Administration Of Rifampin Research Articles

LONG-TERM FOLLOW-UP OF THE RATE OF PHARYNGEAL COLONIZATION WITH HAEMOPHILUS INFLUENZAE TYPE B (Hib) AT A CHRONIC-CARE FACILITY FOLLOWING PROPHYLAXIS WITH RIFAMPIN

Although rifampin is effective in eliminating pharyngeal carriage of Hib, there are few data about Hib colonization rates in treated groups long after administration of rifampin. After two children at a chronic-care facility for severely handicapped children had developed Hib meningitis, pharyngeal cultures using agar plates containing hyperimmune Hib antiserum revealed that 17 of the 97 children (18%) who resided there were colonized with Hib. A repeat survey 11 days after all carriers had been treated with rifampin showed that only 1 of these 97 children (1%) remained colonized with Hib. Six months later the rate of colonization rose significantly: 12 of the 85 available children (14%) were colonized with Hib(X2=11.69; P<0.001). Cultures were positive from 1 of 14 children in whom Hib colonization had previously been eradicated with rifampin. Potential sources for the reintroduction and transmission of Hib included visiting families, members of the staff, the one persistent carrier, and the newly admitted children (2 of 5 of whom were colonized with Hib). Although 6 months after prophylaxis with rifampin the prevalence of colonization with Hib was similar to that before rifampin was administered, no new cases of invasive Hib infections occurred at the facility during the ensuing 3 years. Because colonization with Hib is a dynamic process, reduction of the rate of colonization with Hib by chemoprophylaxis may only be transient, even in relatively closed populations.

Pharmacokinetics of Rifampin in the Presence of Dipyrone in Leprosy Patients

AbstractSome pharmacokinetic parameters such as elimination rate, half-life, AUC etc., of rifampin following p.o. administration of rifampin 600 mg. alone and 600 mg. rifampin in combination with 1000 mg. dipyrone were determined in untreated patients of leprosy. Statistical comparison of the mean values of the parameters suggests that the pharmacokinetic behaviour as well as the bioavailability of rifampin are not statistically affected in the presence of dipyrone.

Activity of rifampin against viridans streptococci.

Optimal antimicrobial therapy for viridans streptococcal endocarditis remains controversial. Rifampin was bactericidal at less than 0.2 micrograms/ml for ten strains of viridans streptococci isolated from patients with endocarditis. Administration of rifampin to one endocarditis patient already receiving penicillin and gentamicin increased the serum bactericidal activity fourfold. Rifampin has been effective in combination therapy for serious staphylococcal and enterococcal infections. The combination of penicillin and rifampin may be an effective, less toxic alternative to penicillin and streptomycin for the treatment of viridans streptococcal endocarditis.

Pharmacokinetics and metabolism of rifampin in humans.

The unique pharmacokinetic properties of rifampin in humans are discussed in this review. These properties can be better understood by assuming the existence of two pharmacokinetic subsystems; one, the primary subsystem, regulates the time course of the concentration of the antimicrobial agent in the other, the secondary subsystem. The first subsystem includes the intestine and the liver (interconnected through the portal blood and the bile), and the second subsystem includes the tissues, kidneys, and blood of the circulatory system. The connection between the two subsystems in normal conditions is the hepatic veins. The rate of excretion of rifampin in human bile depends, although not exclusively, on its rate of transformation into the biologically active desacetyl derivative. The rate of metabolism increases over the first week(s) of treatment, which results in a corresponding increase of desacetylrifampin excretion in bile. The process is limited and, within a given range of single doses, a transport maximum can be identified. Doses in excess of those associated with the transport maximum generate a more than proportional increase in serum concentrations of the drug. Administration of rifampin causes proliferation of the smooth endoplasmic reticulum of the hepatocyte (probably due to glucuronidation of a fraction of rifampin). This observation explains some of the interactions of rifampin with endogenous and exogenous compounds. The unique distribution of rifampin in human tissues probably results from its capacity to cross biological membranes. Excretion of rifampin in urine does not seem to be associated with any active process.

Rifampin in the treatment of leprosy.

