Tobramycin: in vitro and clinical evaluation in 30 patients.

Clinical evaluation of intramuscular tobramycin was accomplished in 30 patients with respiratory, soft tissue, urinary tract, bone or septicemic infections due to gram negative bacilli. Median sensitivity to tobramycin of Pseudomonas aeruginosa isolates (19 strains) was 0.62 mug/ml and range 0.31-2.5 mug/ml; less activity was observed for Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae and Enterobacter species isolates but median minimum inhibitory concentrations were less than or equal to 2.5 mug/ml. Therapy resulted in clinical and bacteriologic cures in 16 patients (53 per cent) including 13 of 16 (181 per cent) with urinary tract infections; 9 of the 14 patients who did not obtain bacteriologic cure had satisfactory clinical responses. Tobramycin was effective for selected gram negative bacillary infections and particularly for P. aeruginosa.

Comparison of gentamicin, carbenicillin and gentamicin, and carbenicillin in Pseudomonas sepsis in monkeys.

Intravenous inoculation of 6.0 x 10(10)Pseudomonas aeruginosa organisms into rhesus monkeys 4 days after intratracheal inoculation of 2.5 mg of vincristine sulfate resulted in fatal sepsis in all of three untreated control monkeys. After intramuscular administration of either 2.5 mg of gentamicin or 50 mg of carbenicillin per kg per day, three of four monkeys in each group survived. When both antibiotics were given at the same dose but in separate sites, six of eight monkeys survived. Antibacterial activity of serum from infected monkeys or normal monkeys was not appreciably different when the two antibiotics were combined. Under the conditions of this study, there was no apparent difference in response of monkeys treated either with gentamicin or carbenicillin alone or with the combination of the two antibiotics.

Comparison of colistin-carbenicillin, colistin, and carbenicillin in Pseudomonas sepsis in monkeys.

Intravenous inoculation of 6.2 x 10(10) to 6.7 x 10(10)Pseudomonas aeruginosa organisms into rhesus monkeys 5 days after intratracheal inoculation of 2.0 to 2.5 mg of vincristine sulfate resulted in fatal sepsis in 8 of 10 untreated monkeys. When similarly infected monkeys were treated intramuscularly with 2.5 mg of colistin or 50 mg of carbenicillin per kg per day, all three monkeys in each treatment group survived; one of three monkeys receiving both antibiotics at the above doses died. Six of seven monkeys treated with 1.25 mg of colistin per kg per day and three of seven treated with 25 mg of carbenicillin per kg per day died; four of nine monkeys receiving both antibiotics at these doses died. A combination of the data obtained at both dose levels tested shows that 6 of 10, 3 of 10, and 5 of 12 monkeys, respectively, died after treatment with colistin, carbenicillin, and the colistin-carbenicillin combination. Antibacterial activity of serum from both infected and normal monkeys was not appreciably different when the two antibiotics were given singly or in combination. Under the conditions of this study and with the doses employed, the response of monkeys treated with the antibiotic combination did not differ significantly from that of monkeys treated with a single agent.

Effect of vincristine sulfate on Pseudomonas infections in monkeys.

In rhesus monkeys, intravenous challenge with 0.6 x 10(10) to 2.2 x 10(10)Pseudomonas aeruginosa organisms caused acute illness of 4 to 5 days' duration with spontaneous recovery in 13 of 15 monkeys; blood cultures became negative 3 to 17 days after challenge. Leukocytosis was observed in all monkeys. Intravenous or intratracheal inoculation of 2.0 to 2.5 mg of vincristine sulfate was followed by leukopenia in 4 to 5 days. Intravenous inoculation of 4.2 x 10(10) to 7.8 x 10(10) pyocin type 6 Pseudomonas organisms in monkeys given vincristine sulfate 4 days previously resulted in fatal infection in 11 of 14 monkeys, whereas none of four receiving Pseudomonas alone died. These studies suggest that an antimetabolite-induced leukopenia predisposes to severe Pseudomonas sepsis and that such monkeys may serve as a biological model for study of comparative efficacy of antimicrobial agents.

Comparison of clindamycin, erythromycin, and methicillin in streptococcal infections in monkeys.

Intravenous inoculation of a group A hemolytic streptococcus caused lethal infections in all of eight untreated monkeys. Intramuscular injections of clindamycin-2-phosphate in a daily dose of 25 mg/kg given in equal morning and afternoon doses for 10 days resulted in survival of all of eight monkeys. Similar results were observed with the same dose schedule of clindamycin hydrochloride given intragastrically; no fatalities occurred among eight monkeys. In monkeys receiving erythromycin stearate intragastrically or methicillin intramuscularly, three of eight and four of eight monkeys, respectively, died. Duration of both illness and positive blood cultures was greater in the erythromycin- and methicillin-treated survivors than in the clindamycin-treated monkeys. The differences in results between clindamycin and erythromycin could not be correlated with serum antibacterial activity levels, which were similar, or with minimal inhibitory concentrations, which were 0.02 mug/ml with both antibiotics. With methicillin, however, the minimal inhibitory concentration was 0.16 mug/ml and serum antibacterial activity varied from titers of less than 1:2 to 1:8. As in previous studies of staphylococcal infections in monkeys with the same antibiotics, in vitro susceptibility data and serum antibacterial activity did not completely correlate with in vivo results.

