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PubMedDate not supplied

The Malta Project--a country freed itself of leprosy. A 27-year progress study (1972-1999) of the first successful eradication of leprosy.

The successful conclusion of the first leprosy eradication program carried out with combination therapy is reported. This program started in Malta in June 1972. It was based on extensive experimental and clinical studies and was formally concluded on 31 December 1999. No new infections occurred after the start of this 27-year progress report. The youngest patient was 16, and the eldest 83 years old. Of the total of 261 cases in the project, 201 had already received pretreatment [mainly with diaminodiphenylsulfone (DDS)] at the start. Sixty-one cases had no pretreatment. These were predominantly elderly patients who were late in deciding to have treatment. The very long follow-up period totaling 27 years was consistently maintained in order to be able to refute all potential objections empirically, e.g. with regard to relapses at a late stage. Besides the overall symptoms which are typical for the broad picture of leprosy, the involvement of the eyes was very striking (at least 50%). The therapeutic effect was of very rapid onset in these cases without surgery. Rifampicin (RMP) + isoniazid + prothionamide + DDS (trade name Isoprodian-RMP) was used as medication in a fixed combination. This fixed combination had already proved to be highly effective in the treatments during the course of the project, surprising therapy results (including lifesaving effects) were also noticed in other diseases.

Aged↗

PubMed1987

Pulmonary tuberculosis treated with isoprodian and rifampicin or pyrazinamide.

Three regimens of 9 months' duration, 2 containing Isoprodian (isoniazid, prothionamide and dapsone) and either rifampicin or pyrazinamide and the third, a former standard regimen, isoniazid, streptomycin and pyrazinamide, were allocated at random to 436 untreated African tuberculosis patients. In the course of the trial 83 were excluded for various reasons and 93 were lost. After 3 months of hospitalization, patients took either Isoprodian or isoniazid at home for 6 months and were then followed up for 24 months. The Isoprodian plus rifampicin regimen achieved 97% bacteriological cure, the Isoprodian plus pyrazinamide regimen 86% and the standard regimen 91%. Of 35 patients found to harbour drug-resistant strains 22 were cured. There were 15 relapses in all. Absconding was the most common cause of failure.

Adult↗

PubMed1991

A case of relapse with drug-susceptible M. leprae after multidrug therapy.

A male born in 1930 was diagnosed as smear-positive borderline leprosy in 1971, and was treated with dapsone and/or sulfamethoxypyridazine from 1972 to 1980 with clinical improvement. However, new skin lesions with smears strongly positive appeared in August 1980, and he was diagnosed as having downgraded to lepromatous (LL) leprosy, but the bacilli recovered from the skin biopsy were fully susceptible to both dapsone and rifampin by mouse foot pad technique. Between 1981 and 1983, the patient was treated with 24 months of rifampin 600 mg and dapsone 100 mg daily, supplemented with prothionamide 500 mg daily during the initial 3 months, and his skin lesions gradually improved during treatment with the combined regimen. Afterward, the patient was kept under surveillance without treatment. From 1984 to 1986, his skin smears were negative, and no bacilli could be found from a skin biopsy taken in 1985. Then in 1987, 52 months after stopping treatment, new skin lesions appeared with a high concentration of Mycobacterium leprae (2 x 10(6)/mg tissue). The drug-susceptibility test again demonstrated that the organisms were fully susceptible to both dapsone and rifampin. Apparently the relapse was due to remultiplication of drug-susceptible persisters.

Adult↗

PubMedDate not supplied

[Clinical and bacteriological assessment 8 years after triple-drug therapy for multibacillary leprosy in Senegal].

Increasing resistance to dapsone (DDS) leads to recommend triple drug chemotherapy (TCT) in multibacillary leprosy (ML). To determinate long term evolution, we evaluated patients who received TCT 8 years ago. Between 1974 and 1976, 30 patients with ML received TCT (rifampicin, prothionamid, and DDS) during 6 or 12 months. At this time satisfactory clinical and bacteriological findings were reported, and from then DDS was given alone. Twelve of the thirty patients have been evaluated in 1983. Six patients had bacteriological index greater than or equal to 2+, three of them had clinical relapse. Seven of the twelve patients did not take regularly DDS; the six relapses belong to this group.