The minimal inhibitory concentration of rifampin for Mycobacterium leprae is less than 1 microgram/ml. Therapy with rifampin has proved efficacious both in mice experimentally infected with M. leprae and in humans with leprosy. Rifampin kills M. leprae more rapidly than do other antileprosy drugs currently available. Consequently, M. leprae bacilli from patients with lepromatous disease are rendered noninfectious within three weeks after the institution of rifampin therapy, as determined in the mouse footpad test system. Administration of this antibiotic substantially reduces the quantities of M. leprae discharged in the nasal secretions of lepromatous patients within three weeks, thus rapidly decreasing the potential infectivity of these individuals. Intermittent rifampin therapy for leprosy has been successful, with a low incidence of adverse reactions to the drug. Worldwide, the prevalence of primary and secondary resistance of M. leprae to dapsone has increased markedly. Therefore, the World Health Organization recommends a multidrug regimen that includes intermittent administration of rifampin for the treatment of leprosy.

Short-term administration of rifampin in the prevention or eradication of infection due to foreign bodies.

Short-term administration of rifampin was evaluated as a means of preventing or eradicating infection due to foreign bodies. Tissue cages were implanted into guinea pigs and subsequently infected with 10(3) colony-forming units of Staphylococcus aureus Wood 46. Infection developed in all tissue cages. Rifampin was administered thereafter intraperitoneally at a dosage of 7.5 mg/kg every 12 hr for 48 hr, and the tissue-cage fluid was monitored for possible development of infection by quantitative bacteriologic methods for 15 days. In all cases rifampin prevented or eradicated tissue-cage infection if treatment was initiated either 3 hr before or less than or equal to 12 hr after inoculation of microorganisms but was ineffective if initiated greater than 12 hr after inoculation. In cases of failure of treatment, rifampin-resistant variants could be demonstrated. Rifampin seems to prevent or eradicate tissue-cage infection only if given early after bacterial inoculation.

Treatment of tuberculosis and other mycobacterial diseases.

In controlled clinical trials, several regimens have proven effective in treating tuberculosis. The drugs must be given in combination to avoid the emergence of resistant organisms. The simplest regimen is based on the administration of isoniazid and rifampin for 9 months. Ethambutol or streptomycin generally is added for an initial 2-8 weeks. Good results also have been reported using twice weekly administration of the isoniazid and rifampin after an initial 1 month of daily treatment. Relapse rates of less than 3% have been reported with these regimens. A table shows the recommended doses for the drugs. If neither isoniazid nor rifampin can be used, the patient needs to be given at least 2 and preferably 3 drugs to which his organisms are known to be susceptible. Additionally, these drugs must be administered for at least 18 months. Several circumstances are associated with a higher rate of drug resistant organisms and call for susceptibility studies: tuberculosis among individuals known to have a higher prevalence of drug resistance such as Asians or Hispanics; previous treatment; persistence of culture-positive sputum after 3 months of therapy; and exposure to drug resistant tuberculosis. The recommendations for the treatment regimen need to be changed in several special situations, including: infection with mycobacteria other than "M. tuberculosis;" tuberculosis in children; disease in organ systems other than the lungs; and the presence of certain patient characteristics, concurrent diseases, or the development of adverse drug reactions. Much scientific data supports the value of isoniazid (INH) in the prevention of tuberculosis. Isoniazid preventive therapy is recommended for several groups, listed in order of priority: household members and other close associates of potentially infectious tuberculosis cases; newly infected persons; persons with significant reactions to tuberculin skin test and abnormal chest roentgenograms; persons with significant reactions to tuberculin skin tests who are in special clinical situations; and tuberculin skin test reactors under age 35 with none of the other risk factors. Prior to administration of INH preventive therapy, it is important to: exclude bacteriologically positive or progressive tuberculous disease; question for a history of prior INH administration to exclude those who have had a adequate course of the drug; check for contraindications to the administration of INH for preventive therapy; and identify patients for whom preventive therapy is not contraindicated but in whom special precautions are indicated. Other drugs might be effective for preventive therapy, but as yet there are currently no data available documenting the efficacy of any drug other than INH.

Non-competitive inhibition of hepatic and intestinal aryl hydrocarbon hydroxylase activities from rats by rifampin.

