Influence of gentamicin dose size on the efficacies of combinations of gentamicin and penicillin in experimental streptomycin-resistant enterococcal endocarditis.

We have evaluated the benefits of low versus high doses of gentamicin combined with procaine penicillin (1.2 X 10(6) U three times daily) in the treatment of streptomycin-resistant experimental enterococcal endocarditis in rabbits. The mean peak serum gentamicin concentration in animals treated with low-dose gentamicin (0.75 mg/kg three times daily) was 3.06 micrograms/ml (range, 2.1 to 4.2 micrograms/ml), and it was 8.05 micrograms/ml (range, 4.5 to 16.1 micrograms/ml) in animals treated with high-dose gentamicin (2 mg/kg three times daily). The mean log10 colony-forming units of enterococci per gram of cardiac valve vegetation in animals treated with procaine penicillin combined with low- or high-dose gentamicin were 2.4 +/- 1.2 and 1.4 +/- 1.3, respectively (P = not significant) after 3 days of treatment and 1.7 +/- 1.2 and 1.7 +/- 1.5, respectively (P = not significant), after 5 days of therapy. The median peak serum bactericidal titer was 1:8 in animals treated with low- or high-dose gentamicin. We detected no significant difference between low- or high-dose gentamicin combined with procaine penicillin in the efficacy of treatment of streptomycin-resistant experimental enterococcal endocarditis.     

Treatment of experimental endocarditis due to Enterococcus faecalis using once-daily dosing regimen of gentamicin plus simulated profiles of ampicillin in human serum.

We compared the efficacy of ampicillin, both alone and in combination with gentamicin given once a day (q.d.) or three times a day (t.i.d.), in the treatment of experimental enterococcal endocarditis. Ampicillin was administered by using humanlike pharmacokinetics that simulated the profiles of this drug in human serum. An open one-compartment mathematical model developed in this study was used to estimate the decreasing doses administered with a computer-controlled infusion pump that simulated in rabbits the human serum pharmacokinetics after intravenous administration of 2 g of ampicillin every 4 h. Animals with catheter-induced endocarditis were infected intravenously with 10(8) CFU of Enterococcus faecalis J4 (MICs and MBCs of ampicillin and gentamicin, 2 and 128 and 16 and 64 micrograms/ml, respectively) and were treated for 3 days with ampicillin alone or in combination with gentamicin at 2 mg/kg of body weight subcutaneously t.i.d. or at 6 mg/kg subcutaneously q.d. The serum ampicillin levels and pharmacokinetic parameters of the humanlike pharmacokinetics of ampicillin in rabbits were similar to those found in humans treated with 2 g of ampicillin intravenously. The results of therapy for experimental endocarditis caused by E. faecalis J4 showed that the residual bacterial concentration in aortic valve vegetation was significantly lower in the animals treated with combinations of ampicillin plus gentamicin given q.d. or t.i.d. than in those treated with ampicillin alone (P < 0.01). The dosing interval of gentamicin did not significantly affect (q.d. versus t.i.d.; P = 0.673) the therapeutic efficacy of the combination of ampicillin plus gentamicin.     

Antimicrobial therapy of experimental endocarditis caused by nutritionally variant viridans group streptococci.

Rabbits with nutritionally variant viridans group streptococcal experimental endocarditis were treated three times daily for 3 days with procaine penicillin (1.2 X 10(6) U) alone or together with low-dose streptomycin (2 mg/kg), high-dose streptomycin (8 mg/kg), low-dose gentamicin (0.32 mg/kg), or high-dose gentamicin (1.05 mg/kg). The mean 0.5-h serum concentrations of streptomycin were 5.3 and 22.5 micrograms/ml in the low- and high-dose group, respectively, and the concentrations of gentamicin were 0.7 and 2.5 micrograms in the low- and high-dose groups, respectively. The combination of procaine penicillin with each dose of aminoglycoside was significantly more effective (P less than 0.001) than was procaine penicillin alone. In combination with procaine penicillin, the higher dose of streptomycin was significantly more effective (P less than 0.02) than the lower dose of streptomycin. The higher dose of streptomycin was not significantly more effective than either dose of gentamicin. The results of treatment with the high or low dose of gentamicin were virtually identical.     

