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In. Giachetto Larraz, Gustavo A; Pardo Casaretto, Lorena Victoria; Speranza Mourine, María Noelia. Prescripción de antimicrobianos para infecciones frecuentes en pediatría. Montevideo, Bibliomédica, 2020. p.31-52, tab.
Monography in Spanish | LILACS, UY-BNMED, BNUY | ID: biblio-1373292
In. Giachetto Larraz, Gustavo A; Pardo Casaretto, Lorena Victoria; Speranza Mourine, María Noelia. Prescripción de antimicrobianos para infecciones frecuentes en pediatría. Montevideo, Bibliomédica, 2020. p.161-187, tab.
Monography in Spanish | LILACS, UY-BNMED, BNUY | ID: biblio-1373298
Rev. peru. med. exp. salud publica ; 36(1): 74-80, ene.-mar. 2019. tab, graf
Article in Spanish | LILACS | ID: biblio-1004402


RESUMEN El objetivo del estudio fue determinar la equivalencia terapéutica evaluada mediante estudios in vitro de cuatro marcas de medicamentos conteniendo amoxicilina, doxiciclina y fluconazol adquiridos en establecimientos farmacéuticos de Lima Metropolitana y establecer su intercambiabilidad con un producto de referencia (PR). Se empleó un método validado de espectrofotometría ultravioleta visible para determinar el perfil de disolución. El factor de similitud (f2) se utilizó para establecer la equivalencia terapéutica, considerándose equivalentes si los valores de f2 se encontraban entre 50 y 100. Para doxiciclina los cuatro medicamentos fueron equivalentes in vitro al PR, para amoxicilina sólo dos medicamentos fueron equivalentes in vitro al PR y para fluconazol ninguno fue equivalente in vitro al PR. Se concluye que algunos medicamentos de amoxicilina y fluconazol que circulan en el mercado nacional no cumplen con la equivalencia terapéutica evaluada mediante estudios in vitro; es decir, no son intercambiables.

ABSTRACT The objective of the study was to determine the therapeutic equivalence evaluated through in vitro studies of four brands of drugs containing amoxicillin, doxycycline, and fluconazole purchased at pharmaceutical facilities in Metropolitan Lima, and to establish their interchangeability with a reference product (RP). A validated method of visible ultraviolet spectrophotometry was used to determine the dissolution profile. The similarity factor (f2) was used to establish the therapeutic equivalence, being considered equivalent if the values of f2 were between 50 and 100. For doxycycline, the four drugs were equivalent in vitro to the RP; for amoxicillin, only two drugs were equivalent in vitro to the RP; and for fluconazole, none was equivalent in vitro to the RP. It is concluded that some amoxicillin and fluconazole drugs circulating in the national market do not meet the therapeutic equivalence assessed by in vitro studies; in other words, they are not interchangeable.

Fluconazole/pharmacokinetics , Doxycycline/pharmacokinetics , Amoxicillin/pharmacokinetics , Anti-Bacterial Agents/pharmacokinetics , Antifungal Agents/pharmacokinetics , Peru , Therapeutic Equivalency , Cross-Sectional Studies
Einstein (Säo Paulo) ; 17(1): eAO4396, 2019. tab
Article in English | LILACS | ID: biblio-984360


ABSTRACT Objective Analyze the microbiological effectiveness, based on the pharmacokinetics/pharmacodynamics correlation of vancomycin in pediatric patients, and to propose dose adjustment. Methods This is an observational, cross-sectional study, conducted in a pediatric hospital, over a 1-year period (2016 to 2017). Children of both sexes, aged 2 to 12 years, were included in the study; burn children, and children in renal replacement therapy were excluded. For the pharmacokinetic analysis, two samples of 2mL of whole blood were collected, respecting the 2-hour interval between each withdrawal. Results Ten pediatric patients with median age of 5.5 years and interquartile range (IQR) of 3.2-9.0 years, median weight of 21kg (IQR: 15.5-24.0kg) and median height of 112.5cm (IQR: 95-133cm), were included. Only one child achieved trough concentrations between 10µg/mL and 15µg/mL. Conclusion The empirical use of vancomycin in the children studied did not achieve the therapeutic pharmacokinetic/pharmacodynamic target for minimum inhibitory concentration of 1µg/mL.

RESUMO Objetivo Analisar a efetividade microbiológica considerando a correlação farmacocinética/farmacodinâmica de vancomicina em crianças e propor uma estimativa de ajuste na dose. Métodos Trata-se de um estudo observacional, transversal, realizado em hospital pediátrico, no período de 1 ano (2016 a 2017). Foram incluídas crianças de 2 a 12 anos de ambos os sexos, tendo sido excluídas crianças queimadas ou submetidas à terapia renal substitutiva. Para análise farmacocinética, foram coletadas duas amostras de 2mL de sangue total, respeitando o intervalo de 2 horas entre cada coleta. Resultados Foram incluídos dez pacientes pediátricos com idade de 5,5 anos (mediana) e intervalo interquartil (IQ) de 3,2-9,0 anos, peso de 21kg (mediana; IQ: 15,5-24,0kg) e altura de 112,5cm (mediana; IQ: 95-133cm). Apenas uma criança alcançou concentrações mínimas entre 10µg/mL e 15µg/mL. Conclusão A utilização empírica de vancomicina na população de crianças não alcançou o alvo farmacocinético/farmacodinâmico terapêutico para concentração inibitória mínima de 1μg/mL.