Rifampin is a semisynthetic antibiotic which is known to alter hepatic cytochrome P-450 mediated drug metabolizing enzymes. Using benzo(a)pyrene as the substrate we have shown that rifampin acts as a non-competitive inhibitor of hepatic microsomal aryl hydrocarbon hydroxylase in vitro at or below 0.10 mM and that it is also a non-competitive inhibitor of intestinal aryl hydrocarbon hydroxylase at or below 0.075 mM. These results suggest that the administration of rifampin with other drugs may result in altered drug biotransformation.

Failure of rifampin to induce the metabolism of clonidine in normal volunteers.

Patients receiving rifampin and methadone often incur withdrawal symptoms related to an increased rate of metabolism of methadone induced by rifampin. In order to test the hypothesis that clonidine metabolism is similarly altered by rifampin, six normal volunteers received clonidine 0.2 mg bid for four days and clonidine concentration was assayed by a RIA procedure. Beginning on day 5, rifampin 600 mg q12h was added to the clonidine regimen. Both drugs were taken for a total of seven days. On the last day of the study, blood was again sampled for clonidine. On days 4 and 12, urine was collected for d-glucaric acid. The results demonstrate that there is no change in the elimination kinetics of clonidine before and during rifampin administration. However, there was an increase in UDGA following the rifampin dosing. It is concluded that patients receiving rifampin can also receive clonidine for treatment of narcotic withdrawal.

Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid.

The effect of prednisolone and rifampin, alone and in combination, on the biodisposition of isoniazid in slow and rapid inactivators of isoniazid was investigated. In one investigation, we made serial determinations of plasma isoniazid concentrations up to 8 h and of isoniazid and acetylisoniazid in excreted urine up to 8.5 h in patients receiving isoniazid alone on one occasion and isoniazid plus prednisolone or isoniazid plus rifampin on another. Prednisolone caused a significant decrease in the plasma isoniazid concentrations in both slow and rapid inactivators. It also enhanced the renal clearance of isoniazid in both slow and rapid inactivators and increased the rate of acetylation of isoniazid in slow inactivators only. Rifampin had no effect on the biodisposition of isoniazid in either slow or rapid inactivators. In a second investigation, one group of slow and rapid inactivators received isoniazid and rifampin, and a different group received prednisolone, in addition. Plasma isoniazid concentrations in slow inactivators receiving prednisolone were significantly lower than in those who received isoniazid and rifampin only. In rapid inactivators, plasma isoniazid concentrations were similar in the two groups of patients, suggesting that concomitant administration of rifampin had considerably modified the prednisolone effect on the biodisposition of isoniazid in these patients.

The early bactericidal activity of drugs in patients with pulmonary tuberculosis.

Counts of colony-forming units of Mycobacterium tuberculosis in sputum were done on selective medium during the first 2 wk of treatment of 124 patients with pulmonary tuberculosis. The 27 chemotherapy regimens studied included daily administration of thiacetazone, p-aminosalicylic acid, pyrazinamide, rifampin, streptomycin, ethambutol, and isoniazid alone and certain 2-drug, 3-drug, and 4-drug combinations. Thiacetazone and p-aminosalicylic acid appeared to be only bacteriostatic. The mean fall in counts and the differences between regimens containing the remaining bactericidal drugs were greater during the first 2 days of treatment than during the remaining 12 days. The early (0-to-2-day) falls were much larger with isoniazid than with other drugs. Rifampin was less bactericidal, and may have reduced the bactericidal activity of the 3-drug and 4-drug combinations, including isoniazid. Although streptomycin and pyrazinamide were only slightly bactericidal alone or in a 2-drug combination, the 3-drug regim...

Rifampin-lnduced Organic Brain Syndrome

RIFAMPIN, a semisynthetic antibiotic derived from rifamycin B, is a frequently employed antituberculous agent used in conjunction with one or more other drugs in the treatment of tuberculosis. It is also recognized to be effective in eliminating meningococci from the nasopharynx of asymptomatic carriers ofNeisseria meningitidis.1Rifampin acts by inhibiting DNA-dependent bacterial RNA polymerase in susceptible organisms.2The more commonly encountered side effects caused by rifampin include gastrointestinal disturbances, eg, nausea, vomiting, diarrhea, and heartburn. A case of acute organic brain syndrome was associated with rifampin administration in the treatment of pulmonary tuberculosis. Report of a Case A 60-year-old man with no history of psychiatric disorders was admitted to the Veterans Administration Hospital on transfer from a local private hospital with a diagnosis of pulmonary tuberculosis demonstrated by the presence of acid-fast bacilli on Zeihl-Neelsen stain of sputum and subsequently by culture. He had no history of