Treatment of streptomycin-susceptible enterococcal experimental endocarditis with combinations of penicillin and low- or high-dose streptomycin.

We used two strains of streptomycin-susceptible enterococci (MIC, 64 and 128 micrograms of streptomycin per ml, respectively) isolated from patients with infective endocarditis. When combined with penicillin, 20 micrograms of streptomycin per ml killed both strains synergistically in vitro whereas combinations of 5 and 10 micrograms of streptomycin per ml did not act synergistically against either strain. By using the rabbit model of enterococcal experimental endocarditis, animals were treated for 3 days with procaine penicillin (1.2 X 10(6) U intramuscularly three times daily) together with low-dose streptomycin (3.5 mg/kg) or high-dose streptomycin (10 mg/kg) intramuscularly three times daily. The peak concentrations of streptomycin in serum at 0.5 h were 9.2 and 26.8 micrograms/ml in the low- or high-dose group, respectively. When combined with procaine penicillin, both dosages of streptomycin were more effective (P less than 0.01) than procaine penicillin alone for the treatment of enterococcal experimental endocarditis. There was no significant difference in the efficacy of procaine penicillin plus low-dose streptomycin versus procaine penicillin plus high-dose streptomycin therapy of enterococcal experimental endocarditis.     

Synergy between amoxicillin and gentamicin in combination against a highly penicillin-resistant and -tolerant strain of Streptococcus pneumoniae in a mouse pneumonia model.

In vivo synergy with beta-lactam antibiotics and aminoglycosides has been studied only with penicillin-susceptible Streptococcus pneumoniae strains. We evaluated the interaction between amoxicillin (AMX) and gentamicin (GEN) on the basis of in vitro checkerboard and time-kill curves and of findings in a mouse model of acute bacteremic pneumonia due to a highly penicillin-resistant and -tolerant S. pneumoniae strain of serotype 19 (penicillin and AMX MICs of 4 micrograms/ml; gentamicin MIC of 16 micrograms/ml). Checkerboard results at 18 h of incubation showed indifference. With regard to AMX alone, in vitro time-kill curves demonstrated synergy between AMX (1 microgram/ml) and GEN (16 micrograms/ml) at 5 and 8 h of incubation and for AMX (16 micrograms/ml) in combination with GEN (16 micrograms/ml) at 3, 5, and 8 h of incubation. In leukopenic mice, pulmonary killing curves after a single drug injection demonstrated that AMX (100 mg/kg of body weight) with GEN (16 mg/kg) was more effective than AMX alone (P = 10(-4). With repeated-dose treatment, a synergy was apparent at 8 h after four injections with AMX (100 mg/kg) in combination with GEN (8 or 16 mg/kg) (P < or = 0.05). The cumulative survival rate with AMX (100 mg/kg) every 8 h, combined with GEN (4 or 8 mg/kg) every 8, 12, or 24 h, was better than with AMX alone. Combined use of AMX and GEN may be a valuable therapeutic alternative for pneumococcal pneumonia due to highly penicillin-resistant S. pneumoniae strains.     

Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States.

Three hundred fifty-two blood culture isolates of viridans group streptococci obtained from 43 U.S. medical centers during 1993 and 1994 were characterized. Included were 48 isolates of "Streptococcus milleri," 219 S. mitis isolates, 29 S. salivarius isolates, and 56 S. sanguis isolates. High-level penicillin resistance (MIC, > or = 4.0 micrograms/ml) was noted among 13.4% of the strains; for 42.9% of the strains, penicillin MICs were 0.25 to 2.0 micrograms/ml (i.e., intermediate resistance). In general, amoxicillin was slightly more active than penicillin. The rank order of activity for five cephalosporins versus viridans group streptococci was cefpodoxime = ceftriaxone > cefprozil = cefuroxime >> cephalexin. The percentages of isolates resistant (MIC, > or = 2 micrograms/ml) to these agents were 15, 17, 18, 20, and 96, respectively. The rates of resistance to erythromycin, tetracycline, and trimethoprim-sulfamethoxazole were 12 to 38%. Resistance to either chloramphenicol or ofloxacin was uncommon (i.e., < 1%). In general, among the four species, S. mitis was the most resistant and "S. milleri" was the most susceptible.     

