Parallel assessment of 24 monthly doses of rifampin, ofloxacin, and minocycline versus two years of World Health Organization multi-drug therapy for multi-bacillary leprosy

Monthly doses of rifampin, ofloxacin, and minocycline (ROM) are expected to be effective treatment for multi-bacillary leprosy. Patients with MB leprosy received ROM (n = 10) or World Health Organization multi-drug therapy (MDT) (n = 11). Treatment with ROM was given as 24 consecutive monthly observed doses of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg). Treatment with MDT was given as 24 consecutive monthly observed doses of rifampin (600 mg) and clofazimine (300 mg), and unobserved daily dapsone (100 mg) and clofazimine (50 mg). Twenty patients completed the 24-month regimens with > 99% compliance. Treatments with ROM and MDT were safe, tolerable, and caused similar improvements in lesions, bacterial indices, and histology. All MDT recipients developed clofazimine-induced pigmentation. Six ROM and nine MDT recipients assessed at five or more years after completion of treatment had no evidence of relapse. Twenty-four months of treatment with ROM is a safe, well-tolerated, and convenient regimen that may provide an alternate therapy to MDT for MB leprosy. Larger trials with sufficient follow-up would better define the role of ROM.     

Relapse as histoid leprosy after receiving multidrug therapy (MDT); a report of three cases

The histoid type of leprosy has been described as occurring in lepromatous leprosy patients who relapse after many years of apparently successful dapsone monotherapy. Three patients who had received the World Health Organization-recommended regimens of multidrug therapy (WHO/MDT) relapsed as histoid leprosy 12-15 years after completion of treatment. In one patient, through mouse foot pad studies, the bacilli were found to be sensitive to rifampin and clofazimine and resistant to dapsone. In the other two patients mouse foot pad studies were inconclusive. The patients were re-started on WHO/MDT. Two patients took regular treatment and improved, both clinically and bacteriologically. One patient was irregular in treatment, and 1 year after re-starting WHO/MDT nodules were still present although the bacterial index had fallen slightly.     

Sulfone-resistance of Mycobacterium leprae--monotherapy with diaminodiphenylsulfone--the value of triple-drug combinations

While the emergence of drug resistance in Mycobacterium leprae was foreseen and known for a long time, it is now presented as a tragedy jeopardizing leprosy control through monotherapy. This resistance has been mainly reported in the United States. It is not observed in other parts of the world. In our opinion, the unfavorable observations made at present result from an incorrect implementation of dapsone (DDS) therapy in the patients, resulting in low sulfone blood levels, as a consequence of the use of complex disubstituted sulfones, insufficient daily dapsone dosages, irregular or noncompliance to treatment, premature interruption of treatment, etc. Two measures are required in order to prevent the emergence of primary or secondary resistance to dapsone in M. leprae. First, it is necessary to go back to the previous regimen of 200 mg dapsone daily in an adult. It yields the "maximum tolerated effective dosage." It should never have been rejected in favor of 100 mg daily as currently recommended at the moment. The second measure is the implementation of multiple drug therapy (MDT), using concurrently DDS in association with rifampin and clofazimine. This is a logical and rational approach, at least from a theoretical point of view. However, MDT is most unfortunately quite expensive and therefore inapplicable in most countries with high prevalence, since they are poor and underdeveloped. Implementation of MDT also raises great problems, since dosages have to be strictly adhered to in order to prevent a potentially catastrophic emergence of multiple drug resistance in M. leprae.     

A Case of Acquired Rifampin Resistance in Mycobacterium Bovis Bacillus Calmette-Guérin-induced Cystitis: Necessity for Treatment Guidelines.

