Application of pharmacokinetic/pharmacodynamic analysis to evaluate the adequacy of antimicrobial therapy for pediatric acute otitis media in Spain before and after the introduction of the PCV7 vaccine.

OBJECTIVE: To evaluate, by applying pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the change in antibiotic susceptibility after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Spain had any influence on the usefulness of the antimicrobials more frequently used as empirical treatment of pediatric acute otitis media (AOM). METHODS: PK parameters and susceptibility of Streptococcus pneumoniae and Haemophilus influenzae were obtained from bibliography. Monte Carlo simulation was used to estimate the cumulative fraction of response (CFR), understood as the expected probability of therapy success. For amoxicillin and amoxicillin/clavulanate, the target was free antibiotic concentration remaining above the minimum inhibitory concentration (MIC) for ≥50% of the dosing interval (fT>MIC≥50%), whereas for cefuroxime axetil and cefotaxime, the target was fT>MIC≥60%. CFR values ≥90% were considered successful. RESULTS: When all serotypes of S. pneumoniae are considered, amoxicillin and cefotaxime turned out to reach a high probability of success, and difference before and after vaccination was scarce. For H. influenzae, CFR values were higher with amoxicillin/clavulanate than with amoxicillin. For both microorganisms, cefuroxime axetil resulted in low probability of success in the two periods of study. CONCLUSIONS: We have shown that the introduction of the PCV7 vaccination did not lead to changes in the probability of success of the current empiric treatments of the AOM. Integrated PK/PD analysis has demonstrated to be a useful tool to identify changes in antimicrobial activity after the implantation of a vaccination program, providing complementary information to the simple assessment of MIC values.

Impact of high-flux haemodialysis on the probability of target attainment for oral amoxicillin/clavulanic acid combination therapy.

Clearance of small molecules such as amoxicillin and clavulanic acid is expected to increase during high-flux haemodialysis, which may result in lower concentrations and thus reduced efficacy. To date, clearance of amoxicillin/clavulanic acid (AMC) during high-flux haemodialysis remains largely unexplored. Using published pharmacokinetic parameters, a two-compartment model with first-order input was simulated to investigate the impact of high-flux haemodialysis on the probability of target attainment (PTA) of orally administered AMC combination therapy. The following pharmacokinetic/pharmacodynamic targets were used to calculate the PTA. For amoxicillin, the time that the free concentration remains above the minimum inhibitory concentration (MIC) of ≥50% of the dosing period (≥50%ƒT>MIC) was used. For clavulanic acid, the time that the free concentration was >0.1 mg/L of ≥45% of the dosing period (≥45%ƒT>0.1 mg/L) was used. Dialysis clearance reported in low-flux haemodialysis for both compounds was doubled to represent the likely clearance during high-flux haemodialysis. Monte Carlo simulations were performed to produce concentration-time profiles over 10 days in 1000 virtual patients. Seven different regimens commonly seen in clinical practice were explored. When AMC was dosed twice daily, the PTA was mostly ≥90% for both compounds regardless of when haemodialysis commenced. When administered once daily, the PTA was 20-30% for clavulanic acid and ≥90% for amoxicillin. The simulations suggest that once-daily orally administered AMC in patients receiving high-flux haemodialysis may result in insufficient concentrations of clavulanic acid to effectively treat infections, especially on days when haemodialysis occurs.

Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.

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.

Pharmacokinetic/pharmacodynamic evaluation of amoxicillin, amoxicillin/clavulanate and ceftriaxone in the treatment of paediatric acute otitismedia in Spain

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 untype able Haemophilus influenza 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 a teach 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% agains tH. 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 (AU)

