RESUMO
Los antibióticos betalactámicos son los que más se usan en el tratamientoy profilaxis de las infecciones odontogénicas. Con frecuenciaes necesario prescribir un segundo antibiótico que incremente el efectodel primero. Debido a ello se hizo una revisión de los antibióticos y otros medicamentos que administrados simultáneamente o en forma secuencial con betalactámicos producen efectos deseados (sinergismo, potenciación) o indeseados (antagonismo) o provocan efectos adversos en el organismo.
Beta-lactams are the most commonly used antibiotics in the treatmentand prophylaxis of odontogenic infections. It is often necessary toprescribe a second antibiotic to increase the eff ect of the fi rst. For thisreason, we performed a review of antibiotics and other medicationswhich, when administered simultaneously or sequentially with betalactams,produce desirable (synergism, potentiation) or undesirable(antagonism) eff ects or provoke adverse eff ects in the organism.
Assuntos
Humanos , beta-Lactamas/administração & dosagem , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologia , Interações Medicamentosas , beta-Lactamas/efeitos adversos , Cefalosporinas/farmacologia , Antagonismo de Drogas , Sinergismo Farmacológico , Interações Alimento-DrogaRESUMO
Recently, Wong et al. have successfully developed a fluorescent biosensor based on the PenPC ß-lactamase which changes its intrinsic fluorescence in presence of ß-lactam antibiotics (BLAs). Here, we studied systematically this correlation among the fluorescence change of the biosensor and the concentration of different BLAs aimed at developing a novel method for estimating the concentration of a wide range of BLAs. This method showed high precision and specificity and very low interference from clinically relevant samples. We were able to monitor the pharmacokinetics of meropenem in healthy volunteers as well as in an ill animal model too, indicating that the implemented method could be suitable for clinical practice.
Assuntos
Antibacterianos/sangue , Técnicas Biossensoriais/métodos , Tienamicinas/sangue , beta-Lactamas/sangue , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Monitoramento de Medicamentos , Fluorescência , Voluntários Saudáveis , Humanos , Meropeném , Sus scrofa/microbiologia , Tienamicinas/farmacocinética , Tienamicinas/uso terapêutico , beta-Lactamases/sangue , beta-Lactamas/farmacocinética , beta-Lactamas/uso terapêuticoRESUMO
The pharmacokinetics of antibiotics, especially in severely ill patients, may be profoundly altered due to multiple pathophysiological changes. Recent studies have shown that empiric dosing recommendations for ICU patients are inadequate to effectively treat a broad range of susceptible organisms and need to be reconsidered. Therapeutic drug monitoring (TDM) is an important mean for optimizing drug utilization and doses for the purpose of improving the clinical effectiveness. However, it is very challenging to quantify plasma antibiotic concentrations in clinical situations as a routine practice, because of the high costs and complexities associated with advanced instrumental techniques. Currently there are not routine and low cost methods to determine the presence and concentration of ß-lactam antibiotics in plasma patients in a clinical setup. Indeed, such analytical methods are based on chromatographic techniques mainly used in research. Here we describe and comment different techniques, focusing on our preliminary experience using biosensors.
Assuntos
Antibacterianos/farmacocinética , Técnicas Biossensoriais/métodos , Monitoramento de Medicamentos/métodos , Fluorescência , beta-Lactamas/farmacocinética , Antibacterianos/administração & dosagem , Estado Terminal , HumanosRESUMO
INTRODUCTION: Monte Carlo simulations have been used for selecting optimal antibiotic regimens for treatment of bacterial infections. The aim of this study was to assess the pharmacokinetic and pharmacodynamic target attainment of intravenous ß-lactam regimens commonly used to treat bloodstream infections (BSIs) caused by Gram-negative rod-shaped organisms in a Brazilian teaching hospital. METHODS: In total, 5,000 patients were included in the Monte Carlo simulations of distinct antimicrobial regimens to estimate the likelihood of achieving free drug concentrations above the minimum inhibitory concentration (MIC; fT > MIC) for the requisite periods to clear distinct target organisms. Microbiological data were obtained from blood culture isolates harvested in our hospital from 2008 to 2010. RESULTS: In total, 614 bacterial isolates, including Escherichia coli, Enterobacterspp., Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, were analyzed Piperacillin/tazobactam failed to achieve a cumulative fraction of response (CFR) > 90% for any of the isolates. While standard dosing (short infusion) of ß-lactams achieved target attainment for BSIs caused by E. coliand Enterobacterspp., pharmacodynamic target attainment against K. pneumoniaeisolates was only achieved with ceftazidime and meropenem (prolonged infusion). Lastly, only prolonged infusion of high-dose meropenem approached an ideal CFR against P. aeruginosa; however, no antimicrobial regimen achieved an ideal CFR against A. baumannii. CONCLUSIONS: These data reinforce the use of prolonged infusions of high-dose ß-lactam antimicrobials as a reasonable strategy for the treatment of BSIs caused by multidrug resistant Gram-negative bacteria in Brazil.
