Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae.

KPC-producing Klebsiella pneumoniae causes serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producing K. pneumoniae The activities of combination antimicrobials were also determined by the checkerboard method. The MIC50 and MIC90 of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (fT>MIC). The monotherapy MIC50s and MIC90s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC50s and to 1/8 to 1/16 the MIC90s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC50 and MIC90 had better chances of achieving ≥90% probability of target attainment (PTA) of 70% fT>MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40% fT>MIC for MIC50 but not MIC90 The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producing K. pneumoniae.

Strategies for the treatment of polymyxin B-resistant Acinetobacter baumannii infections.

In this study, the activity of meropenem (MEM), fosfomycin (FOF) and polymyxin B (PMB), alone and in combination, was analysed. In addition, optimisation of the pharmacodynamic index of MEM and FOF against six isolates of OXA-23-producing Acinetobacter baumannii (including three resistant to PMB) that were not clonally related was assessed. Antimicrobial combinations were evaluated by chequerboard analysis and were considered synergistic when the fractional inhibitory concentration index (FICI) was ≤0.5. Pharmacodynamic analyses of the MEM and FOF dosing schemes were performed by Monte Carlo simulation. The target pharmacodynamic index (%ƒT>MIC) for MEM and FOF was ≥40% and ≥70%, respectively, and a probability of target attainment (PTA) ≥0.9 was considered adequate. Among the PMB-resistant isolates, combinations of PMB+MEM and PMB+FOF+MEM showed the highest synergistic activity (FICI ≤0.125); isolates that were previously PMB-resistant were included in the susceptible category using CLSI interpretive criteria. Pharmacodynamic evaluation found that for a FOF minimum inhibitory concentration (MIC) of ≤16µg/mL, treatment both by bolus dosing and prolonged infusion achieved adequate PTA, whilst for MIC=32µg/mL only infusion achieved adequate PTA. For a MEM MIC of 4µg/mL, only the bolus treatment scheme with 1.5g q6h and the infusion schemes with 1.0g q8h, 1.5g q6h and 2.0g q8h achieved PTA ≥0.9. Results of antimicrobial and pharmacodynamic analyses can assist in treating infections caused by multidrug-resistant A. baumannii. However, in vivo clinical studies are essential to evaluate the true role of these compounds, including intravenous antimicrobial FOF therapy.

Prevalência de uropatógenos e perfil de sensibilidade aos antimicrobianos em pacientes ambulatoriais de Jataí-GO / Prevalence of uropathogens and antimicrobial susceptibility profile in outpatient from Jataí-GO

Introduction: Urinary tract infections (UTIs) affect people worldwide. Escherichia coli is the main agent of UTI, however the etiology may vary according to the age and sex of the patient. Regional variations in the prevalence and antimicrobial resistance should be considered for therapy choice. Objectives: This study aimed to conduct a survey on the main agents of UTI, and assess the resistance of these microorganisms, during the period of March 2010 to June 2012 in the city of Jataí-GO. Method: A retrospective cross-sectional study were performed, collecting data on the prevalence of uropathogens and their sensitivity profiles which were evaluated by disk diffusion method. Results: During this period, 2,181 urine cultures were evaluated, of which 510 (23.4%) were positive, predominantly female (81.4%) and aged between 21 and 64 years old (59.7%). The most frequently isolated microorganism was E. coli (61%), followed by Staphylococcus saprophyticus (9.4%), and Proteus (9.4%). The prevalence of these bacteria according to the patient sex has suffered a statistically significant change (p < 0.05). It was possible to detect high resistance rate of E. coli to some antibiotics of choice for UTI treatment, such as ampicillin (57.9 %), pipemidic acid (50.5 %), nalidixic acid (48.6 %), and trimethoprim-sulfamethoxazole (44.8%). Conclusion: These data demonstrate the need to know the reality of each region in order to establish an appropriate empirical therapy, when it is not possible to perform culture and antimicrobial susceptibility testing...

Introdução: Infecções do trato urinário (ITU) afetam pessoas em todo o mundo. Escherichia coli é o principal agente de ITU, no entanto a etiologia pode variar de acordo com o sexo e a idade do paciente. Variações regionais quanto à prevalência e à resistência aos antimicrobianos devem ser consideradas para a escolha terapêutica. Objetivos: Este trabalho teve por objetivo realizar um levantamento sobre os principais agentes de ITU e avaliar o perfil de resistência desses microrganismos no período de março de 2010 a junho de 2012, na cidade de Jataí-GO. Método: Estudo retrospectivo de corte transversal realizado por meio de coleta de dados sobre a prevalência de uropatógenos e seus perfis de sensibilidade avaliados pelo método da difusão. Resultados: Neste período, foram realizadas 2.181 uroculturas, das quais 510 (23,4%) apresentaram resultado positivo, sendo predominantemente do sexo feminino (81,4%) e com idade entre 21 e 64 anos de idade (59,7%). O microrganismo mais frequentemente isolado foi E. coli (61%), seguido de Staphylococcus saprophyticus (9,4%) e Proteus (9,4%). A prevalência dessas bactérias, de acordo com o sexo do paciente, sofreu variação estatisticamente significativa (p < 0,05). Foi possível constatar elevada taxa de resistência de E. coli para alguns antimicrobianos de primeira escolha para tratamento de ITU, como ampicilina (57,9%), ácido pipemídico (50,5%), ácido nalidíxico (48,6%) e sulfazotrim (44,8%). Conclusão: Esses dados demonstram a necessidade de se conhecer a realidade de cada região a fim de se estabelecer uma terapia empírica adequada, quando não for possível a realização da cultura e do antibiograma...