Introducción: La otitis media aguda (OMA) es la infección del tracto respiratorio más común en la infanciaque es tratada con agentes antimicrobianos. El noventa y tres por ciento de los casos diagnosticados en España se tratan con antibióticos, siendo Streptococcus pneumoniae y Haemophilus influenzae no tipable los patógenos aislados más frecuentes. El objetivo de este trabajo ha sido evaluar la utilidad de amoxicilina,amoxicilina/clavulánico y ceftriaxona en el tratamiento empírico de OMA teniendo en cuenta la variabilidad farmacocinética y la sensibilidad antimicrobiana de las cepas pediátricas de los dos patógenos principales responsables de OMA en España, Streptococcus pneumoniae y Haemophilus influenzae. Métodos: Se simularon las concentraciones de fármaco libre para cada antibiótico y se calculó la probabilidad de alcanzar el objetivo terapéutico para cada valor de concentración mínima inhibitoria (CMI) y la fracción de respuesta acumulada (CFR).Resultados: La CFR de amoxicilina osció entre el 83% y el 96% frente a S. pneumoniae y entre el 78% y el86% para H. influenzae. En el caso de amoxicilina/clavulánico, la CFR fue siempre >85%. Con ceftriaxonadurante 3 días, la probabilidad de alcanzar concentraciones libres por encima de la CMI a las 72 horasfue significativamente superior a la probabilidad obtenida con una sola dosis, con valores de CFR que oscilaron entre el 70% y el 84%.Conclusiones: Amoxicilina a altas dosis debería ser la primera opción para el tratamiento de infecciones no complicadas, mientras que amoxicilina/clavulánico deberá utilizarse cuando se sospecha que H. influenzae puede ser responsable de la infección. La administración de ceftriaxona durante 3 días incrementa la probabilidad de erradicar la infección repecto a la administración de una única dosis, aunque son necesarios estudios clínicos para establecer el mejor objetivo terapéutico con ceftriaxona (AU)

Pharmacokinetic/pharmacodynamic evaluation of amoxicillin, amoxicillin/clavulanate and ceftriaxone in the treatment of paediatric acute otitis media in Spain.

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.

Etiología y sensibilidad de los uropatógenos identificados en infecciones urinarias bajas no complicadas de la mujer (Estudio ARESC): implicaciones en la terapia empírica / Etiology and sensitivity of uropathogens identified in uncomplicated lower urinary tract infections in women (ARESC Study): implications on empiric therapy

Pacientes y método: Estudio multicéntrico ARESC de 9 hospitales españoles, que incluyó de forma consecutiva 803 mujeres, de edades entre 18 y 65 años, con cistitis no complicada, con el fin de identificar la etiología y evaluar su sensibilidad a 9 antimicrobianos. Resultados: De 803 pacientes consecutivas con ITU baja no complicada, fueron finalmente incluidas 784 pacientes. El urocultivo fue positivo en el 87,7% de las muestras. De un total de 650 uropatógenos, Escherichia coli (E. coli) fue el más frecuente (79,2%), seguido por Staphylococcus saprophyticus (4,4%), Proteus mirabilis (4,3%), Enterococcus faecalis (3,2%) y Klebsiella pneumoniae (2,3%). E. coli mostró una elevada sensibilidad a fosfomicina (97,2%), nitrofurantoína (94,1%) y algo menor a ciprofloxacino (88,1%). Las tasas de resistencia a fluorquinolonas fueron más elevadas en mujeres postmenopáusicas (17 frente a 10%). E. coli sigue presentando unas elevadas resistencias a ampicilina (65%) y a cotrimoxazol (34%), y en la actualidad, aproximadamente un 25% de las cepas son resistentes a amoxicilina/clavulánico y cefuroxima. Conclusiones: En España se observan elevados índices de resistencia de E. coli a antibióticos de amplio uso. Fosfomicina y nitrofurantoína preservan una elevada actividad in vitro. Considerando otros aspectos prácticos, como la posología (una sola dosis) y la influencia del consumo total de quinolonas sobre los niveles de resistencia en enterobacterias y en otros microorganismos, fosfomicina trometamol representa una alternativa empírica de primera elección para la cistitis no complicada de la mujer (AU)