Efficacy of teicoplanin in two dosage regimens for experimental endocarditis caused by a beta-lactamase-producing strain of Enterococcus faecalis with high-level resistance to gentamicin.

Optimal therapy for the treatment of infections caused by strains of enterococci demonstrating high-level resistance to gentamicin and other aminoglycosides has not been established. The present study examined the efficacy of teicoplanin, a glycopeptide antibiotic active against gram-positive bacterial infections in various animal models, in the treatment of experimental endocarditis due to a beta-lactamase-producing strain of Enterococcus faecalis with high-level resistance to gentamicin. Vancomycin was used as a comparative antibiotic. In the first set of experiments, both antimicrobial agents were administered by continuous intravenous infusion for 5 days at dosages which yielded comparable mean levels in serum (plus or minus the standard deviation) of 14.6 +/- 4.3 micrograms/ml for teicoplanin and 14.3 +/- 2.2 micrograms/ml for vancomycin. These regimens proved similarly effective in sterilizing cardiac vegetations (38 versus 50% of treated animals, respectively; P greater than 0.05). Mean (plus or minus the standard deviation) residual bacterial titers within vegetations were reduced to 3.2 +/- 1.2 log10 CFU/g and 3.4 +/- 1.7 log10 CFU/g, respectively. In separate experiments, the potential of teicoplanin to cure endocarditis was assessed, using two dosage regimens: (i) 30 mg/kg per day (mean level in serum, 13 micrograms/ml) for 10 days or (ii) 150 mg/kg per day (mean level in serum, 84 micrograms/ml) for 5 days. Surviving animals were sacrificed 10 days after the discontinuation of therapy. Both teicoplanin regimens were more effective than the comparative vancomycin (150 mg/kg per day) regimen: 92 versus 43% cured (P =0.025) in the standard-dose group, and 82 versus 37% cured (P = 0.015) in the high-dose group. Results in this rat model of enterococcal endocarditis show that teicoplanin may prove useful in the treatment of serious infections due to high level-gentamicin-resistant enterococci in humans.     

Aztreonam, cefoperazone, and gentamicin in the treatment of experimental Enterobacter aerogenes endocarditis in rabbits.

The effectiveness of aztreonam, cefoperazone, and gentamicin alone and in combination was evaluated in Enterobacter aerogenes endocarditis in rabbits. The minimal inhibitory concentration/minimal bactericidal concentration ratios for E. aerogenes were as follows: aztreonam, 0.4/0.4 microgram/ml; cefoperazone, 0.8/0.8 microgram/ml; and gentamicin, 3.1/3.1 micrograms/ml. With an inoculum of 10(9) organisms per ml, aztreonam and cefoperazone were equivalent in reducing titers of E. aerogenes in broth, and both drugs demonstrated an increased rate of reduction when gentamicin was added; gentamicin alone was least effective. E. aerogenes endocarditis in rabbits was treated intramuscularly with aztreonam (60 mg/kg) every 6 h, with cefoperazone (60 mg/kg) every 6 h, with gentamicin (1.7 mg/kg) every 8 h, and with aztreonam plus gentamicin or cefoperazone plus gentamicin for 5 and 10 days, respectively. All of the therapeutic regimens were effective in reducing vegetation titers as compared with untreated controls. Aztreonam plus gentamicin was more effective than either aztreonam or gentamicin alone. Cefoperazone plus gentamicin was more effective than cefoperazone alone but was not more effective than gentamicin alone. Neither aztreonam and cefoperazone nor aztreonam and gentamicin differed significantly, but gentamicin was significantly more effective than cefoperazone. Aztreonam plus gentamicin did not differ significantly in effectiveness from cefoperazone plus gentamicin. Aztreonam gave a peak level of about 135 micrograms/ml and a half-life of 0.7 h. Cefoperazone gave a peak level of about 155 micrograms/ml and a half-life of 1.1 h. Gentamicin gave a peak level of 7.4 micrograms/ml and a half-life of 1.3 h.     

