RESUMO
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.
Assuntos
Antibacterianos/farmacocinética , Infecções Pneumocócicas/tratamento farmacológico , Vacinas Pneumocócicas/administração & dosagem , Streptococcus pneumoniae/efeitos dos fármacos , Adulto , Antibacterianos/administração & dosagem , Cefotaxima/administração & dosagem , Ensaios Clínicos como Assunto , Humanos , Levofloxacino/administração & dosagem , Penicilina G/administração & dosagem , Infecções Pneumocócicas/microbiologia , Espanha , Streptococcus pneumoniae/fisiologiaRESUMO
INTRODUCTION: In Europe, non-typeable H. influenzae (NTHi) is the leading cause of invasive H. influenzae disease in adults and is associated with high mortality. The goal of this study was to determine whether current antimicrobial treatments for H. influenzae infection in Spain are suitable based on their probability of achieving pharmacokinetic/pharmacodynamic (PK/PD) targets. METHODS: Pharmacokinetic parameters for the antibiotics studied (amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin) and susceptibility data for H. influenzae were obtained from literature. A Monte Carlo simulation was used to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and the cumulative fraction of response (CFR), defined as the expected population PTA for a specific drug dose and a specific microorganism population. RESULTS: Regardless of dosing regimen, all antibiotics yielded CFR values of 100% or nearly 100% for all strains, including BL+, BL- and BLNAR, except amoxicillin and ampicillin for BL+. Thus, if an infection is caused by BL+ strains, treatment with amoxicillin and ampicillin has a high probability of failure (CFR≤8%). For standard doses of amoxicillin, amoxicillin/clavulanic acid and imipenem, PK/PD breakpoints were consistent with EUCAST clinical breakpoints. For the other antimicrobials, PK/PD breakpoints were higher than EUCAST clinical breakpoints. CONCLUSIONS: Our study confirms by PK/PD analysis that, with the antimicrobials used as empirical treatment of invasive H. influenzae disease, a high probability of therapeutic success can be expected.
Assuntos
Infecções por Haemophilus , Infecções Respiratórias , Adulto , Antibacterianos/uso terapêutico , Infecções por Haemophilus/tratamento farmacológico , Haemophilus influenzae , Humanos , Testes de Sensibilidade MicrobianaRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Doenças da Boca/tratamento farmacológico , Algoritmos , Combinação Amoxicilina e Clavulanato de Potássio/farmacocinética , Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Área Sob a Curva , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Compostos Aza/uso terapêutico , Clindamicina/farmacocinética , Clindamicina/farmacologia , Clindamicina/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Relação Dose-Resposta a Droga , Quimioterapia Combinada/farmacocinética , Quimioterapia Combinada/farmacologia , Quimioterapia Combinada/uso terapêutico , Fluoroquinolonas , Fusobacterium nucleatum/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Doenças da Boca/microbiologia , Moxifloxacina , Peptostreptococcus/efeitos dos fármacos , Periodontite/tratamento farmacológico , Periodontite/microbiologia , Porphyromonas gingivalis/efeitos dos fármacos , Prevotella intermedia/efeitos dos fármacos , Quinolinas/farmacocinética , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Fatores de Tempo , Estreptococos Viridans/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate the efficacy of antimicrobial therapy in oral odontogenic infections using estimated pharmacokinetic/pharmacodynamic parameters or efficacy indices, and to compare pharmacokinetic/pharmacodynamic breakpoints with National Committee for Clinical Laboratory Standards' (NCCLS) breakpoints. STUDY DESIGN: Retrospective literature search to obtain minimum inhibitory concentration (MIC) values, pharmacokinetic parameters of antimicrobials and NCCLS breakpoints. Pharmacokinetic simulations were carried out using WinNonlin software (Pharsight Corporation, Mountain View, CA, USA). METHODS: For antimicrobials with time-dependent activity, the time that the plasma drug concentration exceeds the MIC as the percentage of dose interval at steady state was calculated. For antimicrobials with concentration-dependent activity, the total area under the plasma concentration-time curve over 24 hours at steady state divided by the MIC was calculated. Pharmacokinetic/pharmacodynamic breakpoints were calculated according to these parameters. RESULTS: Only amoxicillin/clavulanic acid and clindamycin showed adequate efficacy indices against the most commonly isolated bacteria in odontogenic infections. Metronidazole reached good indices against anaerobes only. Pharmacokinetic/pharmacodynamic susceptibility breakpoints do not coincide exactly with NCCLS breakpoints. CONCLUSION: Owing to the scarcity of double-blind, clinical trials on the use of antimicrobials in endodontics, this study may be useful in determining the best antimicrobial treatment in these infections. However, as we have not used concentration data in infected tissue to determine pharmacokinetic/pharmacodynamic indices, it would be necessary to design clinical trials in order to confirm these results.
Assuntos
Anti-Infecciosos/farmacocinética , Anti-Infecciosos/uso terapêutico , Infecções/tratamento farmacológico , Doenças da Boca/tratamento farmacológico , Doenças Dentárias/tratamento farmacológico , Anti-Infecciosos/farmacologia , Área Sob a Curva , Bactérias/efeitos dos fármacos , Humanos , Infecções/microbiologia , Testes de Sensibilidade Microbiana , Boca/microbiologia , Doenças da Boca/microbiologia , Doenças Dentárias/microbiologiaRESUMO
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)