Background and objective: To determine the etiology and susceptibility of uropathogens identified in women with uncomplicated lower urinary tract infections (UTI). Patients and methods: In a multicenter study (ARESC) in 9 Spanish hospitals, 803 female patients with uncomplicated cystitis were consecutively enrolled and evaluated to identify the uropathogens and their susceptibility to 9 antimicrobials.Results: Of 803 patients with uncomplicated cystitis, 784 patients were included. A positive urine culture was found in 87.7% of the samples. Of the 650 pathogens isolated, Escherichia coli (E. coli) was the most frequent (79.2%) followed by Staphylococcus saprophyticus (4.4%), Proteus mirabilis (4.3%), Enterococcus faecalis (3.2%) and Klebsiella pneumoniae (2.3%). E. coli showed a high rate of susceptibility to phosphomycin (97.2%), nitrofurantoin (94.1%) and somewhat lower to ciprofloxacin (88.1%). Fluorquinolone resistance rates were higher among postmenopausal women (17 versus 10%). E. coli was highly resistant to ampicillin (65%) and cotrimoxazole (34%) and 25% of the strains were resistant to amoxicillin/clavulanalic acid and cefuroxime. Conclusions: In Spain, E. coli shows high resistance rates to widely used antimicrobial antibiotics. Phosphomycin and nitrofurantoin have a high in vitro activity. Taking into account practical aspects such as convenience (only one dose), and the influence of the amount of fluorquinolone use on enterobacteriaceae and other microorganisms resistance levels, phosphomycin trometamol represents the option of first choice for the empirical treatment of uncomplicated cystitis in women (AU)

[Antibiotic therapy in odontogenic infections in children and adolescents: pharmacokinetic/pharmacodynamic analysis]. / Utilización de antimicrobianos en las infecciones odontogénicas en niños y adolescentes: análisis farmacocinético/farmacodinámico (PK/PD).

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.

Utilización de antimicrobianos en las infecciones odontogénicas en niños y adolescentes: análisis farmacocinético/farmacodinámico (PK/PD) / Antibiotic therapy in odontogenic infections in children and adolescents: pharmacokinetic/pharmacodynamic analysis

INTRODUCCIÓN. El objetivo de este estudio es evaluar la eficacia de los tratamientos más utilizados en infecciones odontogénicas en niños y adolescentes aplicando criterios farmacocinéticos/farmacodinámicos (PK/PD).MÉTODOS. Se han simulado las curvas de concentración plasmática libre-tiempo a partir de parámetros farmacocinéticos medios de amoxicilina, amoxicilina-ácido clavulánico, cefuroxima axetilo, espiramicina, clindamicina, azitromicina y metronidazol. Para los antibióticos con actividad dependiente del tiempo, se ha calculado el tiempo durante el cual las concentraciones permanecen por encima de la concentración inhibitoria mínima (CIM90)de los microorganismos (T > CIM). Para los antimicrobianos con actividad dependiente de la concentración, se ha calculado el cociente entre el área bajo la curva y la CIM90 (ABC/CIM90).RESULTADOS. Con amoxicilina-ácido clavulánico(80 mg/kg/día) se han obtenido índices de eficacia adecuados frente a los microorganismos estudiados(T > CIM > 40%), excepto para Veillonella spp. Clindamicina (40 mg/kg/día) también ha presentado índices PK/PD adecuados frente a la mayoría de los patógenos, excepto Lactobacillus, Actinobacillus actinomycetemcomitans, Peptostreptococcus resistente a penicilina y Eikenellacorrodens. Con dosis altas de amoxicilina los resultados nohan sido satisfactorios frente a varias especies bacterianas. Con azitromicina y metronidazol no se han alcanzado valores adecuados frente a la mayoría de patógenos (ABC/CIM90 < 25).CONCLUSIÓN. El tratamiento empírico más adecuado en infecciones odontogénicas en niños y adolescentes esamoxicilina-ácido clavulánico en altas dosis de amoxicilina, aunque se puede utilizar como alternativa clindamicina. Sería conveniente confirmar estos resultados mediante ensayos clínicos, para cuyo diseño y evaluación podría serde gran utilidad la aplicación de estudios PK/PD(AU)

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 ad equate PK/PD indexes except for Lactobacillus, Actinobacillus actinomy cetemcomitans, 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 inclinical trials, in which the PK/PD approach could be useful for the design and assessment of results (AU)

Efficacy of amoxycillin-clavulanate in an experimental model of murine pneumonia caused by AmpC-non-hyperproducing clinical isolates of Escherichia coli resistant to cefoxitin.

