.012) amoxicillin concentrations from 4 h on in simulations with beta-lactamase positive versus negative strains, thus decreasing the time above MIC (T>MIC). From a pharmacodynamic point of view, the theoretical amoxicillin T>MIC against strains with elevated ampicillin/amoxicillin-clavulanic acid MICs should be considered with caution since the presence of beta-lactamase inactivates the antibiotic, thus rendering inaccurate theoretical calculations. The experimental bactericidal activity of cefditoren is maintained over the dosing interval regardless of the presence of a mutation in the ftsI gene or beta-lactamase production.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Antibacterianos/farmacología , Cefalosporinas/farmacología , Genes Bacterianos/genética , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/genética , Peptidoglicano Glicosiltransferasa/genética , beta-Lactamasas/genética , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Antibacterianos/sangre , Cefalosporinas/sangre , Recuento de Colonia Microbiana , Cinética , Pruebas de Sensibilidad Microbiana , Unión Proteica , Espectrofotometría UltravioletaRESUMEN
We investigated the efficacy of 2 formulations of Augmentin on experimental pneumonia due to Haemophilus influenzae (HI) in rabbits. Two strains were used (H128 and 401285) with amoxicillin/clavulanic acid MICs of 1/0.5 mg/l and 4/2 mg/l. Pneumonia was induced in immunocompetent rabbits by inoculation of 10 log(10) CFU HI. The treatments were infused by using computer controlled pumps in order to mimic the human pharmacokinetic (PK) profile of either conventional Augmentin treatment (875/125 mg twice daily) or the sustained release formulation (SR: 2000/125 mg twice daily). After 2 d of treatment, the bacterial concentrations in the lungs were similar for both strains and both treatments: isolate H128, conventional Augmentin reduced bacterial numbers to 3.8+/-2.1 log(10) CFU/g and Augmentin SR to 3.1+/-2.4 log(10) CFU/g; isolate 401285, conventional Augmentin to 3.5+/-2. Thus, both treatments demonstrated similar efficacy against H. influenzae pneumonia in this model, even when induced by a strain with an amoxicillin/clavulanic acid MIC of 4/2 mg/l. These results support current breakpoints for conventional Augmentin against H. influenzae and suggest that Augmentin SR is at least as effective against these isolates.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Antibacterianos/uso terapéutico , Infecciones por Haemophilus/tratamiento farmacológico , Haemophilus influenzae , Neumonía Bacteriana/tratamiento farmacológico , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Animales , Antibacterianos/sangre , Antibacterianos/farmacocinética , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana , Infecciones por Haemophilus/microbiología , Masculino , Pruebas de Sensibilidad Microbiana , Neumonía Bacteriana/microbiología , ConejosRESUMEN
Telithromycin is a new ketolide antimicrobial with a good in vitro activity against both aerobic and anaerobic respiratory pathogens. In this study, we evaluated the antibacterial activity over time of telithromycin (800mg), azithromycin (500mg), and amoxicillin/clavulanate (875/125mg) in serum following single oral doses of these agents to 10 healthy subjects. Inhibitory and bactericidal titers were determined at 2, 6, 12, and 24h after each dose and the median titer was used to determine antibacterial activity. Against two azithromycin-resistant strains of Streptococcus pneumoniae, both telithromycin (MIC=0.25 and 0.5 microg/mL) and amoxicillin/clavulanate exhibited inhibitory and cidal activity for at least 6h. All three antibiotics provided prolonged (>or=12h) inhibitory activity against strains of Hemophilus influenzae (telithromycin MIC=4.0 microg/ml). Both telithromycin and amoxicillin/clavulanate exhibited rapid and prolonged inhibitory activity (>or=12h) against each of the anaerobes studied (Finegoldia [Peptostreptococcus] magna Peptostreptococcus micros, Prevotella bivia, and Prevotella melaninogenica). Moreover, both agents provided bactericidal activity against both Prevotella species. In this ex vivo pharmacodynamic study, we found that telithromycin provided rapid and prolonged antibacterial activity in serum against macrolide-resistant strains of S. pneumoniae, beta-lactamase-positive and -negative strains of H. influenzae, and common respiratory anaerobic pathogens. These findings suggest that telithromycin could have clinical utility in the treatment of community-acquired mixed aerobic-anaerobic respiratory tract infections, including chronic sinusitis and aspiration pneumonia.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Azitromicina/farmacología , Bacterias/efectos de los fármacos , Cetólidos/farmacología , Prueba Bactericida de Suero , Administración Oral , Adulto , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Antibacterianos/farmacología , Azitromicina/administración & dosificación , Azitromicina/sangre , Bacterias Aerobias/efectos de los fármacos , Bacterias Anaerobias/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Haemophilus influenzae/efectos de los fármacos , Humanos , Cetólidos/administración & dosificación , Cetólidos/sangre , Masculino , Persona de Mediana Edad , Peptostreptococcus/efectos de los fármacos , Prevotella/efectos de los fármacos , Prevotella melaninogenica/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Factores de TiempoRESUMEN
A new peroral amoxicillin/clavulanate therapeutic system composed of immediate release tablet and controlled release floating capsule was developed and evaluated by in vivo bioavailability study. Pharmacokinetic (PK) parameters for amoxicillin and clavulanic acid of the new therapeutic systems: AUCt, AUCi, (AUCt/AUCi), Cmax, Tmax, kel, T(1/2) and additionally for amoxicillin T(4) and T(2) were calculated from the plasma levels. The study confirmed enhanced pharmacokinetic parameters of a newly developed therapeutic system containing 1500 mg of amoxicillin and 125 mg of clavulanic acid. Prolonged time over MIC of amoxicillin in relation to a regular immediate release amoxicillin/clavulanate formulation was confirmed.
