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MICs of clarithromycin and its major human metabolite, 14-hydroxy-clarithromycin, for Haemophilus influenzae in combination were reduced two- to fourfold compared with the MICs of each compound alone. Serum reduced the MICs of the parent compound and metabolite two- to fourfold compared with the MICs in medium without serum. In serum spiked with clinically relevant concentrations of clarithromycin and 14-hydroxy-clarithromycin at a fixed ratio of 4:1, 15 of 16 strains (94%) were inhibited and killed by combinations containing 1.2 and 0.3 micrograms/ml, respectively. In time kill experiments, the combination of parent compound and metabolite at one-fourth and one-half of their individual MICs, respectively, reduced bacterial counts by greater than 5 log CFU. The postantibiotic effect of clarithromycin combined with 14-hydroxy-clarithromycin was twice that of clarithromycin when tested alone. When orally administered to gerbils with H. influenzae otitis media, the 14-hydroxy metabolite was significantly more active than clarithromycin in reducing bacterial counts from the middle ear. The in vivo activity of the two compounds in combination was synergistic or additive, depending on the level of H. influenzae present at the time treatment was initiated. Significant reductions in bacterial counts and increases in cure rates were observed when clarithromycin at 50 or 100 mg/kg of body weight was combined with 14-hydroxy-clarithromycin at 12 mg/kg or higher. Results from in vitro and in vivo combinations suggest that routine susceptibility tests and animal efficacy studies with clarithromycin alone may underestimate its potential efficacy against H. influenzae.

Tiacumicins B and C are members of a novel group of 18-membered macrolide antibiotics with in vitro activity against Clostridium difficile. The MICs against 15 strains of C. difficile were 0.12 to 0.25 microgram/ml for tiacumicin B, 0.25 to 1 microgram/ml for tiacumicin C, and 0.5 to 1 microgram/ml for vancomycin. The resistance frequency for both compounds against C. difficile was less than 2.8 x 10(-8) at four and eight times the MIC. The in vivo activities of the tiacumicins against two strains of C. difficile were compared with that of vancomycin in a hamster model of antibiotic-associated colitis. Oral therapy with 0.2, 1, or 5 mg of tiacumicin B or C per kg of body weight protected 100% of clindamycin-treated hamsters exposed to C. difficile ATCC 9689. Oral treatment with identical doses of vancomycin produced a prolonged, dose-dependent survival of hamsters, but it did not prevent the development of fatal colitis at doses of up to 5 mg/kg. When clindamycin-treated animals were exposed to another strain of C. difficile, both tiacumicin B and vancomycin were protective at 5 mg/kg, but not at lower doses. Tiacumicin C was not tested in vivo against the second strain of C. difficile. No tiacumicin B or C was detected in the sera of hamsters treated with single oral doses of 25 mg/kg, while antibiotic levels in the ceca of these hamsters reached 248 micrograms/ml and 285 mg/ml for tiacumicins B and C, respectively. The tiacumicins demonstrated in vitro and in vivo potencies against C. difficile and achieved high concentrations in the cecum, but not the serum, of hamsters after oral administration.

Analogs of 9-deoxo-12-deoxy-9,12-epoxyerythromycin A with an epimeric hydroxy, amino, or ketone substitution at the 11 position of the macrolide ring and an amino or epimeric hydroxy substitution at the 4" position of the cladinose sugar were synthesized in an attempt to produce acid-stable derivatives of erythromycin with improved bioavailability and activity against gram-negative bacteria. These modifications produced compounds with in vitro activities which were generally similar to that of erythromycin. In mice, however, selected analogs were more active than was erythromycin against staphylococci, streptococci, Haemophilus influenzae, and Legionella pneumophila. In mice, the 11-keto (A-63881), 11-epiamino (A-69334), 11-epiamino-4"-amino (A-71671), and 11-epiamino-4"-epiamino (A-73020) analogs achieved peak concentrations in serum and lung, serum half-lives, and/or areas under the serum curve which were greater than those of erythromycin. Improved pharmacokinetics, as compared with those of erythromycin, may explain the increased in vivo antibacterial activities of these compounds.

The activity of the quinolone temafloxacin against respiratory pathogens was compared with those of ciprofloxacin and ofloxacin. MICs for 90% of strains tested indicated that temafloxacin was at least two- to fourfold more potent than the other two quinolones against Staphylococcus aureus, Streptococcus pneumoniae, and Legionella pneumophila. Temafloxacin had potency equal to that of ciprofloxacin and was twofold more active than ofloxacin against Streptococcus pyogenes. Moraxella catarrhalis, and Bordetella pertussis. Against Haemophilus influenzae and Klebsiella pneumoniae, temafloxacin was four- and twofold less potent than ciprofloxacin, respectively. When administered orally in mouse protection tests against S. aureus, S. pneumoniae, and S. pyogenes, temafloxacin was at least eight times more potent than ciprofloxacin and was two to four times more active than ofloxacin. Against H. influenzae, temafloxacin was as active as ofloxacin and was two times less active than ciprofloxacin following oral administration in mice. In treating L. pneumophila in guinea pigs and H. influenzae otitis media in gerbils, temafloxacin and ofloxacin were more effective than ciprofloxacin. Against S. pneumoniae otitis media in gerbils, temafloxacin and ciprofloxacin were more active than ofloxacin. Following subcutaneous administration in mice, temafloxacin achieved higher lung levels than ciprofloxacin or ofloxacin did.