Humans , Male , Female , Child, Preschool , Child , Vancomycin/pharmacokinetics , Anti-Bacterial Agents/pharmacokinetics , Time Factors , Vancomycin/administration & dosage , Microbial Sensitivity Tests , Cross-Sectional Studies , Drug Monitoring/methods , Dose-Response Relationship, Drug , Anti-Bacterial Agents/administration & dosage
J. appl. oral sci ; 27: e20180663, 2019. tab, graf
Article in English | LILACS, BBO | ID: biblio-1040224


Abstract Objective: To investigate the use of polymethyl methacrylate (PMMA) electrospun fiber mats containing different amounts of polyethylene oxide (PEO) as a doxycycline delivery system and to test antibacterial activity against an oral pathogen. Methodology: PMMA powders or PEO (mol wt 200 Kd) (10,20,30% w/w/) were dissolved in N, N-dimethylformamide (DMF) to obtain a final polymer concentration of 15% in DMF (w/v). 2% Doxycycline monohydrate was added to the solutions and submitted to vortex mixing. The solution was transferred to a plastic syringe and fit into a nanofiber electrospinning unit. The parameters applied were: voltage at 17.2 kV; distance of 20 cm between the needle tip and the collector plate; target speed at 2 m/min; and transverse speed at 1cm/min. Syringe pump speed was 0.15 mm/min. The drug release analysis was performed by removing aliquots of the drug-containing solution (in PBS) at specific periods. Doxycycline release was quantified using RP-HPLC. Fiber mats from all groups had their antibacterial action tested against S. mutans based on inhibition halos formed around the specimens. The experiments were performed in triplicate. Gravimetric analysis at specific periods was performed to determine any polymer loss. Morphological characterization of the electrospun fibers was completed under an optical microscope followed by SEM analysis. Results: The addition of PEO to the PMMA fibers did not affect the appearance and diameter of fibers. However, increasing the %PEO caused higher doxycycline release in the first 24 h. Fibers containing 30% PEO showed statistically significant higher release when compared with the other groups. Doxycycline released from the fibers containing 20% or 30% of PEO showed effective against S. mutans. Conclusion: The incorporation of PEO at 20% and 30% into PMMA fiber mat resulted in effective drug release systems, with detected antibacterial activity against S. mutans.

Polyethylene Glycols/pharmacokinetics , Doxycycline/pharmacokinetics , Polymethyl Methacrylate/pharmacokinetics , Nanofibers/chemistry , Anti-Bacterial Agents/pharmacokinetics , Polyethylene Glycols/chemistry , Streptococcus mutans/drug effects , Time Factors , Water/chemistry , Microscopy, Electron, Scanning , Reproducibility of Results , Analysis of Variance , Chromatography, High Pressure Liquid/methods , Doxycycline/chemistry , Polymethyl Methacrylate/chemistry , Immersion , Anti-Bacterial Agents/chemistry , Molecular Weight
Arq. bras. oftalmol ; 81(6): 510-513, Nov.-Dec. 2018. graf
Article in English | LILACS | ID: biblio-973857


ABSTRACT Purpose: To determine the release profile of moxifloxacin encapsulated in liposomes in the aqueous humor as a controlled release system for intracameral application. Methods: Liposomes containing moxifloxacin were obtained using the lipid film hydration method and were characterized by particle size and encapsulation efficiency. Female rabbits were used for the in vivo profile release study. Liposomes containing moxifloxacin was injected into the anterior chamber of the right eye of each animal. The rabbits were divided into five groups, and a sample of aqueous humor was collected 2, 4, 8, 24, and 48 h after administration of liposomes containing moxifloxacin administration. Moxifloxacin concentrations in the aqueous humor were analyzed using high-performance liquid chromatography. Results: The average size of the liposomes containing moxifloxacin was 60.5 ± 0.72 nm with a particle size distribution of 0.307. The encapsulation efficiency of moxifloxacin in liposomes was 92.24 ± 0.24%. The results of an in vivo release study of liposomes containing moxifloxacin, showed that the maximum moxifloxacin concentration was achieved within the first 2 h after administration (5.27 ± 1.09 mg/mL) and was followed by a decrease in intracameral concentration (0.35 ± 0.05 mg/mL) until the 24 h mark. Conclusions: The in vivo experiments resulted in liposomes containing moxifloxacin that were homogenous in size and exhibited high drug encapsulation efficiency. The results indicate that liposomes containing moxifloxacin offers a satisfactory aqueous humor release profile after intracameral application.

RESUMO Objetivo: Determinar o perfil de liberação, no humor aquoso, de moxifloxacino encapsulado em lipossomas como um sistema de liberação controlada para aplicação intracameral. Métodos: Lipossomas contendo moxifloxacino foram obtidos através do método de hidratação do filme lipídico e caracterizados por tamanho da partícula e eficiência de encapsulação. Utilizaram-se coelhos fêmeas foram para o estudo do perfil de liberação in vivo. Lipossomas contendo moxifloxacino foram injetados na câmara anterior do olho direito de cada animal. Os coelhos foram divididos em cinco grupos, e uma amostra de humor aquoso foi coletada 2, 4, 8, 24 e 48 h após a administração de lipossomas contendo moxifloxacino. As concentrações de moxifloxacino no humor aquoso foram analisadas usando cromatografia líquida de alta eficiência. Resultados: O tamanho médio dos lipossomas contendo moxifloxacino foi de 60,5 ± 0,72 nm com uma distribuição de tamanho de partícula de 0,307. A eficiência de encapsulação de moxifloxacino nos lipossomas foi de 92,24 ± 0,24. Os resultados de um estudo de liberação in vivo de lipossomas contendo moxifloxacino, mostraram que a concentração máxima de moxifloxacino foi atingida dentro das primeiras 2 h após sua administração (5,27 ± 1,09 mg/mL) e foi seguida de um decréscimo na concentração intracameral (0,35 ± 0,05 mg/mL) até a marca de 24 h. Conclusão: Os experimentos in vivo resultaram em lipossomas contendo moxifloxacino que eram homogêneos em tamanho e exibiam alta eficiência de encapsulação do fármaco. Os resultados indicam que lipossomas contendo moxifloxacino oferecem um perfil de liberação de humor aquoso satisfatório após a aplicação intracameral.