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Combinación Amoxicilina-Clavulanato de Potasio/química , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Antibacterianos/química , Antibacterianos/farmacocinética , Administración Oral , Adulto , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Área Bajo la Curva , Bacterias/efectos de los fármacos , Bacterias/crecimiento & desarrollo , Disponibilidad Biológica , Química Farmacéutica , Estudios Cruzados , Preparaciones de Acción Retardada , Composición de Medicamentos , Semivida , Humanos , Concentración de Iones de Hidrógeno , Masculino , Tasa de Depuración Metabólica , Pruebas de Sensibilidad Microbiana , Valores de Referencia , Solubilidad , Tecnología Farmacéutica , Equivalencia TerapéuticaRESUMEN
OBJECTIVES: We conducted a prospective pharmacokinetic study of oral co-amoxiclav in patients with melioidosis to determine the optimal dosage and dosing interval in this potentially fatal infection. PATIENTS AND METHODS: Serial plasma concentrations were measured after administration of two 1 g tablets of Augmentin (1750 mg of amoxicillin and 250 mg of clavulanate) to 14 adult patients with melioidosis. Monte Carlo simulation was used to predict the concentration of each drug following multiple doses of co-amoxiclav at different dosages and dose intervals. The proportion of the dose-interval above MIC (T > MIC) was calculated from 10,000 simulated subject plasma concentration profiles together with chequerboard MIC data from 46 clinical isolates and four reference strains of Burkholderia pseudomallei. RESULTS: The median (range) observed maximum plasma concentrations of amoxicillin and clavulanate were 11.5 (3.3-40.2) mg/L and 5.1 (0.8-12.1) mg/L, respectively. The median (range) elimination half-lives were 94 (73-215) and 89 (57-140) min, respectively. Simulation indicated that co-amoxiclav 1750/250 mg given at 4, 6, 8 or 12 hourly dosing intervals would be associated with a T > MIC of < or = 50% in 0.7%, 2.8%, 8.6% and 33.2% of patients, respectively. Corresponding proportions for T > MIC of > or = 90% were 95.8%, 78.6%, 50.2% and 10.8%, respectively. CONCLUSIONS: The dosing interval for co-amoxiclav (750/250 mg) in melioidosis should not be greater than 6 h.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Melioidosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Amoxicilina/sangre , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Ácido Clavulánico/sangre , Humanos , Melioidosis/microbiología , Persona de Mediana Edad , Factores de TiempoAsunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Quimioterapia Combinada/farmacología , Adulto , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Química Farmacéutica , Preparaciones de Acción Retardada , Quimioterapia Combinada/administración & dosificación , Quimioterapia Combinada/sangre , Quimioterapia Combinada/farmacocinética , Femenino , Humanos , Masculino , Enfermedades de la Boca/tratamiento farmacológico , ComprimidosRESUMEN
The purpose of this study was to apply a replicate design approach to a bioequivalence study of amoxicillin/clavulanic acid combination following a 250/125 mg oral dose to 23 subjects, and to compare the analysis of individual bioequivalence with average bioequivalence. This was conducted as a 2-treatment 2-sequence 4-period crossover study. Average bioequivalence was shown, while the results from the individual bioequivalence approach had no success in showing bioequivalence. In conclusion, the individual bioequivalence approach is a strong statistical tool to test for intra-subject variances and also subject-by-formulation interaction variance compared with the average bioequivalence approach.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Quimioterapia Combinada/farmacocinética , Administración Oral , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Combinación de Medicamentos , Quimioterapia Combinada/sangre , Humanos , Masculino , Comprimidos , Equivalencia Terapéutica , Factores de TiempoRESUMEN