Assuntos
Antibacterianos/administração & dosagem , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , beta-Lactamas/administração & dosagem , Administração Intravenosa , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Brasil , Bactérias Gram-Negativas/classificação , Infecções por Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/microbiologia , Hospitais de Ensino , Humanos , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Fatores de Tempo , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaRESUMO
ABSTRACTINTRODUCTION: Monte Carlo simulations have been used for selecting optimal antibiotic regimens for treatment of bacterial infections. The aim of this study was to assess the pharmacokinetic and pharmacodynamic target attainment of intravenous β-lactam regimens commonly used to treat bloodstream infections (BSIs) caused by Gram-negative rod-shaped organisms in a Brazilian teaching hospital.METHODS: In total, 5,000 patients were included in the Monte Carlo simulations of distinct antimicrobial regimens to estimate the likelihood of achieving free drug concentrations above the minimum inhibitory concentration (MIC; fT > MIC) for the requisite periods to clear distinct target organisms. Microbiological data were obtained from blood culture isolates harvested in our hospital from 2008 to 2010.RESULTS: In total, 614 bacterial isolates, including Escherichia coli, Enterobacterspp., Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, were analyzed Piperacillin/tazobactam failed to achieve a cumulative fraction of response (CFR) > 90% for any of the isolates. While standard dosing (short infusion) of β-lactams achieved target attainment for BSIs caused by E. coliand Enterobacterspp., pharmacodynamic target attainment against K. pneumoniaeisolates was only achieved with ceftazidime and meropenem (prolonged infusion). Lastly, only prolonged infusion of high-dose meropenem approached an ideal CFR against P. aeruginosa; however, no antimicrobial regimen achieved an ideal CFR against A. baumannii.CONCLUSIONS:These data reinforce the use of prolonged infusions of high-dose β-lactam antimicrobials as a reasonable strategy for the treatment of BSIs caused by multidrug resistant Gram-negative bacteria in Brazil.
Assuntos
Humanos , Antibacterianos/administração & dosagem , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , beta-Lactamas/administração & dosagem , Administração Intravenosa , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Brasil , Bactérias Gram-Negativas/classificação , Infecções por Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/microbiologia , Hospitais de Ensino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Fatores de Tempo , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaRESUMO
Since antimicrobial resistance among uropathogens against current first line agents has affected the management of severe urinary tract infection, we determined the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures using Monte Carlo simulation for five antimicrobials (ciprofloxacin, ceftriaxone, piperacillin/tazobactam, ertapenem, and meropenem) commonly prescribed as initial empirical treatment of inpatients with severe community acquired urinary tract infections. Minimum inhibitory concentration determination by Etest was performed for 205 Brazilian community urinary tract infection Escherichia coli strains from 2008 to 2012 and 74 E. coli bloodstream strains recovered from a surveillance study. Pharmacodynamic exposure was modeled via a 5000 subject Monte Carlo simulation. All isolates were susceptible to ertapenem and meropenem. Piperacillin/tazobactam, ceftriaxone and ciprofloxacin showed 100%, 97.5% and 83.3% susceptibility among outpatient isolates and 98.6%, 75.7% and 64.3% among inpatient isolates, respectively. Against outpatient isolates, all drugs except ciprofloxacin (82.7% in aggressive and 77.6% in conservative scenarios) achieved high cumulative fraction of response: car-bapenems and piperacillin/tazobactam cumulative fraction of responses were close to 100%, and ceftriaxone cumulative fraction of response was 97.5%. Similar results were observed against inpatients isolates for carbapenems (100%) and piperacillin/tazobactam (98.4%), whereas ceftriaxone achieved only 76.9% bactericidal cumulative fraction of response and ciprofloxacin 61.9% (aggressive scenario) and 56.7% (conservative scenario) respectively. Based on this model, standard doses of beta-lactams were predicted to deliver sufficient pharmacodynamic exposure for outpatients. However, ceftriaxone should be avoided for inpatients and ciprofloxacin empirical prescription should be avoided in both inpatients and outpatients with complicated urinary tract infection.