Phosphonoacetic acid is a selective antiherpesvirus agent. More than 100 congeners of phosphonoacetic acid were evaluated in vitro and in vivo to understand structure-activity relationships in the hope of designing a superior analog. Results showed that the antiherpesvirus activity had highly specific structural requirements. Neither the carboxylic nor the phosphono groups could be replaced. The distance between these two groups is important. Increase of this distance caused complete loss of activity. However, if this distance was maintained, the addition of groups to the methylene carbon resulted in a reduction, but not loss, of activity. On the other hand, decrease of the carbon chain to formic acid did not deteriorate its antiherpes activity. All analogs tested had lower activity than the parent compound. However, some compounds with decreased activity in vitro appeared to have favorable pharmacological properties in vivo.

Replication of herpes simplex virus in WI-38 cells was inhibited by phosphonoacetic acid, as measured by decreased virus cytopathogenic effect and incorporation of radiolabeled thymidine in virus-infected cells. The drug appeared to have no effect on adsorption, penetration, or release of the virus nor on the synthesis of ribonucleic acid or protein. It appeared to inhibit virus deoxyribonucleic acid synthesis.

Clarithromycin was shown to be effective therapy for Treponema pallidum infections in hamsters. Clarithromycin therapy was effective when initiated either 1 or 8 days after infection. The delay in initiation of therapy allowed an active infection to develop. The treponemal burden in lymph tissue of treated hamsters was eradicated, as determined by dark-field microscopy and by inoculation of lymph material into susceptible hamsters. Treatments with clarithromycin and the 14-hydroxy metabolite of clarithromycin were equally effective. Therapy with clarithromycin and penicillin was not antagonistic and did not appear to be synergistic when the two drugs were given concurrently. Pharmacokinetic evaluation of clarithromycin in hamsters showed that the doses which produced effective therapy yielded concentrations in serum similar to those routinely achieved in human sera. These findings demonstrate that clarithromycin is effective in treating active or incubating syphilis in the hamster model and could be useful in treating humans.

1. Electron microscopic studies have failed to demonstrate virus particles in papillomas of four patients with laryngeal papilloma and one patient from whom the entire base of the papilloma was evulsed and excised from the tracheal wall.2. No growth was obtained at the site of inoculation of the larynx of three female Rhesus monkeys whose true and false cords were inoculated unilaterally with 0.5 ml of a suspension made from papilloma removed from two children and one adult.3. It was not possible to duplicate work reported previously which had indicated the presence of a species-specific virus capable of producing growth of tissue cultures with regrowth after blind serial tissue culture passes.4. Blood samples were collected before and after vaccine therapy in patients with laryngeal papillomas so that in case a virus was isolated, the viral agent could be used as the antigen in a serological reaction; since the virus could not be isolated, there could be no serological evaluation of vaccine therapy.5. The preparation and administration of an autogenous laryngeal papilloma vaccine is described, with the results of this therapy as used in 51 patients.6. Clinical evaluation showed that 28, or 55 per cent, were improved; 13, or 25 per cent, were considered unchanged; and three, or six per cent, deteriorated. Inadequate information was obtained in seven, or 14 per cent.7. The annual operation rate as calculated for 37 patients who had adequate data before and after operation showed that the annual operation rate decreased in 29 patients (78 per cent), did not change in three patients (eight per cent), and increased slightly in five patients (13 per cent). The annual operation rate before vaccine therapy was 4.00; after vaccine therapy was 1.88, an average of 2.12 operations per year.

Disodium phosphonoacetate when administered orally or topically to mice experimentally infected with herpes simplex virus was able to significantly reduce the mortality associated with the agent. In addition, this compound was able to reduce herpesvirus lesions on the corneas of infected rabbits.

The marked antiviral activity of (S,S-1,2-bis(5-methoxy-2-benzimidazolyl)-1,2-ethanediol (Abbott 36683) against rhinoviruses in tissue culture warranted investigation of its antiviral activity in vivo. Antiviral levels in mouse sera were attained with an oral dose as small as 10 mg/kg and detectable antiviral levels of drug were also found in lung, liver, kidney, intestinal contents, and urine of mice given a single 300 mg/kg oral dose. Antiviral serum levels were also obtained when monkeys were given a single oral dose of Abbott 36683. Six chimpanzees were infected with 100 median tissue culture infective dose units (TCID50) of rhinovirus 30. Three of the animals were treated with Abbott 36683, 100 mg/kg daily for 4 consecutive days. Virus shedding occurred in the infected controls but could not be demonstrated in the treated animals from postinfection days 1 to 8. Two of the treated animals did, however, shed virus on day 9. The compound was retested in chimpanzees at dosage levels of 15 and 50 mg/kg daily for 4 days. Each animal was challenged with 100 TCID50of rhinovirus 49. Partial protection was obtained. In a third trial, a single 100 mg/kg dose of the compound was administered to chimpanzees infected with rhinovirus 44. Virus was isolated from all throat smears taken from treated animals, indicating that at the lowest drug level no protection occurred.