Animals , Female , Rats , Aqueous Humor , Drug Delivery Systems/methods , Moxifloxacin/administration & dosage , Anti-Bacterial Agents/administration & dosage , Biological Availability , Chromatography, High Pressure Liquid , Models, Animal , Injections, Intraocular , Moxifloxacin/analysis , Moxifloxacin/pharmacokinetics , Liposomes , Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/pharmacokinetics
Rev. chil. infectol ; 35(2): 105-116, abr. 2018. tab
Article in Spanish | LILACS | ID: biblio-959419


Resumen Las polimixinas están disponibles desde la década de los 60; sin embargo, debido a sus efectos adversos su uso ha sido reservado para el tratamiento de infecciones provocadas por bacterias multi-resistentes. El aumento en la experiencia clínica adquirida en los últimos años y la literatura médica publicada han planteado dudas respecto de la información entregada del producto, poniendo en manifiesto la necesidad de actualizar las recomendaciones posológicas, su farmacocinética y la información farmacocinética/farmacodinámica. Además, las diferencias en cuanto a concentración y dosis entre los distintos productos del colistín pueden dar lugar a errores de indicación/administración y suponer un riesgo para los pacientes. El año 2013, la Agencia Europea de Medicamento (EMA) encargó al Comité de Productos Medicinales para uso Humano (CHPM) la revisión de los datos disponibles y que formulara recomendaciones actualizadas del uso de colistín. Dicho procedimiento arrojó un primer informe en 2014. Esta revisión destaca los aspectos críticos de seguridad y eficacia, revisa los recientes avances farmacocinéticos y de estabilidad, las formas farmacéuticas disponibles en Chile, proporcionando los esquemas actualmente recomendados por agencias sanitarias y expertos en el tema para distintos escenarios clínicos.

Polymyxins have been available since the 1960s, however, because of their adverse effects, their use has been reserved for the treatment of infections caused by multiresistant bacteria. The increase in the clinical experience acquired in recent years and the published medical literature have raised doubts about the information provided by the product, indicating the need to update dosage recommendations, pharmacokinetics and pharmacokinetic/pharmacodynamic information (PK/PD). In addition, differences in concentration and dose between the different products of colistin may lead to errors of indication/administration and pose a risk to patients. In 2013, the European Medicines Agency (EMA) commissioned the Committee for Medicinal Products for Human Use (CHPM) to review available data and to make updated recommendations on the use of colistin. This procedure yielded a first report in 2014. This review highlights critical safety and efficacy aspects, reviews the recent pharmacokinetic and stability advances, the available pharmaceutical forms in Chile, providing the schemes currently recommended by health care agencies and experts in the field.

Humans , Colistin/administration & dosage , Anti-Bacterial Agents/administration & dosage , Chile , Colistin/pharmacokinetics , Drug-Related Side Effects and Adverse Reactions , Anti-Bacterial Agents/pharmacokinetics
Rev. Soc. Bras. Clín. Méd ; 16(1): 59-63, 20180000. ilus
Article in Portuguese | LILACS | ID: biblio-884999


Foi feita uma revisão sobre o uso racional de antimicrobianos em ambiente hospitalar, pois este é um dos principais desafios encontrados na terapia de infecções em ambiente hospitalar. Foram abordados os principais fatores que nos levam ao atual panorama global em relação à resistência antimicrobiana, bem como as principais estratégias para o uso racional dos antimicrobianos, de modo a garantir melhor terapêutica e menor incidência de resistência aos antimicrobianos. A racionalização de antimicrobianos é um componente-chave de uma abordagem multifacetada para a prevenção de resistência antimicrobiana. A boa gestão de antimicrobianos envolve a seleção do medicamento apropriado, otimizando sempre a dose e a duração do tratamento, utilizando bem os parâmetros de farmacodinâmica e farmacocinética, minimizando a toxicidade e as condições para a seleção de cepas bacterianas resistentes e garantindo, assim, sucesso terapêutico. Com o uso racional de antimicrobianos, podemos obter um melhor desempenho no tratamento de doenças infecciosas. Nesta revisão foi demonstrada a existência de várias estratégias de racionalização de antimicrobianos. Portanto, cabe a cada instituição estudar e analisar quais métodos devem ser implantados. Também é de fundamental importância que o prescritor analise as opções terapêuticas disponíveis e busque a individualização do tratamento, sempre visando à otimização terapêutica.(AU)

A review on antimicrobial stewardship was performed, because this is one of the leading challenges found in infectious diseases therapy in hospital settings. The major factors leading to the current global picture regarding antimicrobial resistance, and the main strategies for antimicrobial stewardship, to ensure the best treatment and lower incidence of antimicrobial resistance were discussed. Antimicrobial stewardship is a multifaceted approach considered a key component in the prevention of antimicrobial resistance. The best antimicrobial stewardship program involves selecting the appropriate medication, always optimizing its dose and duration of treatment using pharmacodynamics and pharmacokinetics parameters, minimizing toxicity and the conditions for selecting resistant bacterial strains, and ensuring treatment success. The rational use of antimicrobials can lead to more success in the treatment of infectious diseases. This review shows several strategies for antimicrobial stewardship. Therefore, it is up to each institution to study and analyze which method should be implemented. It is also crucial that the prescriber reviews the therapeutic options available to seek individualization of treatment, always aiming at therapy optimization.(AU)

