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The effect of chemoprophylactic use of rifampin and minocycline on rates of carriage of Neisseria meningitidis in army recruits in Finland.

During an epidemic caused by sulfonamide-resistant group A Neisseria meningitidis (A SuR strain), rifampin (600 mg per day for four days) or minocycline (100 mg every 12 hr for five days) was administered as chemoprophylaxis to 1,540 unvaccinated recruits in the Finnish Armed Forces. Rates of carriage of all strains of N. meningitidis were initially reduced by 78% (from 60% to 13%) in the 389 men receiving rifampin and by 62% (from 70% to 26%) in the 1,151 men receiving minocycline but rose to approximately 30% in both groups four weeks after prophylaxis. The carriage of A SuR strains was similarly reduced. An individual follow-up of 636 trainees demonstrated a high rate of new infections. It is suggested that the long-term inefficiency of rifampin and minocycline is due to their inability to reduce the carriage rates enough to prevent further spread of infection after prophylaxis is descontinued. However, no new cases appeared among the men receiving the prophylaxis. Five strains highly resistant to rifampin were found after the use of rifampin (minimal inhibitory concentration, greater than or equal to 100 microgram/ml), but no minocycline-resistant strains were encountered. No unpleasant side effects were seen in subjects receiving either drug.

Finland

Inhibition of human cytomegalovirus by rifampin.

Replication of human cytomegalovirus (CMV) was inhibited by 50 mug/ml of rifampin. Nevertheless, a number of functions of CMV were still expressed in the presence of rifampin, including early cell rounding, and the development of immuno-fluorescent antigen, haemadsorption antigen, complement-fixing antigen and precipitin antigens. If rifampin was kept in the culture medium for longer than 48 h, infectious virus was not synthesized, but removal of rifampin resulted in restoration of virus titre within 24 h. In parallel with the restoration of infectivity, removal of the drug resulted in a sharp increase in macromolecular synthesis, first RNA and then virus DNA. The results suggest that rifampin blocks a stage in the production of m-RNA species.

Antigens, Viral

Rifampin disrupts conjugal and chromosomal deoxyribonucleic acid metabolism in Escherichia coli K-12 carrying some IncIalpha plasmids.

The effects of rifampin and chloramphenicol on the transfer of ColIdrd-1 have been examined to determined whether transfer requires the synthesis of an untranslated species of ribonucleic acid (RNA), as proposed in models for the transfer of another IncIalpha plasmid, R64drd-11. When RNA synthesis was inhibited throughout mating by rifampin, ColI transfer between dna+ bacteria occurred at the normal rate for about 10 min and then stopped abruptly. Conjugational deoxyribonucleic acid (DNA) synthesis in dnaB mutants indicates that plasmid DNA was made in the rifampin-treated donors to replace the transferred material but the DNA tended to be unstable. In the presence of chloramphenicol, transfer of ColI gradually diminished over a longer period. Rifampin, but not chloramphenicol, was found to have unpredicted effects on chromosomal DNA metabolism in unmated dna+ and dnaB bacteria when they harbor any of three IncIalpha plasmids (ColIdrd-1, R144drd-3, and R64drd-11). Replication of the bacterial chromosome in such cells stopped abruptly about 15 min after the addition of rifampin, and at 41 degrees C, but not 37 degrees C, this was followed by extensive DNA breakdown. These findings suggest that curtailment of IncIalpha plasmid transfer by the drug results from a general disruption of DNA metabolism rather than from inhibition of a species of RNA essential for transfer.

Chloramphenicol

Rifampin-susceptible mutant of vesicular stomatitis virus: protein and RNA synthesis.

A rifampin-susceptible strain (VSV Rif+) was selected from the wild vesicular stomatitis virus (VSV) population unsusceptible to rifampin. The VSV Rif+ was blocked in its intracellular replication in the presence of rifampin. In cells, rifampin affected primarily VSV Rif+ transcription, but to a different extent than in a cell-free system. In addition, a decrease in the amount of VSV Rif+ protein M was detected, linked to a stimulation of protein NS. In the absence of rifampin, protein M, although synthesized, was not immediately incorporated into the cell membrane. An interpretation of these observations is proposed.