The algorithms included in most automated systems used for antimicrobial susceptibility testing (e.g., Vitek 2) consider that Escherichia coli isolates resistant to cefoxitin are AmpC-hyperproducers and, consequently, resistant also to amoxycillin-clavulanate. However, a recent study revealed that 30% of E. coli clinical isolates resistant to cefoxitin remained susceptible in vitro to amoxycillin-clavulanate. The aim of the present study was to evaluate the in-vivo efficacy of amoxycillin-clavulanate in the treatment of an experimental model of pneumonia, using two clonally related isolates (with identical repetitive extragenic palindromic sequence (REP)-PCR patterns) of AmpC-non-hyperproducing and OmpF-lacking E. coli (Ec985 and Ec571) that were resistant to cefoxitin and susceptible to cefotaxime and amoxycillin-clavulanate. MICs were determined using a microdilution technique, and in-vitro bactericidal activity was tested using time-kill assays. The in-vivo efficacy of amoxycillin, amoxycillin-clavulanate and cefotaxime against both isolates was tested in a murine pneumonia model using immunocompetent C57BL/6 mice. Ec571 (a TEM-1/2 producer) was resistant to amoxycillin, whereas Ec985 (a TEM-1/2 non-producer) was susceptible. Amoxycillin, amoxycillin-clavulanate and cefotaxime were bactericidal for Ec985, and amoxycillin-clavulanate and cefotaxime were bactericidal for Ec571 at different concentrations and time-points, as determined using time-kill assays. Treatment with amoxycillin, amoxycillin-clavulanate and cefotaxime reduced the bacterial lung concentration of Ec985 compared with non-treated controls (p <0.05), whereas amoxycillin-clavulanate and cefotaxime showed efficacy against Ec571 when compared with the control and amoxycillin groups (p <0.05). Regardless of the exact underlying mechanism(s) of resistance, amoxycillin-clavulanate was effective in the experimental murine model in the treatment of pneumonia caused by AmpC-non-hyperproducing strains of E. coli resistant to cefoxitin.

The use of pharmacokinetic/pharmacodynamic principles to predict clinical outcome in paediatric acute otitis media.

Double tympanocentesis studies of children with acute otitis media, carried out over an 11-year period, were used to confirm that pharmacokinetic (PK) and pharmacodynamic (PD) parameters can be used as predictors of the bacteriological and clinical efficacy of antimicrobial agents. Predicted susceptibilities of common respiratory pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae, were compared with the bacteriological outcome of treatment in which the high-dose formulation of amoxicillin/clavulanate (90mg/kg/day) given twice daily achieved the greatest bacteriological eradication rates for an oral agent. Further analysis of the data has indicated that failure to eradicate bacteria from the middle ear fluid is strongly correlated with clinical failure.

Efficacy of humanlike Augmentin SR (2000/125 mg) twice daily treatment on Haemophilus influenzae experimental pneumonia in rabbits.

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.

A new amoxicillin/clavulanate therapeutic system: preparation, in vitro and pharmacokinetic evaluation.

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.

[Pharmacokinetic/pharmacodynamic analysis of antibiotic therapy in dentistry and stomatology]. / Análisis farmacocinético/farmacodinámico (PK/PD) de la antibioterapia en odontoestomatología.