Pharmacodynamics of vancomycin alone and in combination with gentamicin at various dosing intervals against methicillin-resistant Staphylococcus aureus-infected fibrin-platelet clots in an in vitro infection model.

We compared the pharmacodynamic activities of vancomycin with or without gentamicin in an in vitro infection model with methicilin-resistant Staphylococcus aureus-infected fibrin-platelet clots. Infected fibrin-platelet clots (FPCs) were prepared with human cryoprecipitate, human platelets, thrombin, and the organism (approximately 10[9] CFU of MRSA-494/g) and were suspended with monofilament line in an infection model capable of simulating human pharmacokinetics. Antibiotics were bolused to simulate vancomycin regimens of 2 g every 24 h (q24h), 1 g q12h, 500 mg q6h, and continuous infusion (steady-state concentration of 20 microg/ml) and gentamicin regimens of 1.5 mg/kg of body weight q12h and 5 mg/kg once daily (q.d.). Model experiments were performed in duplicate over 72 h. FPCs were removed from the models in quadruplicate at 0, 8, 24, 32, 48, 72 h, weighed, homogenized, diluted, and plated to determine colony counts. The inoculum density at 72 h was used to compare bactericidal activities between the regimens. All regimens containing vancomycin significantly decreased the bacterial inoculum compared to the growth control (P < 0.001). Vancomycin monotherapy regimens were similar in bacterial kill regardless of dosing frequency. The addition of gentamicin (either q12h or q.d.) significantly improved the bactericidal activity of the vancomycin q6h, q12h, and q24h regimens (P < 0.001). The greatest reduction in bacterial density at 72 h (P < 0.001) and the most rapid rate of kill (time to 99.9% killing) were achieved with the regimen consisting of 2 g of vancomycin q24h plus gentamicin (q.d. or q12h).     

Activity of trovafloxacin (CP-99,219) against Legionella isolates: in vitro activity, intracellular accumulation and killing in macrophages, and pharmacokinetics and treatment of guinea pigs with L. pneumophila pneumonia.

The activity of trovafloxacin against 22 clinical Legionella isolates was determined by broth microdilution susceptibility testing. The trovafloxacin concentration required to inhibit 90% of strains tested was < or = 0.004 micrograms/ml, in contrast to 0.032 micrograms/ml for ofloxacin. In guinea pig alveolar macrophages, trovafloxacin achieved intracellular levels up to 28-fold over the extracellular concentration, which was similar to the levels obtained with erythromycin. Trovafloxacin (0.25 micrograms/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by > 2 log10 CFU/ml, without regrowth, under drug-free conditions over a 3-day period; trovafloxacin was significantly more active than ofloxacin or erythromycin (0.25 to 1 microgram/ml) in this assay. Single-dose (10 mg of prodrug CP-116,517-27 per kg of body weight given intraperitoneally [i.p.], equivalent to 7.5 mg of trovafloxacin per kg) pharmacokinetic studies performed in guinea pigs with L. pneumophila pneumonia revealed peak serum and lung trovafloxacin levels to be 3.8 micrograms/ml and 5.0 micrograms/g, respectively, at 0.5 h and 4.2 micrograms/ml and 2.9 micrograms/g, respectively, at 1 h. Administration of a lower prodrug dose (1.4 mg of trovafloxacin equivalent per kg i.p.) gave levels in lung and serum of 0.4 microgram/g and 0.4 microgram/ml, respectively, 1 h after drug administration. The terminal half-lives of elimination from serum and lung were 0.8 and 1.1 h, respectively. All 15 infected guinea pigs treated for 5 days with CP-116,517-27 once daily (10 mg/kg/day i.p., equivalent to 7.5 mg of trovafloxacin per kg/day) survived for 10 days after antimicrobial therapy, as did all 15 guinea pigs treated with ofloxacin once daily (10 mg/kg/day i.p.) for 5 days. None of 13 animals treated with saline survived. In a second experiment with animals, trovafloxacin (1.4 mg/kg/day i.p. for 5 days) protected all 16 guinea pigs from death, whereas all 15 animals treated with saline died. Trovafloxacin is an effective antimicrobial agent against Legionella in vitro and in vivo, with the ability to concentrate in macrophages and kill intracellular organisms.     

