In 1979, the Brazilian government, through a national mobilization against tuberculosis, has established the following treatment regimens: Rifampicin (R), Isoniazid (H) and pyrazinamide (Z) - treatment regimen 1 (TR-1) -; and Streptomycin (S), Pyrazinamide (Z), Ethambutol (EMB) and Ethionamide (ETH) - treatment regimen 3 (TR-3).
The TR-1, a first-line regimen, has a high effectiveness, healing around 97,8% of patients with active pulmonary tuberculosis, when used in appropriate form, while the TR-3 is a reserve regimen.
At first, the TR-1 was also recommended for retreatment of both abandon and recurrence cases, while the TR-3 was recommended in cases of TR-1 failure or due to adverse effects of the same.
In 1992, Gerhardt and col., demonstrated that the incidence of TR-1 failure in retreatment was more common than the incidence of TR-1 failure in naive patients (7,4% and 1,7% respectively). So, it was proposed that a fourth drug should be added to the TR-1 as reinforcement, ethambutol or streptomycin (TR-2).
Today, after 18 years of treatment with TR-1 and TR-3, there is a considerable portion of patients with active pulmonary tuberculosis, caused by all regimens resistant bacilli.
It is important to be clear that MDR-TB neither has different clinical findings, compared with non MDR-TB, nor a different infectious agent. The MDR M. tuberculosis is the Koch bacilli that was selected due to inappropriate use of antibiotics.
Researches have shown that the MDR bacilli transmission is the same as the non MDR one, although there are evidences suggesting a major susceptibility of HIV-positive patients.
There is not agreement about the MDR-TB concept. For example, in USA, a resistance to both R and H, is classified as multiple drug resistant. In Brazil, beyond the resistance to R and H, the bacilli must also be resistant to S and/or EMB. Thus, there is resistance to the best regimens, and the treatment becomes very difficult.
We classify the resistance of Mycobacterium tuberculosis to the most common used drugs as primary and acquired. The last, which is the most prevalent type of resistance in developing countries, refers to resistance in a patient whose bacilli were previously sensitive to the regular treatment. It usually happens as a consequence of giving up the therapy before the schedule, so there is the persistence of infection with selected mutant stains (table-1). It is also related to wrong prescription of drugs by the physicians, incorrect use by the patient, or constants modifications on the therapy owed to toxicity of the drugs. As primary resistance, which is the most common form in rich countries, refers to the infecting and making ill of a previously healthy patient from a contact to a person who has MDR tuberculosis, happening usually in prisons, shelters for homeless, hospitals and HIV+ patients.
The current mechanism for the emergence of multiresistants stains, which is a major health problem in our days, is not due to new mechanisms of resistance, but related to mechanisms that we already know (for M. tuberculosis), i.e., mutations on target genes for the antibiotics. The resistance to isoniazid (the most common resistance to first line drugs) is most commonly related to a change on the kat G gene (catalase/peroxidase), and is also responsible for resistance to ethionamide. Resistance to rifampicin is associated to mutation on rpo B gene, and to streptomycin to the genes rps L and rrs. Resistance to rifampicin is most found in association to resistance to isoniazid.
| Drug | Concentration of culture medium (mcg/ml) |
Natural resistance |
|---|---|---|
| R | 40 | 1 mutant(r) in 107 bacilli |
| H | 0,2 | 1 mutant(r) in 104 bacilli |
| EMB | 2,0 | 1 mutant(r) in 105 bacilli |
| S | 4,0 | 1 mutant(r) in 104 bacilli |
| ETH | 20,0 | 1 mutant(r) in 10³ bacilli |
| Z | 25,0 | 1 mutant(r) in 10³ bacilli |
There is suspect of MDR-TB, when both TR-1 and TR-3 fail.
Failure is meant by the demonstration of acid-fast bacilli on sputum smear at the end of treatment. There is failure also when the sputum smear is strongly positive until the fourth month of treatment, or when there is an initial sputum smear positive, followed by a negative and a new positive test, for 2 consecutive months, since the fourth month. An isolated finding of bacilli at the fifth or sixth month of treatment, does not, necessary, mean resistance, and new exams must be done for a better evaluation.