INTRODUCTION: This study evaluates the efficacy of various antimicrobial treatments for orofacial infections on the basis of pharmacokinetic/pharmacodynamic (PK/PD) criteria. METHODS: A complete a literature search was undertaken to establish the MIC90 values of the five microorganisms most frequently isolated in odontogenic infections and the pharmacokinetic parameters of 13 antibiotics used in these infections. Pharmacokinetic simulations were then carried out with mean population parameters and efficacy indexes were calculated for the 47 treatment regimens analyzed. For drugs showing time-dependent antibacterial killing, the time above MIC (t > MIC) was calculated. For drugs with concentration-dependent bactericidal activity, the AUC/MIC was calculated. RESULTS: Amoxicillin-clavulanic (500 mg/8 h or 1000 mg/12 h) and clindamycin (300 mg/6 h) in the time-dependent killing group and moxifloxacin (400 mg/24 h) in the concentration-dependent group showed adequate efficacy indexes against the five pathogens considered to be the most commonly implicated in odontogenic infections. The spiramycin plus metronidazole combination, present in the commercial formulation Rhodogyl, did not reach satisfactory PK/PD indexes. CONCLUSION: PK/PD indexes, which are useful predictors of the potential efficacy of antibacterial therapy, were used with ontogenic infections in the present study. The PK/PD simulations showed that amoxicillin-clavulanic, clindamycin and moxifloxacin were the most suitable antibiotics for this kind of infection. Clinical trials are required to confirm that this methodology is useful in these pathologic processes.

[Optimization of amoxicillin/clavulanate therapy based on pharmacokinetic/pharmacodynamic parameters in patients with diabetic foot infection]. / Optimalizace lécby amoxicilín/klavulanátem na základe PK/PD parametru u nemocných s infekcí pri syndromu diabetické nohy.

AIM OF THE STUDY: Individualized optimization of amoxicillin/clavulanate (AMC) antimicrobial therapy in diabetic foot infection. METHODS: Pharmacokinetic analysis of individual steady-state plasma amoxicillin concentrations was done both in the i.v. infusion phase and in the oral phase of AMC, administered on the basis of the quantitative susceptibility of the detected microbe(s). The in vitro growth/killing dynamic parameters on model of Staphylococcus aureus as the most frequent isolate were evaluated. Therapeutic protocol optimization, leading to prediction of the earliest time to reduce the number of viable bacteria to 10-6 as a surrogate criterion of efficacy, was performed. RESULTS: Based on individual plasma amoxicillin oscillations in 17 patients suffering from infected diabetic foot ulcers and the model microbial dynamic parameters, the reduction of the number of viable bacteria was reached significantly earlier after the administration of continuous i.v. AMC infusion than after the same daily AMC dose administered intermittently. In case of highly susceptible staphylococcal strain, highly frequent oral therapy of AMC (not longer than 8 hrs dosing interval) was also sufficiently effective. Decreasing plasma amoxicillin concentrations exponentially extended the time required for effective reduction of microbes. CONCLUSION: Individualized optimization of amoxicillin/clavulanate dosage on the basis of growth/killing microbial dynamic parameters and antibiotic concentration/time fluctuations may enhance the antimicrobial effect and the treatment of infected non-critical ischemic diabetic foot ulcers.

Building in efficacy: developing solutions to combat drug-resistant S. pneumoniae.