Efficacy of teicoplanin-gentamicin given once a day on the basis of pharmacokinetics in humans for treatment of enterococcal experimental endocarditis

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 microg/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.     

Effect of gentamicin dosing interval on efficacy of penicillin or ceftriaxone treatment of experimental endocarditis due to penicillin-susceptible, ceftriaxone-tolerant viridans group streptococci.

The efficacy of ceftriaxone or penicillin alone or combined with gentamicin at different dosing intervals was evaluated in experimental endocarditis due to a penicillin-susceptible, ceftriaxone-tolerant strain of Streptococcus sanguis I. The difference between monotherapy with ceftriaxone and procaine penicillin approached statistical significance (P = 0.052). Ceftriaxone combined with gentamicin administered as a single daily dose was less effective than was procaine penicillin combined with gentamicin administered in a single daily dose or in three divided doses.     

Enhanced activity of the combination of penicillin G and gentamicin against penicillin-resistant viridans group streptococci.

We evaluated the effects of the combination of penicillin G and gentamicin against 10 penicillin-resistant bacteremic isolates of viridans group streptococci for which the MICs of penicillin were 4 to 64 micrograms/ml. In time-kill studies, the combination resulted in more killing of eight isolates for which the MICs of penicillin were from 8 to 64 micrograms/ml than any of the antimicrobial agents tested alone. In general, clearly enhanced antimicrobial activity was observed with the combination.     

Efficacy of Ceftriaxone and Gentamicin Given Once a Day by Using Human-Like Pharmacokinetics in Treatment of Experimental Staphylococcal Endocarditis

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 microg/ml, 4 and 8 microg/ml, and 0.5 and 1 microg/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.     

Characterization of antimicrobial resistance in enterococci of animal origin.

Among 97 enterococci cultured from animals, gentamicin MICs were > or = 2,000 micrograms/ml for 9 isolates and between 250 and 1,024 micrograms/ml for 6 isolates. For two isolates tested (gentamicin MICs, 256 and 512 micrograms/ml, respectively), there was no in vitro synergy with penicillin plus gentamicin, resistance was transferable, and there was no hybridization with a probe specific for 6'-aminoglycoside acetyltransferase-2"-aminoglycoside phosphotransferase. The results of the study indicate the presence of a unique gentamicin resistance genotype in enterococci of animal origin.     

Effect of increased dosages of amoxicillin in treatment of experimental middle ear otitis due to penicillin-resistant Streptococcus pneumoniae.

A gerbil model of acute middle ear otitis was used to evaluate the efficacy of increased dosages of amoxicillin in eradicating infection induced by penicillin-resistant Streptococcus pneumoniae. Three different strains were used: (i) a serotype 23 penicillin-susceptible strain; (ii) a serotype 23 penicillin-resistant strain (MIC of penicillin, 2 micrograms/ml); and (iii) a serotype 19 highly penicillin-resistant strain (MIC of penicillin, 4 to 8 micrograms/ml). Animals were inoculated bilaterally with 10(7) CFU per ear by transbulla challenge and treated 2 to 4 h postinfection by amoxicillin administrated subcutaneously. The course of the disease was monitored bacteriologically on days 2, 4, and 8 postinfection. The three strains had a similar pathogenicity in untreated animals in terms of the duration of the disease, bacterial counts in middle ear (ME) fluid, and systemic complications. Infection due to the penicillin-susceptible strain was cured after two injections of 2.5 mg/kg of body weight. No bacteria were recovered at day 2 after two injections at 10 and 25 mg/kg with the penicillin-resistant and highly penicillin-resistant strains, respectively. Under these experimental conditions, increased does of amoxicillin consistent with MICs were able to clear ME infection. Pharmacokinetic parameters of amoxicillin in serum and ME fluid were within the clinical range at the doses used in the study.     

