Pharmacokinetic/pharmacodynamic evaluation of the antimicrobial therapy of pneumococcal invasive disease in adults in post-PCV13 vaccine period in Madrid, Spain.

The objective of our study was to evaluate by pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the antimicrobials used for the treatment of invasive pneumococcal disease (IPD) in adults, including meningitis, are adequate considering the susceptibility profile of S. pneumoniae in Spain after the implantation of PVC13 vaccine. Pharmacokinetic parameters of benzylpenicillin and cefotaxime were obtained from the literature, and susceptibility data of invasive S. pneumoniae strains recovered in 2017 (post-PCV13 vaccination period) were provided by the Public Health Regional Laboratory of Madrid. We have also studied levofloxacin because it is used to treat pneumococcal pneumonia previously to be diagnosed as bacteremic pneumonia. Monte Carlo simulation was used to estimate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). All doses of benzylpenicillin except 2 mU q6h provide a high probability of treatment success for MIC values ≤ 1 mg/L; 4 mU q4h is even useful for MIC values up to 4 mg/L. This high dose, used for the treatment of meningitis, also provides high probability of treatment success for MIC ≤ 0.5 mg/L. At the susceptibility EUCAST breakpoint (≤ 0.5 mg/L), cefotaxime provides a high rate of PD target achievement, even at the lowest dose (1 g q8h). For meningitis, 2 g q6h ensures probabilities of target attainment ≥90% for MIC up to 1 mg/L. Our study confirms that after the implementation of PCV13 vaccine, the treatment with benzylpenicillin and cefotaxime provides high probability of the therapy success of IPD, including meningitis.

Pharmacokinetics of linezolid in critically ill patients on continuous renal replacement therapy: Influence of residual renal function on PK/PD target attainment.

PURPOSE: To assess the pharmacokinetics of linezolid in septic patients undergoing continuous renal replacement therapy (CRRT) and investigate whether residual renal function affects the probability of attaining the pharmacokinetic/pharmacodynamic (PK/PD) target. MATERIAL AND METHODS: Prospective study conducted in three Spanish hospitals. Linezolid concentrations were measured in plasma and effluent samples and pharmacokinetic parameters were calculated. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) were calculated considering AUC24/MIC>80 and %T>MIC > 85% as the PK/PD indexes related to efficacy. RESULTS: In anuric patients (CrCl<10 mL/min), the contribution of extracorporeal Cl to total Cl was higher (47% vs 16%) than in patients with residual renal function (CrCl≥10 mL/min). For an MIC of 2 mg/L, AUC24/MIC>80 was achieved in >85% of the anuric patients, but in <15% of the patients with residual renal function. CONCLUSIONS: The standard dose (600 mg q12h) ensures a moderately high probability of treatment success in anuric patients when the infection is due to microorganisms with MIC≤2 mg/L; although higher doses increase the probability of treatment success, the safety is compromised. In patients with residual renal function, the standard dose is insufficient, but 900 mg q8h provide higher probability of treatment success without compromising the safety.

Population pharmacokinetics of piperacillin and tazobactam in critically ill patients undergoing continuous renal replacement therapy: application to pharmacokinetic/pharmacodynamic analysis.

OBJECTIVES: To evaluate the pharmacokinetics of piperacillin/tazobactam in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to assess the success of the therapy against susceptible bacteria. PATIENTS AND METHODS: Sixteen patients undergoing CRRT with different degrees of renal function were included in the study. Blood and ultrafiltrate samples were drawn after administration of piperacillin/tazobactam (4/0.5 g) every 4, 6 or 8 h. The data were analysed by a population approach using NONMEM 7.2. The probability of target attainment (PTA) of maintaining free piperacillin levels above the MIC during the entire dosing interval was estimated by simulation of intermittent and continuous infusions. RESULTS: The pharmacokinetics of piperacillin and tazobactam were best described by two-compartment models where the elimination of both drugs was conditioned by renal [dependent on creatinine clearance (CLCR)], non-renal and extracorporeal clearances. A 20 min infusion of piperacillin/tazobactam administered every 6 h provided high PTAs against MICs ≤ 32 mg/L in patients with severe renal failure. In patients with normal or moderate renal function PTAs ≥ 90% were only obtained up to MICs ≤ 8 mg/L with short infusions. However, simulating continuous infusion, higher probabilities of success were obtained against MICs of 32 and 16 mg/L when CLCR was 50 and 100 mL/min, respectively. CONCLUSIONS: Population pharmacokinetic models have been developed and validated for piperacillin and tazobactam. Based on the pharmacokinetic/pharmacodynamic analysis, dosing recommendations are given considering the residual renal function of the patient and the MIC for the isolated bacteria.

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.

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)

[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.

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

INTRODUCCIÓN. Evaluar la eficacia de diferentes tratamientos antimicrobianos en infecciones oro faciales utilizando criterios fármaco cinéticos/fármaco dinámicos (PK/PD).MÉTODOS. Tras llevar a cabo una revisión bibliográfica que permitió conocer los valores de concentración inhibitoria mínima (CIM90) de cinco de los microorganismos más frecuentemente aislados en infecciones odontógenas y los parámetros fármaco-cinéticos de 13 antibióticos utilizados en este tipo de infecciones, se realizaron simulaciones farmacocinéticas con parámetros poblacionales medios y se calcularon los índices de eficacia para las 47 pautas posológicas analizadas. Para los antibióticos dependientes de tiempo se calculó el tsupra CIM, mientras que para los dependientes de concentración se determinó el cociente ABC/CIM90.RESULTADOS. Amoxicilina-ácido clavulánico (500 mg/8 ho 1.000 mg/12 h) y clindamicina (300 mg/6 h), entre los antibióticos con actividad dependiente de tiempo, y moxifloxacino (400 mg/24 h) entre los dependientes de concentración mostraron índices de eficacia adecuados frente a los cinco microorganismos considerados como los más frecuentemente implicados en este tipo de infecciones. La combinación de espiramicina más metronidazol presente en la formulación comercial denominada Rhodogyl®, no alcanzó índices PK/PD satisfactorios. CONCLUSIÓN. Los índices PK/PD son herramientas útiles para predecir la eficacia potencial de la terapia antimicrobiana, y en este caso se han aplicado al tratamiento de infecciones odontógenas. Estas simulaciones PK/PD permiten concluir que amoxicilina-ácido clavulánico, clindamicina y moxifloxacino se presentan como los antibióticos más adecuados que se deben utilizar para el tratamiento de este tipo de infecciones. Sin embargo, sería importante contrastar los resultados obtenidos con un ensayo clínico para confirmar que esta metodología es útil en este tipo de procesos patológicos (AU)

INTRODUCTION. This study evaluates the efficacy of various antimicrobial treatments for oro facial infections on the basis of pharmacokinetic/pharmaco dynamic (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 or1000 mg/12 h) and clindamycin (300 mg/6 h) in the time-dependant killing group and moxifloxacin(400 mg/24 h) in the concentration-dependant 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 (AU)

[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.