Assuntos
Humanos , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Ceftriaxona/farmacologia , Ciprofloxacina/farmacocinética , Ciprofloxacina/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Escherichia coli/isolamento & purificação , Método de Monte Carlo , Testes de Sensibilidade Microbiana/métodos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Piperacilina/farmacocinética , Piperacilina/farmacologia , Pielonefrite/microbiologia , Índice de Gravidade de Doença , Tienamicinas/farmacocinética , Tienamicinas/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaRESUMO
Since antimicrobial resistance among uropathogens against current first line agents has affected the management of severe urinary tract infection, we determined the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures using Monte Carlo simulation for five antimicrobials (ciprofloxacin, ceftriaxone, piperacillin/tazobactam, ertapenem, and meropenem) commonly prescribed as initial empirical treatment of inpatients with severe community acquired urinary tract infections. Minimum inhibitory concentration determination by Etest was performed for 205 Brazilian community urinary tract infection Escherichia coli strains from 2008 to 2012 and 74 E. coli bloodstream strains recovered from a surveillance study. Pharmacodynamic exposure was modeled via a 5000 subject Monte Carlo simulation. All isolates were susceptible to ertapenem and meropenem. Piperacillin/tazobactam, ceftriaxone and ciprofloxacin showed 100%, 97.5% and 83.3% susceptibility among outpatient isolates and 98.6%, 75.7% and 64.3% among inpatient isolates, respectively. Against outpatient isolates, all drugs except ciprofloxacin (82.7% in aggressive and 77.6% in conservative scenarios) achieved high cumulative fraction of response: carbapenems and piperacillin/tazobactam cumulative fraction of responses were close to 100%, and ceftriaxone cumulative fraction of response was 97.5%. Similar results were observed against inpatients isolates for carbapenems (100%) and piperacillin/tazobactam (98.4%), whereas ceftriaxone achieved only 76.9% bactericidal cumulative fraction of response and ciprofloxacin 61.9% (aggressive scenario) and 56.7% (conservative scenario) respectively. Based on this model, standard doses of beta-lactams were predicted to deliver sufficient pharmacodynamic exposure for outpatients. However, ceftriaxone should be avoided for inpatients and ciprofloxacin empirical prescription should be avoided in both inpatients and outpatients with complicated urinary tract infection.
Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Ceftriaxona/farmacologia , Ciprofloxacina/farmacocinética , Ciprofloxacina/farmacologia , Ertapenem , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Humanos , Meropeném , Testes de Sensibilidade Microbiana/métodos , Método de Monte Carlo , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Piperacilina/farmacocinética , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Pielonefrite/microbiologia , Índice de Gravidade de Doença , Tienamicinas/farmacocinética , Tienamicinas/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaRESUMO
A modified E(max)-pharmacokinetic-pharmacodynamic (PK-PD) model was previously proposed in literature for describing the antimicrobial activity of ß-lactam antibiotics based on in vitro experiments. However, bacteria behave differently in vitro and in vivo. Thus, the aims of this study were to model the killing effect of piperacillin (PIP) against Escherichia coli on immunocompromised infected rats using this model and to compare the parameters obtained in vitro and in vivo for the same bacteria/drug combination. The PK-PD parameters determined in vitro and in vivo were as follows: generation rate constant of 1.30 ± 0.10 and 0.76 ± 0.20 h(-1), maximum killing effect of 3.11 ± 0.27 and 1.38 ± 0.20 h(-1) and concentration to produce 50% of the maximum effect of 5.44 ± 0.03 and 1.31 ± 0.27 µg ml(-1), respectively. The comparison between the in vitro and in vivo parameters was not straightforward and had to take into consideration the intrinsic differences of the models involved. So far, the main application of the PK-PD model evaluated is for the comparison of different antimicrobial agent's potency and efficacy, under equivalent conditions.
Assuntos
Antibacterianos/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Modelos Biológicos , Piperacilina/farmacologia , Animais , Antibacterianos/farmacocinética , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Masculino , Piperacilina/farmacocinética , Ratos , Ratos Wistar , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaAssuntos
Antibacterianos/uso terapêutico , Infecções por Bacteroides/tratamento farmacológico , Infecções por Escherichia coli/tratamento farmacológico , Sepse/tratamento farmacológico , beta-Lactamas/uso terapêutico , Animais , Antibacterianos/farmacocinética , Líquido Ascítico/microbiologia , Infecções por Bacteroides/microbiologia , Bacteroides fragilis/efeitos dos fármacos , Sangue/microbiologia , Contagem de Colônia Microbiana , Ertapenem , Escherichia coli/efeitos dos fármacos , Feminino , Camundongos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/uso terapêutico , Piperacilina/farmacocinética , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam , Sepse/microbiologia , beta-Lactamas/farmacocinéticaRESUMO
The pharmacodynamic potency of imipenem, meropenem and ertapenem against extended-spectrum beta-lactamase (ESBL)-producing isolates was investigated. Minimal inhibitory concentration (MIC) determination, confirmation of ESBLs by Etest and the disk approximation test were performed for 133 ESBL-producing isolates of Escherichia coli and Klebsiella spp. Pharmacodynamic exposure, measured as percent of the dosing interval during which free drug was above the MIC (% fT>MIC), was modelled via a 5000-subject Monte Carlo simulation. Bactericidal cumulative fraction of response (CFR), defined as 40% fT>MIC, was calculated against each bacterial population. All agents achieved high bactericidal CFR against all ESBL isolates as a group, but ertapenem (96.26%) was slightly less effective than imipenem (99.96%) and meropenem (99.90%) (P<0.05). Similar results were observed against Klebsiella spp. only (P<0.05). Against E. coli, CFRs were close to 100%. Ertapenem is probably an effective agent against ESBL-producing bacteria, although its ability to achieve bactericidal pharmacodynamic exposures will depend on the bacterial susceptibility.