Humans , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacokinetics , Anti-Infective Agents/pharmacology , Cross Infection , Drug Resistance, Fungal , Drug Utilization/trends
Rev. chil. infectol ; 35(1): 22-28, 2018. tab, graf
Article in Spanish | LILACS | ID: biblio-899773


Resumen La presente revisión resume la evidencia sobre la monitorización terapéutica de tres antimicrobianos basada en datos regionales: vancomicina, amikacina y voriconazol en la población pediátrica. Estos datos coinciden con la literatura internacional en relación al requerimiento de dosis mayores que 40 mg/kg/día de vancomicina, la posibilidad de usar monodosis diarias de amikacina y el requerimiento de dosis mayores de voriconazol en relación a las iniciales recomendadas de 8 mg/kg/día. Contar con datos locales sobre el comportamiento farmacocinético/farmacodinámico de diversos antimicrobianos en la pediatría es de gran valor para adecuar la dosificación de los mismos en nuestra población. Se deberían incrementar los estudios de monitorización terapéutica en el uso de antimicrobianos en pediatría que permitan generar pautas de tratamiento adecuadas para este grupo etario.

This review summarizes recommendations of therapeutic monitoring of three antimicrobials based in regional data: vancomycin, amikacin and voriconazole in pediatric population. Regional evidence agrees with international literature regarding the requirement of higher daily doses than 40 mg/kg/day of vancomycin, as well as with the possibility of use one daily doses of amikacin and to recommend higher doses of voriconazole compared to the initially recommended doses of 8 mg/kg/day. Local data on the pharmacokinetic/pharmacodynamic behavior of various antimicrobials in pediatrics are of great value for dosing adjustment in our pediatric population. More studies in therapeutic monitoring in the use of antimicrobials in pediatrics should be performed in order to allow the generation of adequate treatment guidelines for this age group.

Humans , Amikacin/administration & dosage , Amikacin/pharmacokinetics , Vancomycin/administration & dosage , Vancomycin/pharmacokinetics , Drug Monitoring/trends , Voriconazole/administration & dosage , Voriconazole/pharmacokinetics , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacokinetics , Dose-Response Relationship, Drug , Latin America
Rev. Soc. Bras. Clín. Méd ; 15(3): 201-205, 20170000. ilus
Article in Portuguese | LILACS | ID: biblio-875537


Foram revisados os parâmetros ou índices farmacocinéticos e farmacodinâmicos, com o objetivo de enfatizar sua importância como ferramenta de otimização da terapia antimicrobiana na prática médica. Destacam-se a ligação proteica, o clearance e o volume de distribuição da droga como parâmetros farmacocinéticos fundamentais, que podem ser alterados pelas características dos pacientes e da infecção. Foram apresentados ainda os parâmetros farmacodinâmicos (concentração máxima/concentração inibitória mínima, tempo > concentração inibitória mínima e área sob a curva/concentração inibitória mínima), que representam a relação dose-resposta e são determinantes para a eficácia terapêutica das drogas anti-infecciosas, considerando a dinâmica bactericida/bacteriostática dos diferentes grupos farmacológicos. Discutiu-se ainda o modelo matemático preditor de resultados prováveis para desfechos de tratamentos, como o método de Monte Carlo. Para finalizar, os índices farmacocinéticos e farmacodinâmicos foram apontados como estratégia de racionalização de antimicrobianos e redução da resistência bacteriana.(AU)

The pharmacokinetic and pharmacodynamic parameters were reviewed with the objective to emphasise their importance as tools for optimizing antimicrobial therapies in medical practice. The protein binding, clearance and drug distribution volume are highlighted as fundamental pharmacokinetic parameters that can be altered according to the characteristics of the patient or infection. We present the pharmacodynamic parameters (maximum concentration/minimal inhibitory concentration, time > minimal inhibitory concentration, and area under the curve/minimal inhibitory concentration) that represent the dose-response ratio and are determinants for the therapeutic efficacy of the antimicrobial drugs, considering the bactericidal/ bacteriostatic dynamics of the different pharmacological groups. We also commented on the predictive mathematical model for probable results for treatment outcomes, such as Monte Carlo method. Finally, the pharmacokinetic and pharmacodynamics indexes were shown as a strategy for antimicrobial rationalization and reduction of bacterial resistance.(AU)

Humans , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Bacterial Infections/drug therapy , Prescriptions
Rev. bras. ter. intensiva ; 28(4): 380-386, oct.-dic. 2016. tab
Article in Portuguese | LILACS | ID: biblio-844270


RESUMO Objetivo: Avaliar se a posologia atualmente utilizada de vancomicina para tratamento de infecções bacterianas graves causadas por microrganismos Gram-positivos em pacientes admitidos à unidade de terapia intensiva proporcionam níveis plasmáticos de vale de vancomicina em nível terapêutico, e examinar possíveis fatores associados com níveis de vale de vancomicina adequados nesses pacientes. Métodos: Estudo prospectivo descritivo com amostra de conveniência. Os pacientes que cumpriam os critérios de inclusão tiveram seus dados coletados a partir das anotações da enfermagem e dos registros médicos entre setembro de 2013 e julho de 2014. Incluíram-se 83 pacientes. Os níveis plasmáticos de vale iniciais de vancomicina foram obtidos imediatamente antes da quarta dose de vancomicina. Definiu-se lesão renal aguda como um aumento de, pelo menos, 0,3mg/dL na creatinina sérica dentro de 48 horas. Resultados: Considerando os níveis de vale plasmáticos de vancomicina recomendados para o tratamento de infecções graves por Gram-positivos (15 - 20µg/mL), os pacientes foram categorizados em grupos como níveis de vale de vancomicina baixos, adequados e elevados, respectivamente divididos em 35 (42,2%), 18 (21,7%), e 30 (36,1%) pacientes. Os pacientes com lesão renal aguda tiveram níveis plasmáticos de vale de vancomicina significantemente mais elevados (p = 0,0055, com significância para tendência, p = 0,0023). Conclusão: Preocupantemente, mais de 40% dos pacientes não obtiveram níveis plasmáticos de vale de vancomicina considerados eficazes. São necessários estudos de farmacocinética e de regimes posológicos de vancomicina em pacientes admitidos em unidades de terapia intensiva, para contornar esta elevada proporção de falhas na obtenção de níveis de vale iniciais adequados de vancomicina. Deve ser desencorajado o uso de vancomicina sem monitoramento dos níveis de vale plasmáticos.

