In vitro and in vivo synergism between amoxicillin and clavulanic acid against ampicillin-resistant Haemophilus influenzae type b

Eight strains of ampicillin-resistant β-lactamase-producing Haemophilus influenzae type b were studied in vitro for synergy between amoxicillin and clavulanic acid. The minimal inhibitory concentrations for amoxicillin alone were 6.25 to 12.5 μg/ml, and for clavulanic acid alone they were 12.5 to 25 μg/ml. However, seven of eight strains were inhibited by a combination of 0.36 μg of amoxicillin and 0.36 μg of clavulanic acid per ml. Infant rat models of bacteremia and meningitis were used to test the efficacy of amoxicillin and clavulanic acid alone and in combination upon four strains of ampicillin-resistant H. influenzae. Neither amoxicillin alone (27 animals) nor clavulanic acid alone (20 animals) sterilized the blood or cerebrospinal fluid of the animals. In contrast, 30 of 33 blood cultures and 29 of 33 cerebrospinal fluid cultures were sterile when a combination of the two drugs in the same dosages was used. The observed in vitro and in vivo synergism between amoxicillin and clavulanic acid suggests that the combination may be effective therapy for invasive infections in humans caused by ampicillin-resistant H. influenzae type b.