If there is a suspect of MDR-TB, both culture of bacilli and drug susceptibility tests should be used to guide subsequent therapy.
There is no agreement about the most effective treatment for the multiresistants stains. While newer drugs are in development, basic principles were stippled to rule how to deal with these patients. These principles are: use of at least 4 different drugs, with different mechanisms of action, use of first line drugs if the sensitivity test does not show resistance, and treat for at least 12 months or 6 months after a negative culture or sputum. In Brazil, where we use basic scheme and a reserve one, the conception of resistance is referred to inefficacy of the scheme III (S, ETH, EMB, Z), the ICF from São Paulo city had good results when using a scheme which consists of a aminoglicoside for 6 months (streptomycin if possible, amicacine or kanamicine), a quinolone for 12 months (ciprofloxacine or ofloxacine), clofazine and tiossemicarbazine. In the USA, where multiresistance is resistance to rifampicine and isoniazide, the treatment of choice is the use of at least two drugs that show effectiveness on the culture specimen. The ATS/CDC recommends reinforced treatment (RIPS or RIPE) for all new case of TB in regions where primary resistance to rifampicin and isoniazid is higher than 4%. For untreatable cases by drugs, there is the possibility of surgical intervention, if the lesions are limited and the patient is well preserved. The prevention of MDR-TB is still the most important factor for the control of this problem (early diagnosis, transmission control measures and appropriate treatment for all new cases of tuberculosis).
The appropriated treatment increases the survival rates in patients who are HIV- and HIV+. A better prognosis is related to presence of caverns, absence of extra-lung or disseminated disease and a negative serology for HIV.
Today, the most important point for MDR-TB control is to avoid acquired resistance, instead of alternative drugs or new technical issues.
At first, measures should be taken for preventing MDR-TB.
1-) Combat the irregularity and abandon;
2-)use a reinforced TR-1 with ethambutol or streptomycin in retreatment cases;
3-)hospitalization for therapy, if a patient is incapable of self care;
4-)establish commitment and guidance for household protection;
5-)engineering controls (such as ventilation systems and ultraviolet irradiation) in hospitals and ambulatories;
6-)private room for hospitalized patient;
7-)personal respiratory protective equipment, including high-efficiency particulate (HEPA) respirators.
1) Beate Heym, Nadine Honoré, Chantal Truffot-Pernot, Asesh Banerjee, Catherine Schurra, William R. Jacobs Jr., Jan D. A. van Embden, Jacques H. Grosset, Stewart T. Cole: Implications of multidrug resistance for the future of short-course chemotherapy of tuberculosis: a molecular study. Lancet (1994); 344: 293-98.
2) B. P. Vareldzis, J. Grosset, I. de Kantor, J. Crofton, A. Laszlo, M. Felten, M. C. Raviglione, A. Kochi: Drug-resistant tuberculosis: laboratory issues. Tubercle and Lung Disease (1994); 75: 1-7.
3) Maryann M. Park, Anne L. Davis, Neil W. Schluger, Henry Cohen, William N. Rom: Outcome of MDR-TB Patients, 1983-1993: Prolonged Survival with Appropriate Therapy. Am J. Respir. Crit. Care Med. (1996);153: 317-24.
4) Fiuza de Melo, FA; Ide Neto, J; Seiscento, M; Pinto, JA; Afiune, JB: Tuberculose multirresistente. J. Pneumol. (1993); 19(1): 73-82.
6) Brasil. Ministério da Saúde. Secretaria Nacional de Programas Especiais de Saúde. Divisão de Pneumologia Sanitária. Campanha Nacional Contra a Tuberculose.: Controle da tuberculose: uma proposta de integração ensino-serviço / CNCT/NUTES. - 4a ed. - Brasília, 1994.
7) Current Medical Diagnosis & Ttreatment 1997. 36th Edition.
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