Cell-Free System

Bactericidal activity of streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide alone and in combination against Mycobacterium Tuberculosis.

Log-phase cultures of Mycobacterium tuberculosis in Tween-albumin medium were exposed to streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide in concentrations in the range likely to be present in serum during treatment of patients. The bactericidal activity of the drugs was measured as the decrease in viable counts at 4 and 7 days. The activity of single drugs was highest for streptomycin and next highest for rifampin and isoniazid, but ethambutol only started to kill after 4 days. When exposed to 2 drugs, bactericidal synergism was found with streptomycin/isoniazid and isoniazid/ethambutol; additivity, with streptomycin/rifampin; indifference, with isoniazid rifampin and streptomycin/ethambutol; and antagonism, with rifampin/ethambutol and isoniazid/pyrazinamide. When cultures were exposed to the 3 drugs, isoniazid, rifampin, and ethambutol, marked antagonism was found between isoniazid and rifampin, whereas the addition of isoniazid or an increase in its concentration increased the bactericidal activity.

Drug Interactions

Rifampin in the treatment of experimental brucellosis in mice and guinea pigs.

Rifampin, a broad-spectrum antibiotic able to penetrate intracellularly, was used for treatment of infections with Brucella melitensis in mice and Brucella abortus in guinea pigs. Treatments were administered for seven, 14, or 21 days; mice were given 25 mg of rifampin/kg per day, and guinea pigs 100 mg/kg per day. Efficacy of the drug was determined by comparison of rifampin-treated animals with saline-treated controls and with tetracycline-treated mice (200 mg/kg per day) according to the following criteria: (1) primary infections of the spleen and (in guinea pigs) of the lymph nodes; (2) residual infections of the spleen, i.e., infections shown after complementary treatment with suspensions of killed Corynebacterium parvum or with cortisone; (3) splenomegaly; and (4) serological response (in guinea pigs). Treatment with rifampin, even for one or two weeks, drastically reduced the number of infections by all of these criteris, and treatment for three weeks cured nearly all mice; the incidences of primary and residual infections in rifampin-treated mice after three weeks were 0 and 8.5%, respectively, as compared with 70.3% and 73.5%, respectively, in tetracycline-treated mice. Of 25 guinea pigs treated with rifampin for three weeks, spleen infection was shown in one, and lymph node infections in 10.

Animals

Corneal penetration of rifampin.

We tested the corneal penetration of rifampin in four vehicles: dimethylsulfoxide, polyethylene glycol, an ocular lubricant, and as rifampin ointment. We measured drug concentrations in the aqueous humor in rabbits after topical instillation of 1 and 2.5% rifampin according to two dosage schedules. Drug concentrations in the aqueous humor were bactericidal to Mycobacterium leprae. Since leprosy of the cornea, iris, and ciliary body may develop despite standard systemic bacteriostatic treatment, treatment of leprotic involvement of the anterior eye may be enhanced by intensive topical application of rifampin.

Administration, Topical

Growth conditions and rifampin susceptibility.

The susceptibility of Escherichia coli to rifampin was measured during unlimited growth in rich and poor media and during chemostat growth limited by the carbon source. During batch growth at low turbidities, the susceptibility of the bacteria increased as the growth rate decreased, consistent with the longer time available for drug penetration in the poorer media. During chemostat culture, the bacteria remained highly susceptible or became genetically resistant, dependent on the manner in which the bacteria were exposed to the antibiotic. If the concentration of rifampin was abruptly raised, susceptible cells were replaced by genetically resistant cells. However, if the concentration of antibiotic was raised slowly, the genetically susceptible cells continued to grow. This difference in response of chemostat cultures according to mode of drug administration was attributed to an inducible detoxification of the drug by the bacteria, because the susceptible genotype is maintained only when the concentration of rifampin is increased gradually and when a high population of cells is maintained. Direct evidence for the inactivation of the rifampin from the bioassay of culture supernatants is presented.

