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We compared the efficacy of ceftriaxone combined with gentamicin, both given once a day, with that of cloxacillin given every 4 h plus gentamicin given once a day or in three daily doses (t.i.d.) for the treatment of experimental methicillin-susceptible staphylococcal endocarditis. The antibiotics were administered by using human-like (H-L) pharmacokinetics that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 10 5 CFU of Staphylococcus aureus S5 (MICs and minimal bactericidal concentrations of cloxacillin, ceftriaxone, and gentamicin, 0.5 and 2 μg/ml, 4 and 8 μg/ml, and 0.5 and 1 μg/ml, respectively). The animals were then treated for 24 h with cloxacillin at a dose of 2 g that simulated H-L pharmacokinetics (H-L 2 g) every 4 h alone or combined with gentamicin (administered at doses of H-L 1 mg/kg of body weight every 8 h or H-L 4.5 mg/kg every 24 h) or with ceftriaxone at H-L 2 g every 24 h alone or combined with gentamicin (administered at doses of H-L 1 mg/kg every 8 h or H-L 4.5 mg/kg every 24 h). The results of therapy for experimental endocarditis due to the S5 strain showed that (i) cloxacillin alone is more effective than ceftriaxone alone in reducing the bacterial load ( P < 0.01), (ii) the combination of cloxacillin or ceftriaxone with gentamicin is more effective than each of these drugs alone ( P < 0.01), and (iii) Ceftriaxone H-L plus gentamicin H-L 4.5 mg/kg, both administered every 24 h, showed efficacy similar to that of the “gold standard,” cloxacillin H-L plus gentamicin H-L 1 mg/kg t.i.d. ( P > 0.05). An increase in the interval of administration of gentamicin to once daily resulted in a reduction in the numbers of bacteria in the vegetations equivalent to that achieved with the recommended regimen of cloxacillin plus gentamicin t.i.d. in the treatment of experimental endocarditis due to methicillin-susceptible S. aureus . Ceftriaxone plus gentamicin, both administered once a day, may be useful for home-based therapy for selected cases of staphylococcal endocarditis.

A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in immunocompetent rats and could be used to explore the pathophysiology and to evaluate optimal therapy of this infection in the immunocompetent host.

With the aim of investigating home therapy for enterococcal endocarditis, we compared the efficacy of teicoplanin combined with gentamicin given once a day or in three daily doses (t.i.d.) with the standard treatment, ampicillin plus gentamicin administered t.i.d., for treating experimental enterococcal endocarditis. The antibiotics were administered by using “human-like pharmacokinetics” (H-L), i.e, pharmacokinetics like those in humans, that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 10 8 CFU of Enterococcus faecalis EF91 (MICs and MBCs of ampicillin, gentamicin, and teicoplanin, 0.5 and 32, 16 and 32, and 0.5 and 1 μg/ml, respectively) and were treated for 3 days with ampicillin H-L at 2 g every 4 h plus gentamicin H-L at 1 mg/kg every 8 h, or teicoplanin H-L at 10 mg/kg every 24 h, alone or combined with gentamicin, administered at dose of H-L at 1 mg/kg every 8 h or H-L at 4.5 mg/kg every 24 h. The results of therapy for experimental endocarditis due to EF91 showed that teicoplanin alone was as effective as ampicillin alone in reducing the bacterial load ( P > 0.05). The combination of ampicillin or teicoplanin with gentamicin was more effective than the administration of both drugs alone in reducing the log 10 CFU/gram of aortic vegetation ( P < 0.01 and P < 0.05, respectively). Teicoplanin plus gentamicin H-L at 4.5 mg/kg, both administered every 24 h, showed an efficacy equal to the “gold standard,” ampicillin plus gentamicin H-L at 1 mg/kg t.i.d. ( P > 0.05). Increasing the interval of administration of gentamicin to a single daily dose combined with teicoplanin resulted in a reduction of bacteria in the vegetations equivalent to that achieved with the recommended regimen of ampicillin plus thrice-daily gentamicin in the treatment of experimental endocarditis due to E. faecalis . Teicoplanin plus gentamicin, both administered once a day, may be useful home therapy for selected cases of enterococcal endocarditis.

This study compares the effects of a total daily dose of gentamicin given once a day (q.d.) or three times a day (t.i.d.) in the therapy of experimental endocarditis in rabbits caused by penicillin-susceptible, penicillin-tolerant, or penicillin-resistant viridans streptococci. Four isolates were used in vivo: one penicillin susceptible (MIC < or = 0.03 microgram/ml), one penicillin tolerant (MBC/MIC, < or = 0.03/ > 32 micrograms/ml), and two penicillin resistant (MICs = 0.5 and 2 micrograms/ml). Animals were infected with one of the four isolates and assigned to one of the following treatment regimens: no treatment, procaine penicillin at 1.2 million IU intramuscularly (i.m.) t.i.d., procaine penicillin plus gentamicin at 1 mg/kg of body weight i.m. t.i.d., procaine penicillin plus gentamicin at 3 mg/kg i.m. q.d., or procaine penicillin plus gentamicin at 1 mg/kg i.m. q.d. (only animals infected with the penicillin-susceptible isolate). Serum drug concentrations measured 30 min after administration of 1.2 million IU of penicillin and 1 or 3 mg of gentamicin per kg were 22.6, 3.8, and 8.5 micrograms/ml, respectively. The reduced total daily dose of gentamicin was ineffective among animals infected with penicillin-susceptible viridans streptococci; treatment with 1 mg of gentamicin per kg per day plus penicillin was less effective (P < 0.05) than was treatment with 3 mg of gentamicin per kg per day plus penicillin. The 1-mg/kg/day gentamicin treatment regimen was not further studied. The gentamicin dosing interval did not significantly affect (q.d. versus t.i.d., P > 0.05) the relative efficacy of penicillin plus gentamicin for treatment of experimental endocarditis among animals infected with each of the four isolates tested.