Adolescent↗

PubMed1987

[Fulminant liver failure in tuberculostatic therapy. A contribution to clinical aspects and pharmacokinetics].

A 23-year old female patient on a prolonged regimen of tuberculostatic chemotherapy finally developed fulminant hepatic failure shortly after addition of hormonal contraception. The pathophysiology of this almost fatal drug reaction is described as a pharmacokinetic interaction: the inherent hepatotoxicity of prothionamide-the drug finally prescribed during convalescence-was significantly potentiated by the Cyt-P-450-inducing effect of the progestagen component of the hormonal contraceptive. Potentiation of hepatotoxicity in connection with tuberculostatic regimes containing rifampicin is well known and this pharmacokinetic phenomenon also pertains to the combination with other Cyt-P-450-inducing drugs such as, for instance, anticonvulsants. However, since the maximum of rifampicin-related Cyt-P-450-inducing effect is limited to the initial 2-3 weeks of therapy, the hepatotoxic risk triggered by this rifampicin-related induction may decline during continuation of therapy. This, unfortunately, does not pertain to the other Cyt-P-450-inducers, whose inductive effect is not time-limited. Progressive severe hepatic damage may follow from such interaction as demonstrated in this case report.

Adult↗

PubMed1987

Feasibility of multidrug therapy (MDT) in Hansen's disease in an urban population--Curupaiti State Hospital, Rio de Janeiro, Brazil.

The acceptance of the WHO regimen in a group of 220 patients was approximately 84.5%. Only 11% abandoned the treatment, and the substitution of ethionamide or prothionamide for clofazimine due to excessive hyperpigmentation was necessary in only eight cases. The WHO regimens adopted provided a more frequent (monthly) relationship between the patients and their health service. It was necessary to: a) reorganize the technical-administrative infrastructure, with the intention of providing an improved service to the patients for treatment and control; and b) pay more attention to the problem of deformities and health education activities. As for the side effects of the drugs, 54 patients showed alterations in their liver function tests, which were usually mild and which resolved despite continuation of the treatment. Of the reactional episodes observed during MDT, it would not appear that the therapeutic regimens contributed to their occurrence or aggravation.

Adolescent↗

PubMed1979

[Isoprodiane therapy for previously untreated cavitating pulmonary tuberculosis (author's transl)].

Isoprodiane (a combination of isoniazid, prothionamide and dapsone) was given to 22 persons with open cavitating pulmonary tuberculosis. None of them had been treated before. Microscopic and cultural sputum conversion occurred within an average of 5 and 11 weeks respectively. Treatment was discontinued in five patients: as a safety measure, despite sputum conversion, on account of the extent of the process and the general condition of the patient (one case); because of side-effects (two cases, one of whom was hypersensitive to isoniazid); because the patients failed to continue with the treatment (two cases). The early results were very promising; the long-term results cannot yet be assessed. The therapy did not materially affect the haemoglobin levels.

Adolescent↗

PubMed1983

Application of the ammonia gas-sensing electrode: determination of drugs having a carbothionamido group by decomposition with acid.

A method to determine drugs having a carbothionamido group using an ammonia gas-sensing electrode is described. To obtain analytical accuracy, the effect of factors that influence the potential is also discussed. Ethionamide or prothionamide was refluxed with 20% HCl to give ammonium chloride, hydrogen sulfide, and a carboxylic acid. The ammonia, which evolved at pH greater than 11, was determined. A linear calibration plot was obtained within the drug concentration range of 2 X 10(-5)--1 X 10(-2) M.

Amides↗

PubMed1989

Pharmacochemical aspects of leprosy. Recent developments and prospects for new drugs.

From a pharmacochemical point of view the existing anti-leprotics as well as possible innovations in the chemotherapy of leprosy are discussed. Of the main anti-leprotics, which are used nowadays--dapsone, rifampicin, clofazimine, isoniazide, ethionamide and prothionamide--the mechanism of action, the main problems in their application and possibilities to develop improved variants are reviewed. Based on the chemistry of Mycobacterium leprae, the target systems for new anti-leprotics are identified. These systems include the cell wall, the catabolism of reactive oxygen species, the metabolisms of carbon sources, the amino acid metabolism and the uptake of iron. Two possible new lead structures from other fields, 4-quinolones and mycobacterial ribonucleotide reductase inhibitors are presented.