The in vitro effect that the presence of components of non-specific immunity (serum plus polymorphonuclear neutrophils) has on the bactericidal activity of co-amoxiclav was explored against Streptococcus pneumoniae strains exhibiting an amoxicillin MIC > or =4 mg/L. Eight penicillin-resistant clinical isolates non-susceptible to co-amoxiclav with MICs of 4 (two strains), 8 (four strains) and 16 mg/L (two strains) were used. Values of MBC were identical to MIC values in all cases. Time-kill curves were performed with co-amoxiclav concentrations achievable in serum after a single oral dose administration of the new 2000/125 mg sustained-release formulation. Results were expressed as percentage of reduction of initial inocula after 3 h incubation. Control curves showed growth with no reduction of initial inocula. Against strains with MIC of 4 and 8 mg/L, the results obtained with the antibiotic alone or with the presence of factors of non-specific immunity were similar, with a weak combined effect due to the intrinsic activity of co-amoxiclav (reductions of initial inocula ranging from 70 to 99.16%). Against strains with MIC of 16 mg/L, the addition of PMN in the presence of serum increased the reduction of bacterial load provided by the aminopenicillin, even at sub-inhibitory concentrations (25.8% versus 51.1% at 0.5 x MIC concentration--8/0.5 mg/L). This combined activity against strains with an amoxicillin MIC of 16 mg/L which decreased the bacterial load may be important in preventing bacterial proliferation within the host and the transmission of resistant clones to others.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Amoxicilina/farmacología , Quimioterapia Combinada/farmacología , Neutrófilos/inmunología , Streptococcus pneumoniae/efectos de los fármacos , Administración Oral , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Quimioterapia Combinada/administración & dosificación , Quimioterapia Combinada/sangre , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
A new amoxicillin/clavulanic acid tablet formulation (Solutab tablet, Forcid Solutab) containing amoxicillin/clavulanic acid (875/125) has been developed. The aim of the present study was to demonstrate bioequivalence between the new tablet formulation (test), taken as an intact tablet and after prior dispersal, versus the originator product viz. Augmentan film-coated tablet (875/125) used as reference. The study was performed in 48 healthy volunteers according to an open, single-dose, crossover design. Bioequivalence was demonstrated using Cmax and AUC(0-infinity) as primary parameters of evaluation for both amoxicillin and clavulanic acid with 90% confidence intervals of the ratios Solutab tablet/Augmentan within the range of 0.8-1.25. The duration of the plasma concentration exceeding the amoxicillin minimal inhibitory concentration (MICs) was calculated using individual plasma concentration-time curves and compartmental analysis. The data showed that the bioavailability characteristics of the test tablet, taken intact or in dispersed form, and the reference tablets were very similar. The analysis, moreover, also confirmed the appropriateness of using a b.i.d. dosage regimen for both formulations, taking into account the pharmacodynamic breakpoint values for some major pathogens.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Quimioterapia Combinada/farmacocinética , Adulto , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/sangre , Área Bajo la Curva , Química Farmacéutica , Estudios Cruzados , Esquema de Medicación , Quimioterapia Combinada/administración & dosificación , Quimioterapia Combinada/sangre , Femenino , Semivida , Humanos , Absorción Intestinal , Masculino , Persona de Mediana Edad , Comprimidos , Equivalencia TerapéuticaRESUMEN
The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in dogs, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single dose in an open, randomized, two-way crossover study involving 24 male Beagle dogs treated with two Amoxi-Clav formulations (A Clavubactin and B Synulox, each with 200/50 mg). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin was 1.5 h (t1/2 = 1.52 +/- 0.19 h, Cmax = 11.4 +/- 2.74 microg/mL), and that of clavulanic acid 0.76 h (t1/2 = 0.71 +/- 0.23 h, Cmax = 2.06 +/- 1.05 microg/mL). There was a fivefold variation in the AUCt of clavulanic acid for both formulations, while the AUCt of amoxicillin varied by a factor of 2. The mean ratio of the AUCt amoxicillin : clavulanic acid was 12.7 +/- 3.65 for formulation A and 11.8 +/- 5.22 for formulation B (P = 0.51).