A case of presumed bacillus Calmette-Guérin (BCG) cystitis in an elderly female patient following direct intravesical BCG instillation treatment for papillary transitional cell carcinoma is reported. The organism cultured from urine samples was eventually identified as a rifampin-resistant Mycobacterium bovis BCG isolate. Because the patient had received rifampin monotherapy during the course of treatment for presumed BCG disease, the clinical picture favoured acquired rifampin resistance. Sequencing of the target gene for rifampin (rpoB) confirmed a known mutation responsible for conferring high levels of resistance to both rifampin and rifabutin (Ser531Tyr). To the authors' knowledge, this is the first reported case of M bovis BCG disease in a non-HIV patient where the organism had acquired drug resistance to rifampin, and the second reported case of M bovis BCG that had acquired drug resistance. The present case demonstrates the necessity to re-evaluate appropriate guidelines for the effective treatment of BCG disease.     

Rifampin-Induced Immune Thrombocytopenia

In this report, a case of rifampin-induced immune thrombocytopenia with the following characteristics is described: (a) thrombocytopenia follows intermittent drug administration; (b) onset occurs within hours of drug ingestion; (c) IgG antirifampin antibody binds in vitro to normal platelets only in the presence of rifampin; (d) thrombocytopenia resolves quickly in the absence of rifampin; (e) using immunofluorescence microscopy, IgG binding to normal platelets was seen with the patient's serum only in the presence of rifampin, and (f) using fluorescence spectrofluorometry, an absence of rifampin binding to normal platelets was demonstrated. Although the serological studies are not definitive, the mechanism of thrombocytopenia in the patient can best be explained by the formation of immune complexes composed of rifampin-antirifampin antibody binding to platelets causing their rapid clearance from the circulation.     

Oral rifampin for eradication of Staphylococcus aureus carriage from healthy and sick populations: a systematic review of the evidence from comparative trials

BACKGROUND: Rifampin has been used for the eradication of Staphylococcus aureus (S. aureus) colonization in various populations of healthy and sick people. METHODS: We performed a systematic review of the evidence from randomized and nonrandomized controlled trials that compared the effectiveness and safety of a rifampin-based regimen with another regimen in eradicating S. aureus colonization from healthy and sick people. RESULTS: Nine comparative trials (6 of which were randomized controlled trials) were included in our analysis. S. aureus was eradicated more commonly in patients receiving rifampin-containing regimens compared to monotherapy with other systemic agents (ciprofloxacin, cloxacillin, minocycline, or vancomycin), both during early and late (>1 month after therapy) post treatment evaluations (odds ratio [OR] 46.2, 95% confidence interval [CI] 14.4-148, and OR 8.8, 95% CI 3.4-22.5 respectively, 4 studies included). There was no statistically significant difference between rifampin monotherapy and combinations of rifampin with other topical (bacitracin) or systemic (cloxacillin and minocycline) antibiotics in eradicating S. aureus both in early and late evaluations (OR 1.5, 95% CI 0.5-4.4, and OR 1.6, 95% CI 0.7-3.7, respectively, 3 studies included). Eradication of methicillin-resistant S. aureus (MRSA) varied according to the type and duration of the rifampin-containing regimen. It ranged from 25% for the combination of rifampin with trimethoprim/sulfamethoxazole for 5 days to 100% for the combination of oral rifampin and minocycline for 14 days. Discontinuation of rifampin due to drug-related toxicity was necessary in 2% of 282 studied patients. Development of resistance of S. aureus to rifampin during and after treatment with a regimen containing rifampin ranged from 0% to 40% (7 studies) and overall 17% of the 236 patients for whom relevant data was reported. CONCLUSION: The available evidence suggests that oral rifampin is an effective agent for the eradication of S. aureus carriage. However, development of antimicrobial resistance during and after treatment with rifampin occurs in a considerable proportion of patients; using rifampin in combination with another antimicrobial agent may decrease this resistance.     