Bactericidal activities of cefprozil, penicillin, cefaclor, cefixime, and loracarbef against penicillin-susceptible and -resistant Streptococcus pneumoniae in an in vitro pharmacodynamic infection model.

We examined the bactericidal activities of penicillin, cefprozil, cefixime, cefaclor, and loracarbef against three clinical isolates of Streptococcus pneumoniae which were susceptible, moderately susceptible, and resistant to penicillin. An in vitro two-compartment glass infection model was used to simulate human pharmacokinetics in the presence of bacteria. Also, changes in organism susceptibility and development of resistant subpopulations were evaluated. Simulated pediatric dosage regimens and target peak concentrations in the central compartment were as follows: penicillin V-potassium, 26 mg/kg of body weight every 6 h (q6h) and 14 micrograms/ml; cefaclor, 13.4 mg/kg q8h and 16 micrograms/ml; loracarbef, 15 mg/kg q12h and 19 micrograms/ml; cefprozil, 15 mg/kg q12h and 11 micrograms/ml; and cefixime, 8mg/kg q24h and 4 micrograms/ml. Targeted half-lives of each agent were 1 h for penicillin, cefaclor, and loracarbef; 1.3 h for cefprozil; and 3.5 h for cefixime. Growth controls were performed at two different pump rates, 0.8 and 2.0 ml/min (half-lives = 3.5 and 1 h, respectively). Each isolate demonstrated autolysis at the lower rate which was attributed to a decreased supply of fresh nutrients available to the organisms in the infection compartment. Against the susceptible isolate, the time to 99.9% killing was statistically significant between penicillin V-potassium and both cefaclor and cefixime (P < 0.029). Loracarbef never achieved a 99.9% reduction in the inoculum. At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. Against the intermediately resistant isolate, cefprozil was superior to all other regimens with respect to rate of killing (P < 0.013) and extent of killing at 24 h (P < 0.0003). At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. All of the regimens exhibited inferior activity against this penicillin-resistant isolate. A 99.9% kill was never obtained with any of the regimens, nor was there an appreciable decrease in the colony counts. In conclusion, it appears that cefprozil, penicillin, and cefaclor are effective therapies against sensitive and even intermediately sensitive isolates of S. pneumoniae. However, none of the oral therapies appear to be of any benefit against penicillin-resistant isolates. The in vitro model may be an effective tool in evaluating other multiple-dose therapies against this fastidious organism, since the continual supply of fresh medium maintains the viability of S. pneumoniae with minimal stationary-phase autolysis.     

Polyaspartic acid protects against gentamicin nephrotoxicity in the rat

Polyamino acids including polyaspartic acid (PAA) have been reported to provide protection against the development of aminoglycoside-induced nephrotoxicity in the rat as assessed by histopathology scoring. We sought to confirm and extend these observations by determining whether PAA also prevented functional and biochemical lesions of gentamicin-nephrotoxicity in an animal model studied extensively in our laboratory. Rats were given injections of: 1) 0.9% NaCl at 2.5 ml/kg b.wt. per day; 2) PAA (mol.wt. 15,000) at 500 mg/kg per day; 3) gentamicin at 100 mg/kg per day or 4) gentamicin at 100 mg/kg per day and PAA at 500 mg/kg per day for 6 days. Rats injected with gentamicin exhibited: 1) increased urinary excretion of the brush border membrane enzyme alanine aminopeptidase and the lysosomal enzyme N-acetyl-beta-d-glucosaminidase after the first injection; 2) increased total phospholipid and malondialdehyde but decreased catalase activity in the renal cortex; 3) elevation of serum creatinine and depression of creatinine clearance and 4) extensive proximal tubular cell necrosis all determined 24 hr after the last injection of gentamicin. Rats injected with gentamicin plus PAA also exhibited increased urinary excretion of alanine aminopeptidase not different in magnitude from that of rats injected with gentamicin alone, whereas N-acetyl-beta-d-glucosaminidase rose more slowly and returned to base line by day 4. Total renal cortical phospholipid was elevated to the same extent in the two groups. Malondialdehyde was not different from control and catalase activity was significantly less depressed in rats injected with gentamicin plus PAA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Optimal aminoglycoside dosing regimen for penicillin-tobramycin synergism in experimental Streptococcus adjacens endocarditis.