Dapsone↗

PubMed2005

Effect of antituberculous drugs on human polymorphonuclear leukocyte functions in vitro.

The aim of the study was to investigate antituberculous drugs effects on polymorphonuclear leukocyte (PMN) functions (phagocytic activity and intracellular killing activity) in vitro. PMNs obtained from healthy volunteers were incubated with antituberculous drugs (isoniazid [INH], rifampin [RIF], pyrazinamide [PZA], ethambutol [EMB], streptomycin [S], amikacin [A], ofloxacin [OFLX], prothionamide [PTH] and cycloserine [CyC]) and different combinations at therapeutic serum concentrations. Phagocytic activity of PMNs was significantly increased when compared with controls by PTH (p<0.001), A (p<0.001), OFLX (p<0.001), INH+RIF+S combination (p<0.01), A+OFLX combination (p<0.05), A+OFLX+CyC combination (p<0.01) and A+OFLX+CyC+PTH+EMB combination (p<0.01). Intracellular killing activity of PMNs was significantly increased by OFLX when compared with the control (p<0.05). No significant difference was observed in functions of PMN for other drugs when compared with control (p>0.05). Functions of PMN were significantly increased by OFLX when compared with A+OFLX combination (p<0.05). Phagocytic activity of PMNs was significantly increased by A+OFLX+CyC combination and A+OFLX+CyC+PTH+EMB combination when compared with A+OFLX+CyC+PTH combination and A+OFLX+CyC+PTH+PZA combination (p<0.05). No significant difference was found in functions of PMN between the other groups (p>0.05). In conclusion, some antituberculous drugs alone or in combination enhanced PMN functions, although in combination no additive or synergistic effects were detected. Moreover, none of the antituberculous drugs alone or in combination significantly decreased PMN functions. The drugs having adverse effects on immune functions would better be replaced with equally effective drugs or drug combinations having positive effects on PMN functions.

Antitubercular Agents↗

PubMed1996

Bronchopulmonary infection with Mycobacterium malmoense presenting as a bronchoesophageal fistula.

We report a bronchopulmonary infection with Mycobacterium malmoense in a patient with severe immunosuppression due to insulin-dependent diabetes mellitus, humoral immunodeficiency after thymoma (Good's syndrome) and prolonged immunosuppressive treatment after myasthenic crisis. It presented as non-resolving pneumonia of the left lower lobe. Bronchoscopically, a bronchoesophageal fistula was detected. Numerous acid-fast organisms were found in the sputum specimen and in the bronchial biopsy around the fistula. M. malmoense was isolated from sputum, bronchoalveolar lavage and bronchial biopsy. Whereas conventional in vitro susceptibility testing revealed susceptibility only to ethambutol, multi-drug susceptibility testing confirmed susceptibility to rifampicin, ethambutol, clarithromycin and prothionamide. The clinical outcome after 12 months of therapy resulted in a stable remission and considerable suppression of the mycobacterial load, but not in complete eradication.

Aged↗

PubMed1994

[Incompatibility of tuberculosis therapy in a patient with AIDS].

A man with advanced HIV infection (CD4 lymphocytes 90/microliter, CD4/CD8 ratio 0.2) was admitted to hospital with fever, cough and weight loss. The radiological and bronchoscopic findings, together with the presence of acid-fast bacilli in the sputum, pointed to open pulmonary tuberculosis caused by Mycobacterium tuberculosis, a diagnosis confirmed by histological examination and culture. Quadruple antibiotic therapy with isoniazid (INH), rifampicin (RMP), ethambutol (EMB) and amikacin was immediately begun and was at first clinically successful. Ten days later, however, a rash appeared; it was ascribed to RMP (anaphylactoid reaction after re-exposure). All the other first-line drugs tried during the ensuing eight months evoked severe adverse reactions (INH: rash and itching; amikacin: hearing impairment and tinnitus; EMB, pyrazinamide, prothionamide, p-aminosalicylic acid: rash and itching). Treatment was nevertheless clinically and microbiologically successful, and the patient insisted upon a 2 1/2 months' rest without therapy. This period was followed by extrapulmonary spread (severe arthritis of the elbow) and recurrence of pulmonary tuberculosis. The tubercle bacilli were sensitive to all the drugs so far employed. Renewed and lasting control of the infection was achieved only by continuous administration of steroids (prednisolone 10 mg twice daily) in conjunction with an unconventional antibiotic regimen consisting of amikacin, protionamide, terizidone, clarithromycin and sparfloxacin for some five months. Because of an episode of cerebral convulsions during treatment of cytomegalovirus retinitis with ganciclovir, the terizidone was discontinued (it was suspected of interacting with ganciclovir). The patient has had no more fits and sputum culture has remained negative for six months.