In vitro exposure of bacteria to antimicrobial impregnated-central venous catheters does not directly lead to the emergence of antimicrobial resistance

OBJECTIVE: Use of central venous catheters (CVCs) impregnated with minocycline and rifampin reduces the density of bacterial growth on catheters and decreases the incidence of catheter-related bloodstream infections. Questions have been raised over the possibility that the use of these catheters will lead to the emergence of antibiotic-resistant organisms. In this study, we sought to determine if in vitro exposure of four test organisms to catheter segments impregnated with minocycline and rifampin would lead to the development of antibiotic resistance. METHODS: Catheter segments (1.0 cm) were placed on the surface of agar plates previously inoculated with bacterial suspensions, such that a subconfluent lawn of colony growth would be apparent after 24 h incubation at 35 degrees C in air. Test organisms included American Type Culture Collection strains of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa. Zones of inhibition of colony growth surrounding catheters were measured at 24-h intervals up to 7 days (two catheter segments per test). Colonies on agar surfaces located at varying distances from catheter segments were examined for minocycline and rifampin resistance following various periods of exposure (six catheter segments per test). In addition, selected colonies were subsequently exposed to minocycline and rifampin in broth and examined for selection of minocycline and rifampin resistance (> 28 colonies per selection test). RESULTS: Inhibitory zones of 14 to 47 mm were observed with S aureus, S epidermidis, E faecalis, and E coli. Growth of P aeruginosa was not inhibited by CVC segments. Testing of colonies of the first four organisms at various distances from CVC segments after varying periods of exposure revealed only a single instance of the emergence of resistance (eg, S aureus vs rifampin). Recovery of resistant clones was enhanced with minocycline and rifampin broth selection; however, a direct link between CVC exposure and the emergence of resistance was not established. CONCLUSIONS: Our in vitro data suggest that the exposure of Gram-positive cocci to either rifampin or minocycline can lead to the development of resistance. However, exposure of bacteria to these antibiotics in combination does not directly lead to resistance. Clinical investigations will be required to determine the true risk and implications of the development of resistance.     

Drug resistance trends among previously treated tuberculosis patients in a national registry in Peru, 1994-2001.

SETTING: National mycobacteriology reference laboratory in Peru conducting routine testing of susceptibility to isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin, in Mycobacterium tuberculosis isolates from previously treated patients. OBJECTIVE: To determine the percentage of isolates resistant to each of five anti-tuberculosis agents and to ascertain in these data the presence of trends of clinical relevance. DESIGN: Retrospective study of a national registry of M. tuberculosis isolates from patients referred for drug susceptibility testing between 1994 and 2001. RESULTS: Among 14,736 isolates tested, 10,837 (73.5%, 95%CI 72.8-74.3) demonstrated anti-tuberculosis resistance, and 8455 (57.4%, 95%CI 56.6-58.2) demonstrated resistance to at least both isoniazid and rifampin, by convention defined as multidrug-resistant tuberculosis (MDR-TB). A significant increasing trend could be discerned for resistance to each of the drugs tested and in isolates classified as MDR-TB (P < 0.001 for trend). Additional clinically relevant trends were found in polyresistance and multidrug resistance percentages. CONCLUSIONS: Data from a national reference laboratory can be used to inform the design of retreatment regimens.     

Therapeutic considerations in the treatment of Legionella infections

Selection of therapy for legionella infections originated with the clinical observation after the 1976 Philadelphia outbreak that patients treated with erythromycin or tetracycline did better than those who received cephalosporins or aminoglycosides. Early in vitro antibiotic susceptibility studies suggested that rifampin and erythromycin were both active against Legionella pneumophila. However, subsequent in vitro susceptibility studies to other antibiotics have produced variable results, depending on the medium and methodology used. Antibiotic studies within polymorphonuclear leukocytes and alveolar macrophages indicate that those actively concentrated within these cells are predictive of successful therapy. These include erythromycin, rifampin, and certain quinolones. On the other hand, beta-lactam antibiotics such as penicillin, cefoxitin, and imipenem are less likely to be successful because of their lack of concentration within phagocytes. These observations have been confirmed in animal model studies where erythromycin, rifampin, and quinolones have demonstrated efficacy. The addition of rifampin to erythromycin or to doxycycline may be more effective than therapeutic results with either antibiotic alone. Although erythromycin is presently the treatment of choice for legionellosis, the addition of rifampin is recommended, particularly in immunocompromised patients. Doxycycline has served as an appropriate alternative agent, the newer quinolones may be useful and are deserving of carefully designed clinical trials.     