ABSTRACT Objective: This study aimed to assess whether currently used dosages of vancomycin for treatment of serious gram-positive bacterial infections in intensive care unit patients provided initial therapeutic vancomycin trough levels and to examine possible factors associated with the presence of adequate initial vancomycin trough levels in these patients. Methods: A prospective descriptive study with convenience sampling was performed. Nursing note and medical record data were collected from September 2013 to July 2014 for patients who met inclusion criteria. Eighty-three patients were included. Initial vancomycin trough levels were obtained immediately before vancomycin fourth dose. Acute kidney injury was defined as an increase of at least 0.3mg/dL in serum creatinine within 48 hours. Results: Considering vancomycin trough levels recommended for serious gram-positive infection treatment (15 - 20µg/mL), patients were categorized as presenting with low, adequate, and high vancomycin trough levels (35 [42.2%], 18 [21.7%], and 30 [36.1%] patients, respectively). Acute kidney injury patients had significantly greater vancomycin trough levels (p = 0.0055, with significance for a trend, p = 0.0023). Conclusion: Surprisingly, more than 40% of the patients did not reach an effective initial vancomycin trough level. Studies on pharmacokinetic and dosage regimens of vancomycin in intensive care unit patients are necessary to circumvent this high proportion of failures to obtain adequate initial vancomycin trough levels. Vancomycin use without trough serum level monitoring in critically ill patients should be discouraged.

Humans , Male , Female , Adult , Aged , Vancomycin/administration & dosage , Gram-Positive Bacterial Infections/drug therapy , Intensive Care Units , Anti-Bacterial Agents/administration & dosage , Vancomycin/pharmacokinetics , Prospective Studies , Drug Monitoring/methods , Creatinine/blood , Dose-Response Relationship, Drug , Acute Kidney Injury/complications , Middle Aged , Anti-Bacterial Agents/pharmacokinetics
Braz. j. infect. dis ; 20(2): 184-192, Mar.-Apr. 2016. tab, graf
Article in English | LILACS | ID: lil-780812


Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182) vs linezolid (N = 171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Organophosphates/adverse effects , Organophosphates/therapeutic use , Organophosphates/pharmacokinetics , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacokinetics , Oxazoles/adverse effects , Oxazoles/therapeutic use , Oxazoles/pharmacokinetics , Double-Blind Method , Acute Disease , Treatment Outcome , Skin Diseases, Bacterial/metabolism , Skin Diseases, Bacterial/drug therapy , Linezolid/adverse effects , Linezolid/therapeutic use , Linezolid/pharmacokinetics , Latin America
Rev. chil. infectol ; 33(1): 7-11, feb. 2016. tab
Article in Spanish | LILACS | ID: lil-776953


Background: Gentamicin is indicated as empiric treatment for neonatal sepsis. Plasmatic levels dosification of gentamicin is a common practice. The relationship between peak plasma concentration (Cmáx) with minimum inhibitory concentration (MIC) (Cmáx/MIC) is the parameter that best predicts treatment efficacy. Aim: To determine pharmacokinetics of gentamicin in term newborn infants. Methods: Term newborn infants receiving gentamicin, without critical illness in which plasmatic levels of gentamicin was performed were included. Elimination clearance (Cl) elimination half-life (t½) and volume of distribution (Vd) were calculated. In each case the value of Cmax/MIC parameter was calculated, considering a MIC value of 1 μg/mL for Escherichia coli. Results: Thirteen newborns were included. The mean PK values were Cl: 0.26 mL/hour, Vd: 0.54 L/kg and t½: 6.8 h. Cmax/MIC was > 8 in 6 newborns. Conclusions: Pharmacokinetic parameters of gentamicin are predictable in term newborn infants. With gentamicin doses normally used Cmax/MIC values reached 8 in 6 newborns. It is necessary to review the usefulness of plasma drug monitoring and gentamicin dosage in this group of newborns.

Introducción: Gentamicina es utilizada como tratamiento empírico en la sepsis neonatal. El monitoreo de su concentración plasmática es una práctica frecuente. La relación entre la concentración plasmática máxima (Cmax) y la concentración inhibitoria mínima (Cmax/ CIM) es el parámetro que mejor predice la eficacia. Objetivo: Determinar los parámetros farmacocinéticos (FC) de gentamicina en recién nacidos (RN) de termino. Material y Métodos: Se incluyeron RN de término, sin enfermedad crítica, en tratamiento con gentamicina (4 mg/kg/24 h) en los que se realizó monitoreo de su concentración plasmática. Se determinaron: clearence de eliminación (Cl), vida media de eliminación (t½) y volumen de distribución (Vd). Se estimó la Cmax/CIM, considerando una CIM de 1 μg/mL para Escherichia coli. Resultados: Participaron 13 RN. La media de Cmax fue 8,19 μg/mL y de Cmin 0,73 μg/mL. La media de los parámetros farmacocinéticos fue: Cl 0,26 mL/h, Vd 0,54 L/kg, t½ 6,8 h. La razón Cmáx/CIM fue ≥ 8 en 6 de los 13 RN. Conclusiones: Los parámetros FC de gentamicina en RN de término, sin enfermedad crítica, son predecibles. La posología habitual no permitió obtener valores de Cmax/CIM > 8 en todos los casos. Es necesario revisar la necesidad de monitorizar su concentración plasmática en forma sistemática y la posología de gentamicina en este grupo de pacientes.

