LETTER TO THE EDITOR
Early bactericidal activity: a dependable and necessary methodology
Moises Palaci; David Jamil Hadad; Valdério do Valle Dettoni; Reynaldo Dietze
Center for Infectious Disease/Biomedical Center, Universidade Federal do Espírito Santo
Tuberculosis worldwide presents a major challenge for public health. In Brazil the yearly rate of incidence is of 51.3 / 1000,000 persons (MINISTRY OF HEALTH, 2002). According to STYBLO (MINISTRY OF HEALTH, 2002) this incidence of tuberculosis would be reduced if at least 70% of sputum smear - positive patients were diagnosed and of these, at least 70% were cured. Otherwise this endemic disease will continue to be uncontrolled.
In Brazil, patients are treated with short duration chemotherapy for six months which includes rifampicin, isoniazid and pirazinamide during the first two months followed by rifampicin and isoniazid in the next four months. Use of these drugs during the last four months is justified, because of their action on intracellular slow growth bacilli as well as on those of intermittent growth found in caseous necrosis, which is essential for the successful sterilization of tissue lesions (MINISTRY OF HEALTH, 2002).
Short duration chemotherapy is highly effective achieving up to 95% of remission (MINISTRY OF HEALTH, 2002). Nevertheless six months are too long a period to ensure a high rate of adherence. Therefore, identification of new drugs that will permit to shorten treatment time is a priority for tuberculosis control programs worldwide.
The primary objective of clinical trials for the evaluation of new drugs or therapeutic schemes for treatment of tuberculosis is the cure with no recurrence in the two years after completion of treatment. The 95% rate of cure sought with short duration chemotherapy is a challenge to clinical trials because of the considerable sample size required to prove statistical significance among control (combination of three drugs) and test (with addition of the new drug) groups. The large number of patients to be included and the need for at least two years of follow-up are responsible for the long duration and high financial costs of these trials, both aspects not attractive for the pharmaceutical industry. Faster and less expensive methodologys are being developed for the rapid evaluation of new drugs. Early bactericidal activity (EBA) represents one of these methods (MITCHISON, 1993).
Early bactericidal activity consists of quantifying the bacillary load (number of colony forming units [CFU] in a solid culture medium) present in the sputum smears collected over 12 hours (7.OO P.M - 7.OO AM) during the first two days of treatment. This is based upon the fact that decrease of the number of CFU during the first two days is statistically related to the efficacy of the therapeutic schemes used and represents a clinical parameter of decrease of infectiousness (JINDANI et cols, 1980, KENNEDY et cols, 1993). Studies of EBA may be used to compare the action of various doses of a drug, different drugs in the same class and different classes of drugs. Therefore such studies represent a preliminary stage useful for obtaining quick information on the action of a drug in human beings with tuberculosis (JINDANI et cols, 1980; MITCHISON, 1998).
Sterilizing tissue activity of an anti-tuberculosis drug is calculated measuring the rate of decrease of the bacillary load. This type of analysis is called prolonged study of the EBA. This procedure is based upon a recent study of the EBA of isoniazid orally administered in daily doses of 300mg and of 18.5 mg. of rifampicin 600 mg and of moxifloxacin 800 mg over five days. The EBA of isoniazid practically disappeared after two days of administration. On the contrary, the bactericidal activity of rifampicin persisted for at least five days (SIRGEL et cols. 2000).
Patients with positive sputum smear not previously cared for are treated with a drug, usually for seven days. The amount of sputum the patient is able to produce is collected daily during 12 to 16 hours This sputum samples are submitted to quantitative cultures. Patients with hemptysis and severe forms of tuberculosis such as miliary disease or meningoencephalitis that demand urgent therapeutic action are not eligible. After the seven days of continued oral use of the drug patients must complete the standard short duration chemotherapy. Prior to treatment and at the end of the study a sensitivity test to drugs is usually performed.
It is now a priority to call the attention of the international scientific community to the need of studies on the EBA of antimicrobial drugs. This represents a quick research methodology to select the must promising drug for addition to an antimicrobial scheme (GILLESPIE et cols, 2003).
For the last few years, EBAs of anti-tuberculosis drugs that were given alone or combined were studied. Such procedure permits the exact quantification of the number of colony forming units by milliliter of sputum and the quantification of the antimicrobial activity of each drug on the lung during the time interval.
Studies of EBA may theoretically increase the risk of acquired resistance to the drugs studied by means of the selection of naturally resistant bacilli found in the microbial load (MINISTRY OF HEALTH 2002). Studies carried out prior to the polychemotherapy era led to appearance of resistance after 20 days use of streptomycin as monotherapy in 109 patients with lung tuberculosis treated in clinical trails funded by the BRITISH MEDICAL RESEARCH COUNCIL (1948). With regard to monotherapy with isoniazid, TOMAN (1980) described the appearance of resistance to this drug only after six weeks of usage.