Long-term efficacy of 2 year WHO multiple drug therapy (MDT) in multibacillary (MB) leprosy patients

Relapse rate estimates after 2 year WHO multiple drug therapy (MDT) in multi-bacillary (MB) leprosy vary. Between 1987 and 1994, 500 MB leprosy patients completing 2 year MDT were enrolled in a prospective relapse study. The majority of patients (N = 316) were treated and followed at the physician-staffed Cebu Skin Clinic (CSC), whereas others (N = 184) received therapy from government clinics and were followed by CSC technicians in the field. Relapse definition was an increased bacteriologic index (BI) and new skin lesions, supplemented with mouse footpad inoculations. Through 2002, follow-up was 5368 person-years, with a mean of 10.8 years per patient. The absolute relapse rate was 3% (15/498; 0.28/100 person-years), with a cumulative risk estimate of 3.9% at 15 yrs. For a subset of 217 patients followed for >or=12 yrs or until relapse, relapses occurred in 9% (13/142) attending the CSC, versus 3% (2/75) assessed in the field (p = 0.09). The rate for patients followed at CSC for >or=12 yrs and a pre-treatment BI >or=2.7+ was 13% (13/98). All relapses were BL or LL, with pre-treatment BI's of >or=2.7+. Relapses occurred long after completion of therapy, between 3 and 11 yrs from the midpoint of the examination without relapse to detection, or between 6 to 13 yrs to the actual year of detection, 7 occurring at >or=10 yrs. Lesion material from all relapses contained M. leprae that was rifampin and clofazimine sensitive, whereas 3 showed partial or full dapsone resistance. [Follow-up rigor and time], medical expertise, and pre-treatment bacterial load influence relapse rates after 2 yr MDT.     

Bacillus subtilis Mutant Altered in Spore Morphology and in RNA Polymerase Activity

A Bacillus subtilis mutant, that was selected for rifampin resistance produces spores with an altered morphology. The mutant spores are pleomorphic and differ both in shape and size from the wild-type spores. They frequently have an exosporium that is usually absent from wild-type spores. The mutant spores are similar to the wild-type spores in heat resistance, dipicolinic acid content, and density, but exhibit a slower rate of germination, outgrowth, and growth. In vitro studies show that the RNA polymerase of the mutant is resistant to rifampin inhibition, whereas the wild-type enzyme is completely inhibited by low concentrations of the antibiotic. Rifampin resistance and the altered spore morphology are contransformed with 100% frequency, suggesting that the altered morphology is caused by an alteration in the RNA polymerase.     

Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis

The response to short-course chemotherapy of patients with pulmonary tuberculosis caused by drug-resistant Mycobacterium tuberculosis was examined in 12 controlled trials carried out during the past decade in Africa, Hong Kong, and Singapore. Among those with initial resistance to isoniazid and/or streptomycin, failures during chemotherapy were encountered in 17% of 23 patients given a 6-month regimen of isoniazid and rifampin and in 12% of 264 patients given rifampin only in an initial 2-month intensive phase of their regimen. The proportion of failures fell as the number of drugs in the regimen and the duration of treatment with rifampin were increased, to reach 2% of 246 patients receiving 4 or 5 drugs including rifampin in 6-month regimens. The sterilizing activity of the regimens, whether these included rifampin or pyrazinamide, was little influenced by initial resistance, because the sputum conversion rate at 2 months was similar to that in patients with initially sensitive bacilli, and the relapse rates after chemotherapy were only a little higher. The response in the 11 patients with initial rifampin resistance was, however, much less good, failure during chemotherapy occurring in 5 and relapse afterwards in a further 3 patients. This review demonstrates the value of rifampin in preventing failure caused by the emergence of resistance during treatment and the greater sterilizing activity of rifampin and pyrazinamide compared with that of isoniazid and streptomycin.     