AIDS-Related Opportunistic Infections↗

PubMed1999

Mycobacterium of an unknown strain causing a primary tumoral process of the orbital roof.

PURPOSE. To report an unidentified species of atypical Mycobacterium as the causative agent of a primary orbital roof infection. METHOD. Review of a case from the King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. RESULTS. The patient had a negative history for eye trauma. Computed tomography (CT) of the brain and right orbit confirmed the presence of soft tissue swelling and erosive changes in the orbital roof bone, with intact globe and external ocular muscles. Biopsy of the lesion showed non-caseating, granulomatous osteomyelitis. Various stains of the sample were negative. Since our institution could not identify the causative organism, a biopsy sample was sent to Bioscientia Laboratory in Germany; the culture grew an atypical Mycobacterium of unknown species. Their sensitivity study showed the organism to be resistant to pyrazinamide, isoniazide and streptomycin, but sensitive to rifampicin, ethambutol, and prothionamide. Systemic checkup and investigation ruled out any other systemic involvement. CONCLUSION. A new species of atypical Mycobacterium was recovered from a primary orbital infection. The infection responded to combined antituberculous therapy.

Journal Article↗

PubMed1997

Mycobacterium hassiacum sp. nov., a new rapidly growing thermophilic mycobacterium.

A new rapidly growing, scotochromogenic mycobacterium was isolated from urine. This strain is thermophilic (it grows at 65 degrees C), tolerates 5% NaCl, and was unable to utilize any of the sugars tested or citrate or to take up iron. The isolate splits benzamide, urea, nicotinamide, and pyrazinamide and is sensitive to streptomycin, ethambutol, cycloserine, ciprofloxacin, and chlarithromycin but resistant to isoniazid, rifampin, and prothionamide. These characteristics clearly place this organism in a new mycobacterial species, which was confirmed by the unique 16S rRNA nucleotide sequence. The high level of similarity between this rapid grower and Mycobacterium xenopi is surprising. For this new rapidly growing scotochromogenic and thermophilic mycobacterium we propose the name Mycobacterium hassiacum sp. nov.

Bacteriological Techniques↗

PubMed1998

Mycobacterium bohemicum sp. nov., a new slow-growing scotochromogenic mycobacterium.

A new, slow-growing, scotochromogenic mycobacterium was isolated from sputum of a 53-year-old patient with Down's syndrome suffering from tuberculosis. Growth occurred at temperatures between 25 and 40 degrees C with an optimum at 37 degrees C. This strain had surprisingly few enzymic activities (only positive for 68 degrees C heat-stable catalase and weakly positive for urease) and was sensitive to prothionamide, cycloserine, clarithromycin, gentamicin and amikacin but showed resistance to isoniazid, streptomycin, ethambutol, rifampin and ciprofloxacin. These characteristics assign this organism to a novel mycobacterial species characterized by a unique 16S rDNA nucleotide sequence. The name Mycobacterium bohemicum sp. nov. is proposed for this new, slow-growing, scotochromogenic mycobacterium. The type strain is DSM 44277T.

Base Composition↗

PubMed1980

An evaluation of the potential use of isoniazid, acetylisoniazid and isonicotinic acid for monitoring the self-administration of drugs.