The combination of penicillin and aminoglycoside is the recommended therapy for endocarditis caused by nutritionally variant streptococci (NVS). However, the optimal aminoglycoside dosing regimen remains controversial. We compared the efficacies of four regimens of tobramycin alone or combined with procaine penicillin in the therapy of rabbits with endocarditis caused by Streptococcus adjacens, a new species of NVS. Animals were injected intramuscularly for 4 days with procaine penicillin (150,000 U/kg of body weight twice daily) or tobramycin at a low dose (3 mg/kg every 24 h) or a high dose (12 mg/kg every 24 h) either once or three times daily (t.i.d.) alone or in combination with procaine penicillin. Additional groups of animals were treated with the combination regimens for a shorter period of time (2 days) in order to demonstrate a possible difference in the rapidity of efficacy between the regimens. The MICs and MBCs were 0.015 and 1 micrograms/ml and 8 and 16 micrograms/ml for penicillin and tobramycin, respectively. The mean peak tobramycin levels in plasma were 2.4 +/- 1.3 (1 mg/kg t.i.d.), 5.4 +/- 3.7 (4 mg/kg t.i.d.), and 25 +/- 9.3 (12 mg/kg once daily). The mean penicillin levels in serum were always above the MIC. In vitro kill curves plotted at the time that peak concentrations were reached in plasma showed a concentration-dependent killing effect of tobramycin alone but not in combination with penicillin. In vivo, low-dose tobramycin was significantly less effective than the high dose. Results for the combinations of the different dosing regimens of tobramycin with procaine penicillin were not significantly different. Our results suggest that (i) against susceptible strains of streptococci, aminoglycoside alone exhibits a concentration-dependent killing effect both in vitro and in vivo; (ii) against NVS strains, combinations of penicillin and high- or low-dose tobramycin are equally effective; and (iii) aminoglycoside given once daily or at a low dose t.i.d. with penicillin could be a cost-effective alternative with reduced toxic risk for patients with NVS endocarditis when the bacteria are susceptible to the killing activities of both compounds.     

In vitro and in vivo activity of ciprofloxacin against enterococci isolated from patients with infective endocarditis.

In vitro activity of ciprofloxacin against 27 strains of enterococci was inoculum dependent. Using inocula of 10(5) to 10(6) or 10(7) to 10(8) CFU of enterococci per ml, the MICs for 50 and 90% of strains tested increased from 1 to greater than or equal to 128 micrograms of ciprofloxacin per ml with the higher inoculum compared with the lower inoculum. The MBC for 50% of strains tested increased from 2 to greater than 128 micrograms/ml and the MBC for 90% of strains tested increased from 8 to greater than 128 micrograms of ciprofloxacin per ml with the lower and higher inocula, respectively. The combination of penicillin-gentamicin was more effective in vitro than the combination of ciprofloxacin-gentamicin against the low or high inoculum of enterococci. Using two strains of enterococci, we studied the efficacy of ciprofloxacin in the treatment of enterococcal experimental endocarditis in rabbits. Ciprofloxacin used alone or combined with gentamicin was significantly less effective (P less than 0.01) than procaine penicillin alone or procaine penicillin combined with gentamicin for the treatment of enterococcal experimental endocarditis. The combination of ciprofloxacin-procaine penicillin was not a more effective therapy than procaine penicillin alone.