If the various studies on EBA published during the last 22 years are taken into account .there was no reported case of acquired resistance after use of the drug for a period from 2 days to 2 weeks (JINDANI et cols, 1980; DIETZE et cols, 2001; DONALD et cols, 2001; DONALD et cols, 2001; Donald et cols, 2001; Donald et cols, 2002). This time interval was insufficient to select bacilli naturally resistant to the drug considering the slow replication of M. tuberculosis (18-24 hours). Therefore, as GILLESPIEI et cols (2002) remarked, the study of EBA of an antimicrobial drug represents an ethically justified study because there is no risk of resistance induction during the short period of drug administration.. Currently, moxifloxacyn, gatifloxacyn, levofloxacyn and linezolide (oxazolidinone) seem to be the most promising drugs with activity against M.tuberculosis (GOSLING et al. 2003).
In summary, performance of studies comparing the EBA of these drugs with that of isoniazid in lung tuberculosis and sputum smear- positive patients, is absolutely mandatory. Such studies will permit the international scientific community to quickly choosen the best antimicrobial association to be utilized in clinical trials for shortening of treatment.
References
1. Brasil. Ministério da Saúde. Fundação Nacional de Saúde. Centro de Referência Prof. Hélio Fraga. Sociedade Brasileira de Pneumologia e Tisiologia. Controle da tuberculose: uma proposta de integração ensino-serviço. 5° ed. 2002.
2. British Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. A Medical Research investigation. Brit Med J 1948; 2:769-783.
3. Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, Rose L, Eisenach K, Ellner JJ. Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob Agents Chemother 2001; 45:1972-1976.
4. Donald PR, Sirgel FA, Venter A, Smit E, Parkin DP, Van de Wal BW, Mitchison DA. The early bactericidal activity of a low-clearance liposomal amikacin in pulmonary tuberculosis. J Antimicrob Chemother 2001; 48:877-880.
5. Donald PR, Sirgel FA, Venter A, Parkin DP, Van de Wal BW, Barendse A, Smit E, Carman D, Talent J, Maritz J. Early bactericidal activity of amoxicillin in combination with clavulanic acid in patients with sputum smear-positive pulmonary tuberculosis. Scand J Infect Dis 2001; 33:466-469.
6. Donald PR, Sirgel FA, Venter A, Smit E, Parkin DP, Van de Wal BW, Mitchison DA. The early bactericidal activity of amikacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2001; 5:533-538.
7. Donald PR, Sirgel FA, Venter A, Smit E, Parkin DP, Van de Wal BW, Dore CJ, Mitchison DA. The early bactericidal activity of streptomycin. Int J Tuberc Lung Dis 2002; 6:696-698.
8. Gillespie SH, Gosling RD, Charalambous BM. A reiterative method for calculating the early bactericidal activity of antituberculosis drugs. Am J Respir Crit Care Med 2002; 166:31-35.
9. Gosling RD, Uiso LO, Sam NE, Bongard E, Kanduma EG, Nyindo M, Morris RW, Gillespie SH. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med, 2003; 168:1342-1345.
10. Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 1980; 121:939-949.
11. Kennedy N, Fox R, Kisyombe M, Saruni OS, Uiso LO, Ramsey AR, Ngowi FI, Gillespie SH. Early bactericidal and sterilizing activities of ciprofloxacin in pulmonary tuberculosis. Am Rev Respir Dis 1993; 48:1547-1551.
12. Mitchison DA. Assessment of new sterilizing drugs for treating pulmonary tuberculosis by culture at 2 months. Am Rev Respir Dis 1993; 147:1062-1063.
13. Mitchison DA. Basic concepts in chemotherapy of tuberculosis. Em: Gangadharam PRJ; Jenkins PA eds. Mycobacteria 11 Chemotherapy. New York: Chapman Hall 1998; 15-50.
14. Sirgel FA, Donald PR, Odhiambo J, Githui W, Umapathy KC, Paramasivan CN, Tam CM, Lam KM, Lam CW, Sole KM, Mitchison DA, EBA Collaborative Study Group. A multicentre study of the early bactericidal activity of anti-tuberculosis drugs. J Antimicrob Chemother 2000; 45:859-870.
15. Toman K. Organización Panamericana de la Salud. Tuberculosis Deteccion de casos y quimioterapia. Publicacion Científica 1980; 392.
Publication Dates
-
Publication in this collection
17 June 2004 -
Date of issue
Apr 2004
