Pharmacodynamic assessment of Amoxicillin-Sulbactam against Acinetobacter baumannii: searching the optimal dose and infusion time through a human ex-vivo model

Amoxicillin-sulbactam (AMX-SUL) is an aminopenicillin/ß-lactamase inhibitor combination currently available in 29 countries and may be a suitable option for treating infections caused by Acinetobacter spp. Thus, we sought to search the optimal dosing strategy for this formulation through an ex vivo pharmacodynamic human model against Acinetobacter baumanniii. Four volunteers were randomized to receive alternatively a single dose AMX-SUL infused both either over 30 min or 3h at the following ratios (g/g): 1/0.5; 1/1, and 0/2. Time-kill studies were performed with the 0-, 0.5-, 2-, 4-, 6- and 8-h sera after dose against a clinical isolate of A. baumannii (sulbactam MIC, 4µg/mL). Bactericidal activity (i.e. a mean decrease >3 log10 CFU/mL in the viable cell counts from the initial inoculum) was displayed by the 0.5- and the 2-h sera after dose for all formulations. The 4-h sera proved inhibitory with the AMX-SUL 1g/1g formulation, albeit a trend to regrowth was observed after 24-h incubation. With the AMX-SUL 0g/2g dose, the 4-h sera proved almost bactericidal activity (i.e. a mean decrease of 2.4 log10 CFU/mL in the viable cell counts from the initial inoculum), whereas the 6-h sera was inhibitory, with a trend to regrowth after 24-h incubation. When infused over 3h, AMX-SUL 1g/0.5g and 1g/1g, bactericidal activity was displayed by the 0.5-, 2- and the 4-h sera after dose and the 6-h sera proved inhibitory with the AMX-SUL 1g/1g formulation. The present study, albeit preliminary, might give a rationale for the dosing strategy to treat infections caused by A. baumannii with sulbactam, either alone or combined with amoxicillin. A 2-g sulbactam dose seems to be optimal to be infused over 30 min with a 6-h dosing interval. When infused over 3h, AMX-SUL 1g/1g given every 6h or 8h seems a suitable dosing schedule.

Urine inhibitory titers against resistant Escherichi Coli isolates after oral amoxicillin-sulbactam

It has been previously shown that following the oral administration of amoxicillin-sulbactam (AXS) theurinary activity against Escherichia coli (Ec) is due to beta-lactamase inhibition (i.e.TEM-1) as well asto the intrinsic activity of sulbactam (SB). Similarly, it has been previously demonstrated in volunteers that a single oral dose of AXS 500/500 mg allows high urine inhibitory titers (UITs) against resistant Ec isolates. In this in vitro and ex vivo study we assessed the urinary activity of a new AXS proportion: 875/125 mg. Urine was collected from 12 volunteers at 0-2; 2-4; 4-6 h after a single oral dose of AXS 875/125mg. Previous studies had shown that pooled urine from 12 volunteers did not differ significantly in the UIT as compared to the mean individual values. Urine pools for each period were prepared. Each pool was tested for UIT against 60 Ec isolates received from 10 different laboratories in South American countries: 10 susceptible (S) to AXS; 10 intermediate (I) and 40 resistant (R); the latter ranging 32/16-256/128 mg/l. Amoxicillin (AX) and SB urine concentrations were determined in all the samples. UIT ranged from 1/4 to >1/32 for S and I strains and from 1/1 to 1/4 for R strains. For one strain (AXS, MIC 256/128mg/l) the UIT titer was 1/1 at 2 and 4 h but it was not inhibited at 6 h. AX mean levels ranged from 1872 (2 h) to 522 mg/l (6 h) while SB ranged from 1075 (2 h) to 334 (6 h) mg/l. It is noteworthy that 59/60 strains were inhibited by 128 mg/l SB alone. In conclusion: the AXS 875/125 proportion has a remarkable in vitro and ex vivo activity against Ec urinary isolates.

Actividad in vitro de niveles séricos y urinarios de amoxicilina y amoxicilina-sulbactam sobre 820 cepas de escherichia coli aisladas de infecciones urinarias bajas extrahospitalarias: estudio sudamericano / In vitro activity at serum and urinary levels of amoxicillin and amoxicillin-sulbactam against 820 escherichia coli strains isolated from community acquired urinary tract infections: South American collaborative study

Previamente, habíamos demostrado la actividad que poseen amoxicilina-sulbactam y sulbactam solo frente a Escherichia coli en la orina. Realizamos un estudio para determinar la etiología de las infecciones urinarias bajas no complicadas de la comunidad (IUBNCC) en Sudamérica. Participaron 10 laboratorios de 8 países sudamericanos. Cada laboratorio envió al centro coordinador (CEA, Bs. Aires) los resultados de susceptibilidad a amoxicilina y amoxicilina-sulbactam por el método de discos en 100 aislamientos consecutivos obtenidos de pacientes de 3 a 70 años con IUBNCC y además remitieron 20 cepas de E. coli consecutivas consideradas resistentes a amoxicilina por el método de disco. En el CEA se comprobó la CIM de amoxicilina, amoxicilina-sulbactam (2:1) y sulbactam solo; se determinó el título inhibitorio de la orina (TIO) en 12 voluntarios que recibieron una dosis oral de 500:500 mg de amoxicilina-sulbactam. Las orinas se recolectaron a las 0 a 2,2 a 4 y 4 a 6 h luego de la administración de amoxicilina-sulbactam y los TIO se verificaron sobre 5 cepas de E. coli resistentes (R) y 1 cepa sencible (S) a amoxicilina-sulbactam seleccionadas con diferentes CIM, entre las recibidas de cada centro participante; se determinaron las concentraciones de amoxicilina y sulbactam en la orina por un método microbiológico. Resultados: E. coli fue predominante 820/1.000 (82 por ciento); P, mirabilis y K. pneumoniae (4,3 por ciento ambas); S. saprophyticus (4,1 por ciento) y otros (5,3 por ciento). Susceptibilidad por discos en E. coli: 59,4 por ciento R a amoxicilina; 16,9 por ciento intermedias (I) y 23,7 por ciento S y para amoxicilina-sulbactam 28 por ciento R, 19,2 por ciento I y 52,8 por ciento S. Determinación de CIM: se estudiaron 102 E. coli R a amoxicilina-sulbactam, las CIM 90 (µg/ml fueron: amoxicilina > 2.048; amoxicilina-sulbactam: 256/128 y sulbactam solo, 128. TIO: Variaron desde > 1/32 a las 2 h; 1/16-1/4 a las 4 h y 1/4-1/2 a las 6 h para todas cepas estudiadas. Niveles de ATB en orina (µg/mI): amoxicilina y sulbactam respectivamente a las 2 h: 1.414 y 1.904: a las 4 h: 691 y 1.257 y a las 6 h: 462 y 641. Nuestros resultados confirman el predominio de E. coli en IUBNCC en Sudamérica y explican las discrepancias entre las resistencia supuesta por el método de discos y los éxitos clínicos logrados con amoxicilina-sulbactam en IUBNCC