Comparison of tobramycin, gentamicin, colistin, and carbenicillin in Pseudomonas sepsis in monkeys.

Intravenous inoculation of 3.4 x 10(10) to 7.4 x 10(10)Pseudomonas aeruginosa organisms into rhesus monkeys 4 days after intravenous or intratracheal inoculation of 2.0 to 2.5 mg of vincristine sulfate resulted in fatal sepsis in eight of nine monkeys. After intramuscular administration, in two equal doses, of 5 mg of tobramycin, gentamicin, and colistin per kg per day beginning 16 hr after challenge, 4 of 11, 4 of 11, and 3 of 10 monkeys died, respectively. Administration of daily doses of 100 to 400 mg of carbenicillin per kg was followed by death in 5 of 12. Duration of illness in the surviving monkeys in each therapy group was similar. Under the conditions of this study, prior administration of vincristine sulfate resulted in a decrease in leukocytes and enhanced susceptibility to Pseudomonas infection. Using this model for studies of comparative efficacy of antibiotics, we observed comparable results after treatment with tobramycin, gentamicin, colistin, and carbenicillin.

Therapy of staphylococcal infections in monkeys. VII. Comparison of cyclacillin and nafcillin.

Intravenous inoculation of a penicillin-resistant phage type 80/81 staphylococcus caused lethal infection in seven of eight untreated monkeys. Daily intragastric administration of 50 mg/kg given in two equal morning and afternoon doses of cyclacillin and nafcillin was followed by mortalities of four of four and two of four monkeys, respectively. After 100 mg per kg per day, three of four and one of four monkeys receiving cyclacillin and nafcillin, respectively, died. Thus, mortality in controls and cyclacillin-treated monkeys was seven of eight as compared to three of eight after nafcillin treatment. Although the staphylococcus was more resistant to cyclacillin (minimal inhibitory concentration = 7.80 mug/ml) than to nafcillin (minimal inhibitory concentration = 0.31 mug/ml), regular rapid absorption and high levels of the former suggested potential efficacy. However, the similar mortality in cyclacillin-treated and control monkeys indicated that the in vitro data did not, in this instance, conform to the in vivo observations.

Therapy of staphylococcal infections in monkeys. VI. Comparison of clindamycin, erythromycin, and methicillin.

Intravenous inoculation of a penicillin-resistant, phage type 80/81 staphylococcus caused lethal infection in six of eight untreated monkeys. Daily intragastric administration of clindamycin hydrochloride and erythromycin stearate and intramuscular inoculation of clindamycin-2-phosphate and methicillin, all at a dose level of 50 mg/kg, was followed by mortalities of one of eight, one of eight, none of eight, and one of eight monkeys, respectively. Duration of obvious acute illness in surviving monkeys and time required for complete recovery were not significantly different in the four therapy groups with the exception that duration of acute illness in monkeys treated with clindamycin-2-phosphate (mean, 4.1 days) was significantly shorter than in monkeys given erythromycin stearate (mean, 7.1 days). In vitro sensitivity data and serum antibacterial levels would suggest that methicillin would be the least effective therapeutically, followed by erythromycin stearate and the two clindamycin preparations in that order. However, this prediction was not fulfilled in these studies in experimentally infected monkeys.

Comparison of cephalexin, penicillin V, and ampicillin in streptococcal infections in monkeys.

Intravenous inoculation of a group A hemolytic streptococcus caused lethal infections in all of 11 untreated monkeys. Daily intragastric administration of either 25 or 50 mg per kg per day, given in two equal morning and afternoon doses, yielded similar results in monkeys treated with cephalexin, penicillin V, and ampicillin; all eight monkeys in each therapy group survived. At dose levels of 12.5 mg per kg per day, six of eight, four of eight, and one of eight receiving cephalexin, penicillin V, and ampicillin, respectively, died. The differences observed at the lower dose level between cephalexin and ampicillin could be attributed, in part, to differences in the minimal inhibitory concentrations (MIC) of cephalexin (MIC = 0.24 mug/ml) and ampicillin (MIC = 0.01 mug/ml). The differences in results between penicillin V, which had the same MIC as ampicillin, could perhaps be attributed, in part, to shorter duration of antibacterial activity and higher protein binding of penicillin V. These studies support previous observations that cephalexin at 25 to 50 mg/kg doses is effective in severe streptococcal sepsis in monkeys.