Short-course Chemotherapy for Tuberculosis with Largely Twice-weekly Isoniazid-Rifampin

Although short-course, largely twice weekly chemotherapy for treatment of tuberculosis has been shown to be effective in other countries, when given under closely controlled conditions, it has not been adopted in this country where most patients are older and are treated as outpatients. Since January, 1976, 315 patients (mean age 55.5 years) with proven pulmonary tuberculosis have been treated with rifampin (RIF) 600 mg and isoniazid (INH) 300 mg daily for one month, followed by RIF 600 mg and INH 900 mg twice-weekly for another eight months, self-administered except for a few patients. By three months, 95 percent had converted to negative culture. There were only ten failures among 185 patients in whom final results could be assessed. There has been only one relapse during 1-21 months of follow-up in 175 patients. Serious side effects were few: six instances of jaundice, two of "flu-like syndrome," and one of thrombocytopenia. This form of initial therapy for tuberculosis is safe, effective, and economical.

Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis.

In a study in Singapore, Chinese, Malay, and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide followed either by daily treatment with isoniazid, rifampin, and pyrazinamide (SHRZ/HRZ regimen) or by daily administration of isoniazid and rifampin (SHRZ/HR regimen) allocated at random. Both regimens were given for either 6 or 4 months by random allocation. All 330 patients with drug-sensitive tubercle bacilli before treatment had a favorable bacteriologic response during chemotherapy. During the first 6 months after the end of chemotherapy, there was only a single bacteriologic relapse among 84 SHRZ/HRZ and 80 SHRZ/HR patients treated for 6 months, but 8 (10 per cent) of 80 SHRZ/HRZ and 4 (5 per cent) of 74 SHRZ/HR patients treated for 4 months relapsed. Of a total of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs before treatment, only one had an unfavorable response during chemotherapy, and none of 31 patients relapsed during the first 6 months after stopping chemotherapy. The incidence of adverse reactions was low; 11 (3 per cent) of 397 patients had hepatitis, but not all episodes were attributable to drug toxicity, and one patient had thrombocytopenic purpura.

Further observations on the inhibition of tumor growth by corynebacterium parvum with cyclophosphamide.

The cytotoxic macrophage was further characterized as an important effector cell in the inhibition of tumor growth. When we administered rifampin (a semisynthetic antibiotic that interferes with macrophage function but not viability) with Corynebacterium parvum and/or cyclophosphamide to tumor-bearing C3HeB/FeJ female mice, the tumor growth-inhibitory effects of the C. parvum were reduced. Moreover, when bone marrow cells from those animals were cultured, we found a marked decrease in the cytotoxicity of macrophages comprising clonies arising from colony-forming cells (CFC) in the bone marrow. Such findings supported our contentions that 1) the cytotoxic property of macrophages originates in ancestral stem cells or CFC in bone marrow, and 2) receptor sites of the CFC (or stem cells) that respond to a stimulus for self-replication probably differ from sites that when activated produce progeny with cytotoxic properties. Although the administration of rifampin resulted in macrophages virtually devoid of cytotoxic properties, both relative and absolute numbers of CFC increased.

Tubulointerstitial and Glomerular Nephritis Associated With Rifampin

In a patient with tuberculosis and acute renal failure related to administration of therapeutic rifampin, treatment was discontinued for five weeks. It was reinstituted three weeks later. Unlike other patients previously described, the expected adverse renal reaction occurred only gradually and without symptoms, although tubular and glomerular disease developed. Also unique was a striking deposition of immunoglobulin about the tubules. This finding, in association with interstitial nephritis and tubular glycosuria, is similar to an experimental autologous renal disease mediated by antibody to tubular basement membrane.