The development of our understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine antimicrobial efficacy has advanced substantially over the last 10 years. We are now in a position to use PK/PD principles to set targets for antimicrobial design and optimisation so that we can predict eradication of specific pathogens or resistant variants when agents are used clinically. Optimisation of PK/PD parameters to enable the treatment of resistant pathogens with oral agents may not be possible with many current agents, such as some cephalosporins, macrolides and fluoroquinolones. Aminopenicillins, however, such as amoxicillin, have linear PK and have a good safety profile even at high doses. The new pharmacokinetically enhanced oral formulation of amoxicillin/clavulanate, 2000/125 mg twice daily, was designed using PK/PD principles to be able to eradicate Streptococcus pneumoniae with amoxicillin MICs of up to and including 4 mg/L, which includes most penicillin-resistant isolates. For amoxicillin and amoxicillin/clavulanate, a time above MIC (T > MIC) of 35-40% of the dosing interval (based on blood levels) is predictive of high bacteriological efficacy. This target was met by the design of a unique bilayer tablet incorporating 437.5 mg of sustained-release sodium amoxicillin in one layer plus 562.5 mg of immediate-release amoxicillin trihydrate and 62.5 mg of clavulanate potassium in the second layer, with two tablets administered for each dose. This unique design extends the bacterial killing time by increasing the T > MIC to 49% of the dosing interval against pathogens with MICs of 4 mg/L, and 60% of the dosing interval against pathogens with MICs of 2 mg/L. Based on these results, this new amoxicillin/clavulanate formulation should be highly effective in treating respiratory tract infections due to drug-resistant S. pneumoniae as well as beta-lactamase-producing pathogens, such as Haemophilus influenzae and Moraxella catarrhalis.

Augmentin (amoxicillin/clavulanate) in the treatment of community-acquired respiratory tract infection: a review of the continuing development of an innovative antimicrobial agent.

Amoxicillin/clavulanate (Augmentin) is a broad-spectrum antibacterial that has been available for clinical use in a wide range of indications for over 20 years and is now used primarily in the treatment of community-acquired respiratory tract infections. Amoxicillin/clavulanate was developed to provide a potent broad spectrum of antibacterial activity, coverage of beta-lactamase-producing pathogens and a favourable pharmacokinetic/pharmacodynamic (PK/PD) profile. These factors have contributed to the high bacteriological and clinical efficacy of amoxicillin/clavulanate in respiratory tract infection over more than 20 years. This is against a background of increasing prevalence of antimicrobial resistance, notably the continued spread of beta-lactamase-mediated resistance in Haemophilus influenzae and Moraxella catarrhalis, and penicillin, macrolide and quinolone resistance in Streptococcus pneumoniae. The low propensity of amoxicillin/clavulanate to select resistance mutations as well as a favourable PK/PD profile predictive of high bacteriological efficacy may account for the longevity of this combination in clinical use. However, in certain defined geographical areas, the emergence of S. pneumoniae strains with elevated penicillin MICs has been observed. In order to meet the need to treat drug-resistant S. pneumoniae, two new high-dose amoxicillin/clavulanate formulations have been developed. A pharmacokinetically enhanced tablet dosage form of amoxicillin/clavulanate 2000/125 mg twice daily (available as Augmentin XR in the USA), has been developed for use in adult respiratory tract infection due to drug-resistant pathogens, such as S. pneumoniae with reduced susceptibility to penicillin, as well as beta-lactamase-producing H. influenzae and M. catarrhalis. Amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses (Augmentin ES-600) is for paediatric use in persistent or recurrent acute otitis media where there are risk factors for the involvement of beta-lactamase-producing strains or S. pneumoniae with reduced penicillin susceptibility. In addition to high efficacy, amoxicillin/clavulanate has a well known safety and tolerance profile of the two new high-dose formulations are not significantly different from those of conventional formulations. Amoxicillin/clavulanate is included in guidelines and recommendations for the treatment of bacterial sinusitis, acute otitis media, community-acquired pneumonia and acute exacerbations of chronic bronchitis. Amoxicillin/clavulanate continues to be an important agent in the treatment of community-acquired respiratory tract infections, both now and in the future.

Amoxicillin/clavulanate for infections in infants and children: past, present and future.