1. The possibility of using minute doses of the antituberculosis drug isoniazid (INH) or of its metabolites acetylisoniazid (AcINH) or isonicotinic acid (INA) as innocuous markers for monitoring patient compliance has been investigated. 2. The ingestion of these colourless and tasteless compounds can readily be demonstrated using a sensitive and specific colorimetric method for detecting INA and its metabolite isonicotinylglycine (INAG) in the urine that is rapid and simple to perform. 3. Studies on the kinetics of the urinary elimination of INA and INAG after the ingestion of 6 mg doses of either INH, AcINH or INA by small groups of volunteers indicated the potential suitability of INH or AcINH for monitoring daily or twice-daily self-medication and the appropriateness of INA as a marker for investigating the compliance of drugs prescribed for thrice-daily ingestion. 4. More extensive studies showed that over 99% of the urine samples collected within 18h of dosage with 6 mg INH would give positive results when tested for the presence of INA and INAG, and that doses of 2-6 mg INH could readily by incorporated into capsules or tablets and used as markers for monitoring the ingestion of the antituberculosis or antileprosy drugs dapsone, thiacetazone, ethionamide or prothionamide, or the antihypertensive oxprenolol. Such doses are less than a fiftieth of the normal therapeutic INH dose used in the treatment of tuberculosis. 5. Evidence is presented that INH, AcINH and INA possess most of the characteristics that one would hope to find in a marker for monitoring compliance including very limited inter-individual variability in the rates at which they are converted to the compounds being detected in the urine.

Glycine↗

PubMed1994

An international randomized study with long-term follow-up of single versus combination chemotherapy of multibacillary leprosy.

A total of 307 patients with lepromatous leprosy and borderline lepromatous leprosy were randomized to dapsone monotherapy or to one of two types of drug combinations. A 3-year treatment phase was followed by a 5-year observation phase. The evaluation included 233 patients for whom together there were 1,404 years of observation. A total of 1,956 blinded histopathological specimens were processed centrally. When entering the trial isolates from 13 patients (5.6%) showed dapsone resistance in the mouse footpad test, and these patients were evaluated separately. Dapsone monotherapy (68 patients) had the same frequency of cure as the combination of dapsone and rifampin (77 patients) or the four-drug regimen consisting of dapsone, rifampin, isoniazid, and prothionamide (75 patients). We did not find a significant difference in the clearance of bacteria either between the monotherapy and the two-drug combination or the monotherapy and the four-drug combination. Six months after the initiation of treatment, disease in 15% of the patients who received dapsone monotherapy but none of the patients who received combined treatment were clinically progressive. After another 1 to 9 months of treatment the disease in all patients was stable or regressive. There was no difference in the type or frequency of reactions. Only after the end of the scheduled observation phase three relapses were reported. All three treatment regimens well tolerated. Dapsone monotherapy is highly effective in the treatment of multibacillary leprosy under the conditions of well-controlled treatment. Combination regimens seem only to accelerate the regression of the active disease when they are compared with monotherapy with dapsone. The mouse footpad test does not reflect the clinical resistance and cannot be recommended for use in making therapeutic decisions.

Adolescent↗

PubMed2006

Evaluation of MGIT 960-based antimicrobial testing and determination of critical concentrations of first- and second-line antimicrobial drugs with drug-resistant clinical strains of Mycobacterium tuberculosis.

The objectives of this study were to (i) compare agreement of the MGIT 960 system for first-line drugs with a methodology (the resistance ratio method [RRM]) that had been used in clinical trials, relating drug susceptibility to clinical outcome; (ii) compare the performance of the MGIT 960, RRM, and microtiter plate assay (MPA) methodologies for second-line drug testing; and (iii) define critical concentrations for ciprofloxacin and moxifloxacin for liquid-culture-based testing. The large collection of clinical isolates of Mycobacterium tuberculosis (n = 247) used included 176 (71%) multidrug-resistant isolates. The results for MGIT 960 and the RRM for rifampin and isoniazid (n = 200) were in excellent (99 to 100%) agreement for all strains. For streptomycin, 97% of the results at the critical concentration and 92% at high concentration, and for pyrazinamide 92% of results overall, were concordant, but for ethambutol, fewer than 85% (65% for the critical concentration and 84% for the high concentration) of the MGIT-based results were concordant with those for the RRM. The MGIT 960, RRM, and MPA assays (n = 133) correlated well for most second-line drugs tested. For susceptibility to ofloxacin, the MGIT 960 and MPA results were in full agreement. The amikacin and rifabutin results obtained by MGIT 960 agreed with the RRM results in 131 (99%) cases, and for capreomycin, they agreed for 129 of 133 isolates tested (97%). For prothionamide testing, only a limited number of drug-resistant isolates were available for testing and drawing definitive conclusions. We propose critical concentrations of 1.0 microg/ml and 0.125 microg/ml for ciprofloxacin and moxifloxacin, respectively, for liquid-culture-based testing.

Antitubercular Agents↗