Drug-resistant Mycobacterium tuberculosis in Korean isolates

Tuberculosis is a common disease in developing countries. An increasing incidence of resistance to isoniazid (INH) and streptomycin in organisms isolated from patients who contracted their disease in these countries, particularly in the Far East, is well recognized. This drug resistance has led to the recommendation of empirically beginning a regimen in patients with tuberculosis from the Far East of INH, ethambutol, and rifampin. This report documents the increasing incidence of resistance in isolates from Korea to ethambutol and rifampin in addition to INH and streptomycin. It suggests that the empiric use of INH, ethambutol, and rifampin in this group of patients could potentially lead to resistance to all of these drugs because of a significant amount of multidrug resistance. A regimen of INH, rifampin, pyrazinamide, and capreomycin is suggested as appropriate initial therapy in these patients based on the in vitro sensitivity data presented and initial clinical experience.     

Rifampin resistance. Development during the therapy of methicillin-resistant Staphylococcus aureus infection

The incidence of methicillin-resistant staphylococcal infections, for which vancomycin hydrochloride remains the only active cell-wall antibiotic therapy, is rising. Some physicians have been combining other antibiotics with vancomycin in hopes of obtaining a more effective regimen for the therapy of these infections. Rifampin has been advocated as a concurrent second antibiotic because of its extraordinary potent bactericidal activity for Staphylococcus aureus. When rifampin is used in combination with a cell-wall antibiotic, suppression of the development of rifampin resistance has been thought possible. We report a case of infection caused by a methicillin-resistant S aureus in which the rifampin resistance occurred during therapy with vancomycin and rifampin. The rifampin resistance was stable and was present after ten serial broth and agar passages. Physicians are cautioned against the indiscriminant or routine use of rifampin as a second antibiotic in combination with vancomycin for the therapy of infections caused by S aureus.     

L型结核菌rpoB基因突变与利福平耐药性的关系研究

目的探讨L型结核分枝杆菌rpoB基因突变与利福平耐药性的关系。方法对76株复制肺结核患者L型结核分枝杆菌临床分离株进行药敏试验,同时采用PCR和PCR-DS技术对L型结核菌株进行rpoB基因检测和序列分析。结果药敏结果提示28株L型结核分枝杆菌对利福平耐药,其中20株(71.4%)L型结核分枝杆菌rpoB基因发生突变。结论 L型结核分枝杆菌rpoB基因突变是造成结核分枝杆菌形成利福平耐药性的主要机制。     

Drug resistance patterns and serogroups or serotypes of pneumococcal isolates from cerebrospinal fluid or blood, 1979-1986

In an analysis of 4766 consecutive strains of Streptococcus pneumoniae isolated from cultures of blood from 1979 to 1986 and of 1157 isolates from cerebrospinal fluid (CSF), resistance was found in 380 (8%) of blood and 107 (9.2%) of CSF isolates to one or more of the following antibiotics: penicillin, tetracycline, erythromycin, clindamycin, rifampin, and chloramphenicol. Resistance increased from 3.8% to 14.1% among isolates from blood and from 6.8% to 14.1% among CSF isolates during this period. Comparing 1979-1982 with 1983-1986, we found that significant increases (P less than .01) have occurred in penicillin resistance alone, rifampin resistance alone, and in strains showing multiple resistance. Resistance was found in 15 different serogroups and/or serotypes, although 92.2% of resistant strains belonged to serogroups 6 or 19 or to serotype 14. Of the serogrouped or serotyped strains, 97.4% are represented in the 23-valent vaccine by a vaccine or vaccine-related strain.     

Intravascular hemolysis and acute renal failure following intermittent rifampin therapy.

Renal failure is a rare complication associated with the use of rifampin. Intravascular hemolysis leading to acute renal failure following rifampin therapy is extremely rare. Two patients with leprosy who developed hemolysis and acute renal failure following rifampin are reported.     