Chemical synthesis of the penicillin nucleus in the 1950s made introduction of a broad array of new and important antimicrobials, including ampicillin and amoxicillin, possible. Ampicillin was introduced in 1962 in oral and parenteral forms as the first of the semisynthetic penicillins to provide increased activity against Gram-negative bacteria. Amoxicillin replaced oral ampicillin beginning in 1974 because amoxicillin resulted in higher and more prolonged serum concentrations than did equivalent doses of ampicillin. Amoxicillin/clavulanate (Augmentin) was introduced in the United States in 1984 to enhance the activity of amoxicillin by addition of the beta-lactamase inhibitor, clavulanic acid. During the past 20 years, amoxicillin/clavulanate has proven effective for a variety of pediatric infectious diseases, particularly acute otitis media (AOM). In 2001, a new pediatric formulation, high dose amoxicillin/clavulanate (Augmentin ES-600) was approved for use in the United States. The high dose preparation addressed the needs of pediatricians by providing greater amounts of amoxicillin while maintaining the same daily dose of clavulanic acid as the regular strength formulation. Doubling the dose of amoxicillin for management of recurrent and persistent AOM was recommended in 1999 by the Centers for Disease Control and Prevention because of concern about the increased incidence of nonsusceptible strains of Streptococcus pneumoniae. The original formulation combined amoxicillin/clavulanate in a 4:1 ratio and was followed by a 7:1 ratio formulation. The high dose formulation (600 mg of amoxicillin per 5 ml) provides a 14:1 ratio of amoxicillin to clavulanate. Although management of AOM will likely undergo changes in the coming years, amoxicillin is expected to remain first line therapy for AOM. For children who fail initial therapy with amoxicillin, high dose amoxicillin/clavulanate, an oral cephalosporin or parenteral ceftriaxone is recommended.

Amoxicillin/clavulanic acid: a review of its use in the management of paediatric patients with acute otitis media.

UNLABELLED: Amoxicillin/clavulanic acid (Augmentin), Augmentin ES-600 is a well established, orally administered combination of amoxicillin (a semisynthetic antibacterial agent) and clavulanic acid (a beta-lactamase inhibitor). Amoxicillin/clavulanic acid shows good activity against the main pathogens associated with acute otitis media (AOM), including penicillin-susceptible and -intermediate strains of Streptococcus pneumoniae, and beta-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis. It has moderate activity against penicillin-resistant S. pneumoniae; a high-dose formulation has been developed with the aim of providing better coverage for penicillin-resistant strains. Amoxicillin/clavulanic acid (conventional formulations, mostly 40/10 mg/kg/day in three divided doses) produced clinical response rates similar to those of oral cephalosporin comparators and similar to or significantly greater than those for intramuscular ceftriaxone in randomised trials in paediatric patients with AOM (mean age approximately 2 to 5 years). Clinical response rates were generally similar for amoxicillin/clavulanic acid and macrolide comparators (mean patient age approximately 1 to 6 years), although significantly better clinical and bacteriological responses were seen versus azithromycin in one randomised trial (mean patient age approximately 1 year). The high-dose formulation of amoxicillin/clavulanic acid (90/6.4 mg/kg/day in two divided doses) eradicated a high proportion of penicillin-resistant S. pneumoniae (penicillin MICs 2 or 4 mg/L) in a large noncomparative trial in children with AOM (upper limit of the US indication for S. pneumoniae is 2 mg/L). Amoxicillin/clavulanic acid is generally well tolerated. A low total incidence of adverse events (3.6%) and no serious events were reported from a large paediatric postmarketing study. The most frequently reported adverse events in children are mild gastrointestinal disturbances. Diarrhoea is generally less frequent with twice-daily than with three-times-daily treatment. The new high-dose formulation showed similar tolerability to a conventional twice-daily formulation (45/6.4 mg/kg/day) in a well controlled trial. CONCLUSIONS: Amoxicillin/clavulanic acid is a well established broad-spectrum antibacterial treatment which is effective and well tolerated in the treatment of AOM in paediatric patients. The high-dose combination should prove valuable in treating AOM caused by penicillin-intermediate and -resistant S. pneumoniae (approved in the US for penicillin MIC < or =2 mg/L). Based on recent recommendations and the available data, high-dose amoxicillin/clavulanic acid can be considered a treatment of choice for recurrent or persistent paediatric AOM (after failure of amoxicillin alone) where involvement of resistant pathogens is suspected.