Female , Humans , Infant, Newborn , Male , Anti-Bacterial Agents/pharmacokinetics , Gentamicins/pharmacokinetics , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/blood , Drug Monitoring , Gentamicins/administration & dosage , Gentamicins/blood , Infusions, Intravenous , Retrospective Studies
Rev. Soc. Bras. Med. Trop ; 48(5): 539-545, Sept.-Oct. 2015. tab, graf
Article in English | LILACS | ID: lil-763339


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.

Humans , Anti-Bacterial Agents/administration & dosage , Drug Resistance, Multiple, Bacterial/drug effects , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , beta-Lactams/administration & dosage , Administration, Intravenous , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Brazil , Gram-Negative Bacteria/classification , Gram-Negative Bacterial Infections/metabolism , Gram-Negative Bacterial Infections/microbiology , Hospitals, Teaching , Microbial Sensitivity Tests , Monte Carlo Method , Time Factors , beta-Lactams/pharmacokinetics , beta-Lactams/pharmacology
Braz. j. pharm. sci ; 51(2): 305-315, Apr.-June 2015. tab, ilus
Article in English | LILACS | ID: lil-755067


A bioanalytical method was developed and applied to quantify the free imipenem concentrations for pharmacokinetics and PK/PD correlation studies of the dose adjustments required to maintain antimicrobial effectiveness in pediatric burn patients. A reverse-phase Supelcosil LC18 column (250 x 4.6 mm 5 micra), binary mobile phase consisting of 0.01 M, pH 7.0 phosphate buffer and acetonitrile (99:1, v/v), flow rate of 0.8 mL/min, was applied. The method showed good absolute recovery (above 90%), good linearity (0.25-100.0 µg/mL, r2=0.999), good sensitivity (LLOQ: 0.25 µg/mL; LLOD: 0.12 µg/mL) and acceptable stability. Inter/intraday precision values were 7.3/5.9%, and mean accuracy was 92.9%. A bioanalytical method was applied to quantify free drug concentrations in children with burns. Six pediatric burn patients (median 7.0 years old, 27.5 kg), normal renal function, and 33% total burn surface area were prospectively investigated; inhalation injuries were present in 4/6 (67%) of the patients. Plasma monitoring and PK assessments were performed using a serial blood sample collection for each set, totaling 10 sets. The PK/PD target attained (40%T>MIC) for each minimum inhibitory concentration (MIC: 0.5, 1.0, 2.0, 4.0 mg/L) occurred at a percentage higher than 80% of the sets investigated and 100% after dose adjustment. In conclusion, the purification of plasma samples using an ultrafiltration technique followed by quantification of imipenem plasma measurements using the LC method is quite simple, useful, and requires small volumes for blood sampling. In addition, a small amount of plasma (0.25 mL) is needed to guarantee drug effectiveness in pediatric burn patients. There is also a low risk of neurotoxicity, which is important because pharmacokinetics are unpredictable in these critical patients with severe hospital infection. Finally, the PK/PD target was attained for imipenem in the control of sepsis in pediatric patients...

Desenvolveu-se e aplicou-se método bioanalítico para quantificar concentrações de imipenem livre para estudos de farmacocinética (PK) e de correlação PK/PD dos ajustes de dose requeridos para manter a efetividade antimicrobiana em pacientes pediátricos queimados. Utilizou-se coluna Supelcosil LC18 (250 x 4,6 mm 5 micra), fase móvel binária, consistindo de tampão fosfato 0,01M pH 7,0 e acetonitrila (99:1, v/v) e fluxo de 0,8 mL/min. O método mostrou boa recuperação absoluta (acima de 90%), boa linearidade (0,25-100,0 µg/mL, r2=0.999), boa sensibilidade (LLOQ: 0,25 µg/mL; LLOD: 0,12 µg/mL) e estabilidade aceitável. Os valores de precisão inter/intradia foram 7,3/5,9% e a exatidão média foi de 92,9%. O método bioanalítico foi aplicado para quantificar concentrações de fármaco livre em crianças com queimaduras, Seis pacientes pediátricos queimados (idade média de 7,0 anos, 27,5 kg), com função renal normal e 33% da superfície total queimada foram investigados prospectivamente. Lesões por inalação estavam presentes em 4/6 (67%) dos pacientes. O monitoramento plasmático e a as avaliações de PK foram efetuadas utilizando coleção de amostras seriais de sangue para cada série, totalizando 10 conjuntos. O alvo PK/PD alcançado (40%T>MIC) para cada concentração inibitória mínima (MIC: 0,5, 1,0, 2,0, 4,0 mg/L) ocorreu em porcentagem maior do que 80% dos conjuntos investigados e 100% após o ajuste de dose. Em conclusão, a purificação das amostras do plasma usando técnica de ultrafiltração seguida de quantificação das medidas do imipenem no plasma usando método de cromatografia líquida é bastante simples, útil e necessita de pequenos volumes para as amostras de sangue. Além disso, pequena quantidade de plasma (0,25 mL) é necessário para garantir a efetividade do fármaco nos pacientes pediátricos queimados. Há, ainda, baixo risco de neurotoxicidade, o que é importante, visto que as farmacocinéticas são imprevisíveis nesses pacientes...

Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Child , Chromatography, Liquid/methods , Imipenem/analysis , Imipenem/blood , Clinical Chemistry Tests/methods , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Burn Units
Rev. chil. infectol ; 32(2): 182-189, abr. 2015.
Article in Spanish | LILACS | ID: lil-747521


Vancomycin has been used for more than 50 years in neonatal intensive care units (NICUs) as the therapy of choice for late-onset sepsis, mainly because Coagulase negative Staphylococci (CoNS) are common and mostly resistant to oxacyllin despitelow virulence and unusual association with fulminant sepsis. CUs due to several factors including its high pharmacokinetic variability, difficulty in reaching therapeutic plasmatic drug concentrations and progressively increasing minimum inhibitory concentrations (MIC). The increase of CoNS with higher MICs as well as the rise of infections caused by resistant gram-negative bacilli and candida should move to reconsider Vancomycin as first line treatment. Infections in neonates have a different behavior than in other populations and we consoder of utmost importance to consider the use of oxacyllin as first line antimicrobial therapy for late-onset sepsis.

Vancomicina se utiliza hace más de 50 años en unidades de cuidados intensivos neonatales (UCIN) como terapia de elección en sospecha de sepsis neonatal tardía; su principal indicación se fundamenta en que Staphylococcus coagulasa negativa (SCN) es el principal microorganismo que ocasiona sepsis tardía y éste es habitualmente resistente a cloxacilina; sin embargo, su virulencia es baja y la sepsis fulminante es inusual. Lamentablemente la prescripción de vancomicina se ha convertido en un grave problema en las UCIN, debido a diversas razones incluyendo: alta variabilidad farmacocinética del fármaco, dificultad en alcanzar concentraciones plasmáticas apropiadas y aumento de la concentración inhibitoria mínima (CIM), implicando además una mayor probabilidad de seleccionar cepas resistentes y aumento de otro tipo de infecciones ocasionadas por bacilos gramnegativos resistentes y candidiasis invasora. Considerando lo anteriormente señalado y a lo publicado en la literatura médica con respecto a las infecciones en neonatología, debido a su comportamiento clínico diferente a hospederos en otras etapas de la vida, resulta de suma importancia replantear el uso de vancomicina basado en fundamentos teóricos que avalen la seguridad de no utilizar este antimicrobiano como primera línea en sepsis neonatal tardía.

Humans , Infant, Newborn , Anti-Bacterial Agents/therapeutic use , Cloxacillin/therapeutic use , Sepsis/drug therapy , Staphylococcal Infections/drug therapy , Vancomycin/therapeutic use , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacokinetics , Coagulase , Cloxacillin/adverse effects , Cloxacillin/pharmacokinetics , Drug Repositioning , Intensive Care Units, Neonatal , Practice Patterns, Physicians' , Sepsis/microbiology , Staphylococcal Infections/microbiology , Vancomycin/adverse effects , Vancomycin/pharmacokinetics
Rev. chil. infectol ; 32(2): 135-141, abr. 2015. ilus, tab
Article in Spanish | LILACS | ID: lil-747515


Introduction: Metronidazole is the antibiotic of choice for the management of infections caused by anaerobes. Its administration requires multiple daily doses causing increased medication errors. Due to its high post-antibiotic effect and rapid concentration-dependent bactericidal activity, administration of this antibiotic in an extended dosing interval would achieve PK/PD parameters effectively. Objective: To assess the probability of achieving effective PK/PD relationship with the administration of 1,000 mg every 24 hours of metronidazole for Bacteroides fragilis infections. Methods: A clinical trial was conducted in a group of volunteers who received a single oral dose of 500 or 1,000 mg of metronidazole. Determinations of values of Cmax, t max, and AUCC0-24 h. determined using the trapezoidal method, were obtained for a Markov simulation that would allow for determining the likelihood of achieving a AUC0-24 h/MIC ratio above 70 for infections caused by susceptible B. fragilis. Results: Cmax (24,03 ± 6,89 mg/L) and t max (1,20 ± 0.80 hrs) and the value of AUC0-24 h (241.91 ± 48.14 mg * h/L) were determined. The probability of obtaining a AUC0-24 h/MIC ratio greater than 70 was greater than 99%. Conclusion: From a pharmacokinetic perspective, with the administration of a daily dose of 1,000 mg of metronidazole, it is possible to achieve a therapeutic goal of AUC0-24 h/MIC ratio above 70 for the treatment of anaerobic infections.

Introducción: Metronidazol es el antimicrobiano de elección para el manejo de infecciones anaeróbicas. Su administración requiere de dosis múltiples provocando aumento en errores medicamentosos. Debido al efecto post-antibiótico y a la actividad bactericida concentración-dependiente, la administración de metronidazol en intervalos ampliados de administración permitiría alcanzar parámetros PK/PD efectivos. Objetivo: Evaluar la probabilidad de alcanzar una relación PK/PD efectiva con la administración de 1.000 mg cada 24 h de metronidazol para infecciones por Bacteroides fragilis. Método: Se realizó un ensayo clínico sobre un grupo de voluntarios a quienes se les administró una monodosis oral de 500 y 1.000 mg de metronidazol, respectivamente. Se establecieron parámetros farmacocinéticos empleando el método trapezoidal. Se realizó una simulación de Markov que permitiera establecer la probabilidad de alcanzar una relación AUC0-24 h/CIM > 70 en infecciones por B. fragilis. Resultados: Se determinaron los valores de Cmax (24,03 ± 6,89 mg/L), t max (1,20± 0,8h) y AUC0-24 h (241,91 ± 48,14 mg*h/L), con lo cual la probabilidad de alcanzar una relación AUC0-24 h/CIM > 70 con 1.000 mg de metronidazol fue superior a 99%. Conclusión: Con la administración de 1.000 mg cada 24 h sería posible alcanzar una relación PK/PD efectiva para el tratamiento de infecciones anaeróbicas.