Longitudinal ocular survey of 202 Filipino patients with multi-bacillary (MB) leprosy treated with 2 year WHO-multiple drug therapy

The aim of this study was to describe the ocular conditions in multibacillary (MB) leprosy patients treated with 2 year WHO multiple drug therapy (MDT), consisting of dapsone, clofazimine and rifampin, a regimen expected to reduce ocular complications of leprosy. We conducted comprehensive eye examinations in 202 Filipino MB leprosy patients before, during, and after WHO 2 year MDT. Assessments were carried out for at least 5 years. Inflammatory "lepra" reactions occurred in 62% (reversal reaction, 52%; erythema nodosum leprosum, 10%); most were mild. Eye abnormalities consisted mostly of diminished corneal sensitivity before MDT (6%) and lagopthalmos (n = 7, 3.4%). Six of 7 lagopthalmos cases occurred in a subset of 132 patients with facial patches (5%). Visual acuity scores, intra-ocular pressures and pupil cycle times were unremarkable. Bacillary invasion, keratitis, episcleritis, iridocyclitis, ectropion, synechiae, glaucoma and cataract formation were not detected. Scleral clofazimine pigmentation was frequent, resolving in most within 3 years of treatment cessation. Facial patches at presentation may denote a higher risk for lagopthalmos. We propose the generally low rates of ocular problems reflected mild lepra reactions, due to anti-inflammatory properties of clofazimine, a relatively young cohort, and a readily accessible community-based clinic permitting earlier diagnosis and prompt treatment.     

噬菌体生物扩增法快速测定结核分枝杆菌利福平耐药性

目的　建立快速测定结核分枝杆菌利福平耐药性的噬菌体生物扩增法 ,并探讨其在结核分枝杆菌利福平耐药性测定中的应用价值。方法　应用噬菌体生物扩增法测定 5 2 4株结核分枝杆菌利福平耐药性 ,并与绝对浓度法结果进行比较 ,对不符合的菌株采用BactecMGIT 96 0测定其最低抑菌浓度 (MIC)。结果　噬菌体法测定 5 2 4株结核分枝杆菌临床分离株利福平敏感 30 1株、耐药 2 2 3株 ,绝对浓度法敏感 313株、耐药 2 11株 ;两法测定均为敏感 2 88株、均为耐药 198株。在 38株噬菌体法与绝对浓度法测定结果不符的菌株中 ,35株噬菌体法与MIC测定结果相符合。如以绝对浓度法药敏结果为判断标准 ,则噬菌体法测定利福平耐药性的敏感性为 93 8%、特异性为 92 0 %、阳性预测值为88 8%、阴性预测值为 95 7%、准确性为 92 7%。结论　噬菌体生物扩增法测定利福平耐药性只需 2天时间 ,操作简便 ,不需特殊仪器设备 ,可作为结核分枝杆菌利福平耐药性的快速筛选方法。     

类泛素-蛋白酶体系统和药物外排泵抑制剂对结核分枝杆菌单纯利福平耐药性影响的研究

目的探讨类泛素-蛋白酶体系统对结核分枝杆菌单纯利福平耐药性的影响。方法采用刃天青显色法检测利福平对结核分枝杆菌的最低抑菌浓度(minimum inhibitory concentration,MIC),比较分析结核分枝杆菌Pup、Dop、PafA、Mpa基因的过表达或缺失突变对结核分枝杆菌利福平MIC的差异;检测分别加入羰基氰氯苯腙、利血平、维拉帕米和氯丙嗪4种外排泵抑制剂前后各菌株对利福平MIC的影响。结果结核分枝杆菌Pup、Dop、PafA和Mpa基因的过表达均能增强单纯耐利福平结核分枝杆菌对利福平的耐药性,而Pup、Mpa、Dop和PafA基因的缺失均能显著降低单纯耐利福平结核分枝杆菌对利福平的耐药性,P值均0.05。4种药物外排泵抑制剂能不同程度的降低各过表达菌株对利福平的MIC,P值均0.05,并且,类泛素-蛋白酶体系统与外排泵抑制剂之间存在一定交互作用。结论类泛素-蛋白酶体系统对结核分枝杆菌单纯利福平耐药性的产生有影响;类泛素-蛋白酶体系统可能通过调控外排相关通路蛋白来影响结核分枝杆菌单纯利福平耐药性的产生。