Outcome of treatment of respiratory tract infections due to Streptococcus pneumoniae, including drug-resistant strains, with pharmacokinetically enhanced amoxycillin/clavulanate.

The efficacy of a new pharmacokinetically enhanced formulation of amoxycillin/clavulanate (AMX/CA) 2000/125 mg, twice daily, designed to provide adequate levels of amoxycillin over the 12-h dosing interval to eradicate penicillin-resistant Streptococcus pneumoniae (PRSP) with amoxycillin (+/-clavulanic acid) MICs of /=4 mg/l. In the pooled comparator group, the success rate at follow-up was 86.5% (45/52). For PRSP (AMX/CA MICs of 0.5-8 mg/l), the overall success rate was 98.2% (55/56) at follow-up for AMX/CA 2000/125 mg and 50.0% (2/4) for comparators. AMX/CA 2000/125 mg shows efficacy comparable to that of the comparators evaluated against S. pneumoniae infections. Due to its favorable pharmacokinetic/pharmacodynamic profile and promising clinical success, the new AMX/CA 2000/125 mg formulation should be considered for the empirical treatment of respiratory tract infections in regions with a high prevalence of antimicrobial-resistant S. pneumoniae and in patients at high risk of antimicrobial-resistant S. pneumoniae infection as this formulation covers many PRSP that are non-susceptible to amoxycillin (+/-clavulanic acid) (MICs of >/=4 mg/l) as well as common beta-lactamase-producing respiratory pathogens.

The efficacy and safety of oral pharmacokinetically enhanced amoxycillin-clavulanate 2000/125 mg, twice daily, versus oral amoxycillin-clavulanate 1000/125 mg, three times daily, for the treatment of bacterial community-acquired pneumonia in adults.

This double-blind, double-dummy, parallel-group study was designed to show that a pharmacokinetically enhanced formulation of oral amoxycillin-clavulanate (16:1, 2000/125 mg), twice daily, is at least as effective clinically and microbiologically as oral amoxycillin-clavulanate 1000/125 mg, three times daily, in the 10 day treatment of community-acquired pneumonia (CAP) in adults. The pharmacokinetically enhanced formulation is designed to provide higher serum concentrations of amoxycillin for a longer period than standard dosing to achieve coverage of Streptococcus pneumoniae isolates with amoxycillin-clavulanic acid minimum inhibitory concentrations (MICs) up to and including 4 mg/l. A total of 344 patients with CAP from 77 centres received amoxycillin-clavulanate 2000/125 mg twice daily for 10 days (169 patients) or amoxycillin-clavulanate 1000/125 mg three times daily for 10 days (175 patients). The most common pathogen isolated was S. pneumoniae (52.3% of patients, amoxycillin-clavulanate 2000/125 mg group; 46.8% of patients, amoxycillin-clavulanate 1000/125 mg group). In the clinical per-protocol (PP) population at test of cure (days 18-39), the clinical success rate in the amoxycillin-clavulanate 2000/125 mg group was at least as good as in the amoxycillin-clavulanate 1000/125 mg group (91.5 and 93.0%, respectively; 95% CI, -8.3, 5.4). The radiological and bacteriological success rates at test of cure for the PP populations were 92.4 and 90.6% in the amoxycillin-clavulanate 2000/125 mg group and 93.9 and 84.4% in the amoxycillin-clavulanate 1000/125 mg group, respectively. The clinical, bacteriological and radiological success rates at the end of therapy (days 11-17) for the PP populations were all over 85%. Both regimens were well tolerated, with no differences in adverse events between the groups. Amoxycillin-clavulanate 2000/125 mg, twice daily, is well tolerated and at least as effective clinically as amoxycillin-clavulanate 1000/125 mg, three times daily, in patients with CAP and may also be appropriate for the treatment of infections due to S. pneumoniae strains with high-level penicillin resistance.