Drug Resistance, Microbial

Rifampin-resistant mutants of Myxococcus xanthus defective in development.

Rifampin, an antibiotic which is known to bind to and inhibit RNA polymerase, was used to probe the molecular regulation of development in Myxococcus xanthus. Rifampin-resistant mutants were screened for defects in fruiting-body formation. About 20% of the isolates in the initial screenings showed major defects in developmental aggregation or sporulation. Eleven independent mutants with wild-type growth rates and stable phenotypes were analyzed by transduction. In these strains, the rifampin-resistant and nonfruiting phenotypes showed cotransduction frequencies equal to or greater than 99.0 to 99.9%. The RNA polymerase activities were resistant to rifampin in vitro, indicating that the RNA polymerase is altered in these strains. Although their fruiting phenotypes are heterogeneous, these strains can be divided into two classes based on the level of aggregation. The results suggest that RNA polymerase plays a significant role in the regulation of development in M. xanthus since mutations which cause no apparent changes in vegetative growth result in striking defects in fruiting-body formation.

DNA-Directed RNA Polymerases

Pleiotropic effect of a rifampin-resistant mutation in Bacillus subtilis.

Rifampin-resistant (Rifr) mutants were isolated spontaneously from Bacillus subtilis strain 168. A fraction of the mutants did not grow on a minimal medium. A high concentration of one of the L-amino acids (glutamic acid, glutamine, arginine, proline, aspartic acid, or asparagine) was required to restore their growth on the medium. Further analysis of one of the mutants (strain RF 161) suggested that the mutant is unable to use ammonia as a nitrogen source and requires amino acids instead. Activity of glutamate synthase was not detected in the crude extract of the mutant. The Rifr mutation was closely located to cysA and the drug resistance was cotransformed with the property of amino acid requirement at 100% frequency. All revertants to prototrophy tested showed the rifampin-sensitive (Rifs) property. The activity of the DNA-dependent RNA polymerase of the mutant was resistant to rifampin. It is concluded that some alteration of RNA polymerase may cause absence of the activity of an enzyme involved in the nitrogen metabolism.

Amino Acids

Combined amphotericin B and rifampin treatment of experimental Candida albicans keratitis.

In a model of experimental Candida albicans keratitis in rabbits, treatment with a combination of amphotericin B and rifampin was compared with treatment with amphotericin B alone. Both modes of therapy substantially reduced the number of organisms in the cornea below the number in untreated control corneas. In the group treated with combined therapy, there were significantly fewer organisms in the cornea after three days of therapy than in the group treated with amphotericin B alone. The results of this study indicate that the treatment of C albicans keratitis in rabbits with combined amphotericin B and rifampin is more effective than treatment with amphotericin B alone.

Amphotericin B

Absorption of rifampin from various preparations and pharmaceutic forms.

The absorption of 9 rifampin preparations was measured in two seaparate crossover studies on 10 healthy female volunteers. In the first set of experiments, one of the three capsule preparations was absorbed more slowly than the other ones. The absorption of two syrup preparations was nearly twice that of the best capsule preparation. In the second set, the absorption of the commercial tablets appeared to be somewhat faster than that of the reference capsule preparation. One tablet dissolved slowly in vitro and yielded very low serum concentrations. On the basis of these results the equiactive dose of rifampin in syrup form may be 25% to 50% lower than that of the other forms.

Adult

Successful treatment of Candida endophthalmitis with a synergistic combination of amphotericin B and rifampin.

Candida endophthalmitis, caused by transient candidemia, developed in a 14-year-old white girl receiving intravenous hyperalimentation. Antifungal synergism was established in vitro for the combination of amphotericin B and rifampin against the C. albicans isolate. A combined ten-day course of intravenous amphotericin B and oral rifampin was followed by the elimination of the infection and the preservation of good visual acuity.

Administration, Oral

Polymyxin B and rifampin: new regimen for multiresistant Serratia marcescens infections.

