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BJID 2009; 13 (October)

Pharmacodynamic Assessment of Amoxicillin-Sulbactam Against Acinetobacter baumannii: Searching the Optimal Dose and Infusion Time Through a Human ex-vivo Model

Carlos Bantar 1, Liliana Fernández Canigia 2, María Alejandra Berger 2, Jorge L Soutric 3 and Héctor J Arenoso 3 Laboratorio Domingo I Nanni; Entre Rios, PR, Argentina; 2Laboratorio de Microbiología,Hospital Alemán and 3Laboratorios Bagó S.A.; Buenos Aires, Argentina

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 modelagainst 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 meandecrease ≥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 AMXSUL 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 inthe 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 rationalefor 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. Key-Words: Amoxicillin-sulbactam, Acinetobacter.

Acinetobacter baumannii is becoming animportant pathogen associated with nosomial infections worldwide [1]. It is invariably multiresistant and one major concern is the increasing incidence of carbapenem-resistant isolates, since these antibiotics are frequently the therapeutic choice for these infections [2]. Carbapenem resistance in South America has already reached levels that significantly influence therapeutic choices [3,4] andthis looks set to be a problem in several other regions [5,6]. Acinetobacter spp. has been found at the fourth rank in hospitalized patients with pneumonia in Latin America [6] and at the second one in patients with nosocomial pneumonia in Argentina [7], with carbapenem resistance increasing dramatically [4], especially in Argentina [4,7] and in Colombia [4,8]. This kind of resistance has alsobeen reported at modest rates in Chile [4] and Brazil [4,9], albeit it seems to remain stable in some regions of this late country [10]. As a result, old antibiotics, such as colistin and ampicillinsulbactam, have emerged as the obligate alternative for treating serious infections associated with A. baumannii [11]. Both early [12] and present [13] evidences suggest that sulbactam is active in vitroagainst Acinetobacter spp, whereas some reports showed that this drug, given as a combination of ampicillin-sulbactam, may yield acceptable clinical success when treating infections associated with this
Received on 13 April 2009; revised 28 September 2009. Address for correspondence: Dr.Carlos Bantar. Colón 128, (3100) Paraná, Entre Ríos.Fax: (54343)4310783. E-mail: This...
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