Significance of penicillin tolerance in vivo: prevention of experimental Streptococcus sanguis endocarditis

To determine whether in-vitro tolerance to penicillin among viridans streptococci influences the efficacy of penicillin in vivo, we studied four strains of dextran-producing. Streptococcus sanguis serotype II. All four strains were inhibited in vitro by 0.1 mg/l penicillin or less; one was not-tolerant, one intermediate, and two were tolerant to the lethal action of penicillin. The combination of penicillin and streptomycin killed all strains completely within 24 h in vitro. Sera from rabbits injected with penicillin were inhibitory for all strains, but were bactericidal only for the non-tolerant strain. The incidence of endocarditis in untreated rabbits with left heart catheters was 100% after inoculation of each of the four strains. Despite attempted prophylaxis with procaine penicillin G, endocarditis developed in 44 of 70 rabbits (63%) injected with the tolerant strains, contrasting with 2 of 22 (9%) for the non-tolerant strain (P=0.0001). The probability that penicillin would fail to prevent endocarditis was directly related to its minimal bactericidal concentration for each strain (r=0.95). In contrast, the combination of penicillin plus streptomycin always prevented endocarditis. We conclude that penicillin tolerance can be a crucial determinant of the response of viridans streptococci to penicillin in vivo.