Imipenem was very active in vitro against 36 Staphylococcus aureus isolates from cases of infective endocarditis; the MBC90 was 0.06 mg/l (four- to eight-fold more active than nafcillin). The in-vitro activity of imipenem against 22 Streptococcus faecalis isolates from proven endocarditis cases was similar to that of penicillin G (MBC90 = 8 mg/l). Imipenem was compared with nafcillin and with penicillin plus gentamicin in the therapy of experimental endocarditis induced in rabbits by Staph. aureus and Str. faecalis, respectively. The dosages were chosen to simulate closely serum antibiotic concentrations found in humans receiving standard parenteral regimens. Imipenem was more rapidly bactericidal than nafcillin in experimental staphylococcal endocarditis. The mean +/- S.D. Staph. aureus concentrations within aortic valve vegetations (log10 cfu/g) after 5 days of therapy were as follows: imipenem = 1.39 +/- 0.61 versus nafcillin 2.39 +/- 0.36 (P less than 0.02). Both the imipenem and nafcillin regimens resulted in 'sterile' vegetations in congruent to 50% of rabbits with experimental staphylococcal endocarditis after 5 days of therapy (P greater than 0.05). Imipenem was also equivalent to penicillin plus gentamicin in the therapy of experimental enterococcal endocarditis for 5 days, as assessed by the mean cfu/g vegetation and the percentage of vegetations rendered sterile. However, 7 days of therapy cured experimental enterococcal endocarditis in 72% of rabbits receiving penicillin plus gentamicin versus 20% for imipenem alone (P less than 0.05). Imipenem deserves further evaluation in the therapy of infective endocarditis, both in experimental animal models of infection and in humans. This agent may prove useful in the therapy of staphylococcal endocarditis in a variety of difficult clinical situations. Therapy of enterococcal endocarditis with imipenem alone is not advisable, pending further data.

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.

Azlocillin was more active in vitro than ticarcillin or carbenicillin against 561 aminoglycoside-resistant strains of Pseudomonas aeruginosa collected from 74 hospitals distributed over a wide geographic area in the eastern United States.Azlocillin was compared with various other antimicrobial agents in discriminative animal models of Ps. aeruginosa pyelonephritis, osteomyelitis, endocarditis, and meningitis in a variety of mammalian species.Cefsulodin was more effective than azlocillin in reducing Ps. aeruginosa kidney concentrations in rat pyelonephritis induced by intrarenal inoculation. The mean±s.D. log l0 cfu/g kidney after three days of therapy were as follows: controls = 5-4±1-5, azlocillin=4-4±1-8, cefsulodin = 2-6±0-9 (/»-0-01) but the MBC for the test strain was eight-fold higher for azlocillin (8 vs. 1 mg/1) and effective concentrations were maintained longer in rat serum for cefsulodin as against azlocillin. In addition, ticarcillin reduced kidney bacterial concentrations faster than azlocillin in a mouse pyelonephritis model induced by intravenous Ps. aeruginosa inoculation with subsequent iron loading.Azlocillin was less effective than tobramycin in experimental chronic Ps. aeruginosa osteomyelitis induced in rabbits by direct injection into the tibia. An azlocillin-tobramycin regimen was not more effective than tobramycin alone. After 28 days of therapy, the percentages of positive bone cultures after death were as follows: no antibiotic (controls) = 92%, azlocillin = 95%, tobramycin = 76%, azlocillin plus tobramycin = 60%.Both ticarcillin and azlocillin were less active than tobramycin in experimental Ps. aeruginosa endocarditis induced in rabbits by intravenous inoculation of 10 8 cfu following 1 h of catheter induced aortic valve trauma. The best results were noted with an azlocillin-tobramycin regimen. The mean±s.D. log, 0 cfu Ps. aeruginosa/g vegetation after five days of therapy were as follows: no antibiotic controls = 81 ±11, tobramycin=4-5 ±0-8, ticarcillin = 6-9 ±0-8, azlocillin = 5-7 ± 1-5, ticarcillin phis tobramycin=4-9+1-0, azlocillin plus tobramycin = 3-3 ± 1-6. Sterile vegetations were rarely attained with any regimen.The mean percentage penetration into purulent cerebrospinal fluid (CSF) in experimental Ps. aeruginosa meningitis for azlocillin was 13-3%, comparable to many other /J-lactam antibiotics. Azlocillin was the single most active (P-0-0\) agent evaluated after 8 h intravenous infusions in this model. An azlocillin-amikacin regimen was more rapidly bactericidal (P<001) than either agent alone in vivo. None of the agents evaluated alone or in combination, however, produced a sterile CSF after 8 h of therapy in any animal.

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