Induction and inhibition of hepatic drug metabolizing enzymes by rifampin

The effects of the antibiotic rifampin on microsomal drug metabolizing enzymes were investigated. On acute administration, rifampin (100 mg/kg i.p.) doubled hexobarbital sleeping time and zoxazolamine paralysis time in mice. The in vitro metabolism of zoxazolamine (0.25 mM) and 17β-estradiol (10 μM) were inhibited 50% by rifampin in concentrations of 0.4 and 0.3 mM, respectively. The inhibition of ethylmorphine N-demethylase was competitive with an apparent K i , of 52 μM. Repeated administration of rifampin to mice (50 mg/kg i.p. daily for 6 days) increased liver weight by 20%a cytochrome P-450 (50%), NADPH cytochrome c reductase (43%,). ethylmorphine N-demethylase (85%), zoxazolamine hydroxylase (77%), benzpyrene hydroxylase (174%). and 17β-estradiol metabolism (89%). Microsomal protein (mg/g). aniline hydroxylase and p-nitrophenol glucuronyl transferase activities were unaffected. Rat microsomal drug metabolizing enzyme activity was also inhibited after acute administration of rifampin as exemplified by an increase in hexobarbital sleeping time of 44% and a competitive inhibition of ethylmorphine N-demethylase by rifampin. The K i , (33 μM) was close to that obtained with the mouse enzyme. The similarity in the in vivo and in vitro inhibition suggests that rifampin binds to microsomes in a similar manner in both species. Chronic administration of rifampin to rats (50 mg/kg i.p.) twice daily for six days did not lead to induction, indicating a species difference with respect to rifampin's inducing ability. Rifampin did not modify microsomal induction in rats by phenobarbital when both drugs were administered concomitantly. The mechanism responsible for the species difference and the clinical relevance of these results are discussed.

Effect of rifampin on immunity to tuberculosis and on delayed hypersensitivity to purified protein derivative.

Mice vaccinated with mycobacterial ribonucleic acid (RNA) produced a high immune response and did not develop delayed hypersensitivity to purified protein derivative (PPD), and rifampin had no effect on the immune response. Mice vaccinated with viable H37Ra cells produced a high immune response and did develop delayed hypersensitivity to PPD. Rifampin had no effect on this immune response, but reduced the footpad reactions to PPD. Both mycobacterial RNA and poly(A:U) served as adjuvants for induction of hypersensitivity to PPD. This hypersensitivity was reduced by the administration of rifampin. Rifampin had no effect on the production of mycobacterial growth inhibitory factor, which is produced following vaccination of mice with mycobacterial RNA or viable H37Ra cells. Rifampin had no effect on the nonspecific phase of the granulomatous response, but did inhibit the secondary allergic phase of this response. The action, therefore, of rifampin that inhibits the induction of delayed hypersensitivity but had no effect on the immune responses against tuberculosis leads to a separation of tuberculin hypersensitivity from cellular immunity to tuberculosis.

Rifampin and warfarin: a drug interaction.

The drug interaction between warfarin and rifampin is not well known. Rifampin has been reported to increase the warfarin requirements in human subjects ingesting these agents simultaneously. The concomitant administration of rifampin and warfarin resulted in the need for an unusually high maintenance dose of warfarin (20 mg per day) in order to produce a therapeutic effect. Withdrawal of rifampin decreased the warfarin requirement by 50%. This effect may be mediated by the ability of rifampin to induce microsomal enzymes and, thus, the catabolism of warfarin. The effect of rifampin on the warfarin requirement of our patient appeared to be maximal 5 to 7 days after the initiation of rifampin and extended a similar length of time after rifampin withdrawal. This interaction appears to be clinically significant.

Pyoderma Gangrenosum and Leukemia

To the Editor.— The excellent article by Drs. Perry and Winkelmann on bullous pyoderma gangrenosum and leukemia in theArchives(106:901, 1972) prompts us to report a case of ours. In this case, there has been recent development of pyoderma gangrenosum while the patient was receiving treatment for acute lymphoblastic leukemia. The lesions, which were resistant to most drugs, eventually cleared up with administration of rifampin. Report of a Case A 13-year-old Chinese schoolgirl was found to have acute lymphoblastic leukemia in September 1971. She was anemic, but was otherwise well. There was a hepatomegaly of 3 cm below the right costal margin. The other organs were not enlarged. Hematologic studies showed the following results: total red blood cell count, 3 million/cu mm; hemoglobin, 9.0 gm/100 ml; total leukocyte count, 26,700/ cu mm, with 63% blast cells, 31% lymphocytes, and 6% neutrophils; platelet count, 20,000/cu mm; reticulocyte count, 2%; packed