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

Abstract

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 log 10 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 log 10 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.

Acinetobacter Baumannii Nosocomial Infections

“…Sulbactam without ampicilin showed bactericidal properties at a dose of 2g administered every 6 hours. The desired therapeutic effect was also achieved when ampicilin plus sulbactam were administered in prolonged intravenous infusions (26). An additional property of sulbactam is its synergy with multiple antibiotic families, including cephalosporines, aminoglycosides, fluorochinolones, colistin and tigecycline (27).…”

Global Spread of Drug-Resistant Acinetobacter Baumannii : Molecular Epidemiology And Management Of Antimicrobial Resistance

“…It is not usually tested by automated in vitro susceptibility tests and is mostly available in combination with ampicillin in a formulation with a fixed 1:2 concentration ratio. An in vivo pharmacodynamic study of healthy volunteers showed that bactericidal or inhibitory levels may be achieved in the serum when at least 2 g of sulbactam are infused every 6 h [128].…”

Pharmacokinetics and pharmacodynamics of a novel amoxicillin/sulbactam/prednisolone intramammary infusion in lactating cows after repeated administrations

“…In vivo studies have demonstrated that a bacteriological cure rate of 67% was achieved when intramammary AMX was used against these common pathogens ( Roberson et al 2004). In human medicine, several studies have reported the efficacy of a AMX/SUL combination in the treatment of bacterial infections, including E. coli and Acinetobacter baumannii (Bantar et al 1999(Bantar et al , 2009). Moreover, the results of our preliminary study showed that a good bactericidal activity in vitro was achieved for the AMX/SUL (4 : 1) combination against these common mastitis pathogens (unpublished results).…”