Polymyxin B and rifampin were given to 12 patients with multi-drug-resistant nosocomial Serratia marcescens infections. Eight cures were achieved; drug hepatotoxicity occurred once; one fatal suprainfection was encountered; and two patients died during therapy of causes related to severe underlying illnesses. Polymyxin B and rifampin were uniformly synergistic in vitro against the infecting strains and against 40 additional clinical isolates of S. marcescens.

Adult

Comparative effects of sulfones and rifampin on growth of Mycobacterium lepraemurium in macrophage diffusion chamber cultures.

A cell-impermeable diffusion chamber technique has been developed that lends itself to growth studies of Mycobacterium lepraemurium. This technique, in which the organism grows within macrophage cultures inside the chambers that are maintained on monolayer cultures of macrophages, provides a method for a strict in vitro evaluation of antileprosy drugs without the influence of a multiplicity of host factors. This system was used to compare the effect of three sulfone derivatives and rifampin on the growth of M. lepraemurium within these diffusion chamber cultures. Two sulfones, 4,4'-diaminodiphenyl sulfone and 4,4'-diacetamidodiphenyl sulfone, as well as rifampin, suppressed the growth of M. lepraemurium, but monoacetyl sulfone 4-amino-4'acetamidodiphenyl sulfone had no effect. The results indicate that the diffusion chamber technique can be used to evaluate the inhibitory effect of antileprosy drugs on the growth of M. lepraemurium. Also, the method provides for the first time a relatively rapid in vitro method for directly comparing the effects of drugs or their analogs when outside the metabolic influence of an animal host. This technique may be a useful tool for chemotherapy studies with other antileprosy compounds.

Animals

New tool for studying interactions of components of ribonucleic acid polymerase: rifampin-dependent mutants.

Mutants of Escherichia coli showing a rifampin-dependent phenotype were isolated from cells of strain CP78 mutagenized with ethyl methane sulfonate or nitrosoguanidine when an antibiotic underlay technique was used. The mutants varied greatly in their rifampin requirement. The minimum necessary concentration ranged from 1 to 50 micrograms/ml. The mutants could be divided into four phenotypic classes. These dependent mutants and their revertants should be a useful tool for probing interactions between the component polypeptides of ribonucleic acid polymerase and for studying the linkage of transcription with other cellular processes.

DNA-Directed RNA Polymerases

Mycobacterium ulcerans infection: treatment with rifampin, hyperbaric oxygenation, and heat.

The effectiveness of hyperbaric oxygenation (HBO), heat, and rifampin for treating mice infected with Mycobacterium ulcerans was analyzed. Four hundred mice were innouclated in the hind footpads with 10(8) organisms. The seven treatment groups (50 mice each) were HBO (2.5 ATA for 1.5 h, twice a day), rifampin (RIF) (20 mg/kg body weight/d), heat (mice maintained at 37 degrees C), and all combinations of the three treatments. The severity of infection in the treated mice was compared weekly for 20 weeks with that of infected controls. The most effective treatments were RIF/HEAT and RIF/HBO/HEAT, RIF/HBO/HEAT treatment was further evaluated to determine the effectiveness of treating mice at various stages of infection. Three hundred mice were inoculated in the hind footpads, and, as the infection progressed, they were separated into groups (50 mice/group) according to the severity of infection. The treatment groups were compared to positive controls. The effectiveness of therapy was indirectly proportional to the severity of infection.

Animals

Staphylococcus aureus endocarditis. Combined therapy with vancomycin and rifampin.

Two children with persistent bacteremia and endocarditis due to Staphylococcus aureus failed to respond to vancomycin therapy, even though serum levels greatly exceeded the inhibitory concentrations. The Staphylococcus from one patient was resistant to methicillin; the other patient had a penicillin hypersensitivity. There was a wide disparity between the minimum inhibitory and the minimum bactericidal concentrations of vancomycin. Striking clinical and laboratory evidence of improvement was demonstrated with the addition of rifampin therapy.

Blood