Humans , Male , Female , Adolescent , Adult , Middle Aged , Young Adult , Anti-Bacterial Agents/pharmacokinetics , Bacteroides Infections/drug therapy , Bacteroides Infections/metabolism , Bacteroides fragilis , Metronidazole/pharmacokinetics , Administration, Oral , Anti-Bacterial Agents/administration & dosage , Drug Administration Schedule , Markov Chains , Metronidazole/administration & dosage
J. oral res. (Impresa) ; 4(1): 25-31, feb.2015. ilus, tab, graf
Article in English | LILACS | ID: lil-776894


The use of prolonged local drug delivery to the oral cavity offers multiple benefits, such as increasing the pharmacological action in the desirable local site and reducing the usual dose and the adverse effects. Pilocarpine is a cholinergic drug approved by the FDA for the treatment of glandular hypofunction; however, the extent of its adverse effects limits its use. Objective: The main aim of this study was to analyze the physical and chemical properties of films, including pH, thickness, solubility, consistency and the ability to release pilocarpine for a prolonged time. Additionally, theantimicrobial activity in two opportunistic pathogens in hyposialia (Streptococcus mutans and Candida albicans) was also assessed. Methodology: Chitosan and HPMC (Methocel K4M CR) films were prepared in 1 percent acetic acid and pilocarpine was added under magnetic stirring. PH, thickness and time of solubility in artificial saliva, as well as diffusion and drug release kinetics per cm2 (OD=420nm) were assessed by spectrophotometry. The antimicrobialactivity was tested by disk diffusion test against St. mutans ATCC 700610 and C. albicans ATCC 90029 at concentrations of hyposalivation (1.44x1.2x106 CFU and 103 CFU, respectively). Results: All the films, except for Hydroxypropyl methylcellulose / Pilocarpine formulation, were found to have optimal physical-chemical properties for handling, maintaining drug diffusion in 76 percent per cm2 for four hours extended-release without showing antimicrobial activity at concentrations of hyposalivation. Conclusion: The films had optimum handling properties and a constant drug release; however, antimicrobial activity was not found...

El uso local de administración prolongada de fármacos en la cavidad oral proporciona múltiples ventajas, aumentando la acción farmacológica en el sitio local deseable, reducción de la dosis usual y disminución de los efectos adversos. La pilocarpina es una droga colinérgica aprobada por la FDA para el tratamiento de la hipofunción glandular, sin embargo la amplitud de sus efectos adversos limitan su uso. Objetivo: Con el objetivo de analizar las propiedades físico-químicas de las biopelículas se evaluó el pH, grosor, solubilidad, uniformidad y la capacidad de liberar prolongadamente pilocarpina, así como su actividad antimicrobiana ante los dos microorganismos patógenos oportunistas en la hiposialia (Streptococcus mutans y Candida albicans). Metodología: Se elaboraron biopelículas de Quitosán e Hidroxipropilmetilcelulosa (Methocel K4MCR) en ácido acético al 1 por ciento, adicionadas con pilocarpina bajo agitación magnética, evaluando el pH, grosor y el tiempo de solubilidad en saliva artificial, así como la uniformidad de difusión y cinética de liberación de la droga por cm2 mediante espectrofotometría (OD=420nm). Mediante difusión en disco se evaluó la actividad antimicrobiana ante Streptococcus mutans ATCC 700610 y Candida albicans ATCC 90029 en concentraciones encontradas en hiposalivación (1.44 x 106 UFC y 1.2 x 103 UFC respectivamente). Resultados: Todas las biopelículas, a excepción de la formulación Hidroxipropilmetilcelulosa e Hidroxipropilmetilcelulosa/ Pilocarpina resultaron tener las propiedades físico-químicas óptimas de manipulación, manteniendo una uniformidad de difusión de la droga en 76 por ciento por cm2 con liberación prolongada por 4 horas, sin mostrar actividad antimicrobiana en concentraciones de hiposalivación. Conclusión: Las películas obtuvieron las propiedades óptimas de manipulación, y una constante liberación del fármaco, sin embargo, ninguna formulación presentó actividad antimicrobiana...

Anti-Bacterial Agents/pharmacology , Biofilms , Methylcellulose/chemistry , Pilocarpine/pharmacology , Chitosan/chemistry , Anti-Bacterial Agents/pharmacokinetics , Mouth/microbiology , Candida albicans , Hydrogen-Ion Concentration , Drug Liberation/physiology , Pilocarpine/pharmacokinetics , Solubility , Streptococcus mutans , Time Factors , Xerostomia , Xerostomia/microbiology
Braz. j. infect. dis ; 18(5): 512-517, Sep-Oct/2014. tab, graf
Article in English | LILACS | ID: lil-723083


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.

Humans , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Anti-Bacterial Agents/pharmacokinetics , Ceftriaxone/pharmacokinetics , Ceftriaxone/pharmacology , Ciprofloxacin/pharmacokinetics , Ciprofloxacin/pharmacology , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Escherichia coli/isolation & purification , Monte Carlo Method , Microbial Sensitivity Tests/methods , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/pharmacokinetics , Penicillanic Acid/pharmacology , Piperacillin/pharmacokinetics , Piperacillin/pharmacology , Pyelonephritis/microbiology , Severity of Illness Index , Thienamycins/pharmacokinetics , Thienamycins/pharmacology , Urinary Tract Infections/drug therapy , Urinary Tract Infections/microbiology , beta-Lactams/pharmacokinetics , beta-Lactams/pharmacology