Current problems with tuberculosis treatment

]0

13th FOtfUM hV MICROBIOLOGY

Shoeb, II.A., Bowman, B.U., Jr., Ottolenghi, A.C & Merola, A.J. (I 985b), Evidence for the generation of active oxygen by isoniazid treatment of extracts of Mycobacleriura tuberculosis H37Ra. Antimicrob. Agents Chcmother., 27, 404-407. Subbaiah, T.V., Mi!chison, D.A. & Selkon, J.B. (1960), The susceptibility to hydrogen peroxide of Indian and British isoniazid-sensitive and isoniazid-resistant tubercle bacilli. Tubercle, 41,323-333. Takiff, H.E., Salazar, L., Guerrero, C., Philipp, W., Huang, W.M., Kreiswirth, B., Cole, S.T., Jacobs, W.R., Jr. & Telenti, A. (1994), Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB and detection of quinolone resistance mutations. Antiraicrob. Agents Chemother., 38, 773-780. Telenti, A., Imboden, P,, Marchesi, F., Lowfie, D., Cole, S., Colston, M.J., Matter, L., Schopfer, K. & Bodmer, T. (1993a), Detection of rifampicin-resistanee mutations in Mycobacterium tuberculosis. Lancet, 341, 647-650. Telenti, A., Imboden, P., Marchesi, F., Schmidheini, T. & Bodmer, T. (1993b). Direct, automated detection of

rifampin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand eonformarion polymorphism analysis. Antimicrob. Agents Chemother., 37, 2054-2058. Williams, D.L., Waguespack, C., Eisenach, K., Crawford, J.T., Portaels, F., Salfinger, M., Nolan, C.M., Abe, C., Sticht-Froh, V. & Gillis, T.P. (1994), Characterization of dfampin resistance in pathogenic mycobaeteda. Antiraicrob. Agents Chemother., 38, 2380-2386. Winder, F.G. (1982), Mode of action of the anfimycobacterial agents and associated aspects of the molecular biology of the mycobacteria, in "l'he biology of the mycobacteria". (C. Ratledge & J. Stanford, vol. 1) (pp. 354-438). Academic Press, London. Zhang, Y., Garbe, T. & Young, D. (1993), Transformation with katG restores isoniazid ~cusifivity in Mycobacterium tuberculosis isolate:~ resistant to a range of drug concentrations. Mol Microbiol., 8, 521-524. Zhang, Y., Heym, B . Allen, B,, Young, D. & Cole, S. (1992), The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature (Lond,), 358, 591-593.

Current problems with tuberculosis treatment J. G r o s s e t Laboratoire Central de Bact~riologie-Virologie et Hygiene, Groupe Hospitalier Pitid-Salp~tri~re, 75651 Paris Cedex 13

T h e basis o f t u b e r c u l o s i s t r e a t m e n t

Tuberculosis is localized primarily in the lung, the main lesion bein G the pulmonary cavity, which c o n t a i n s a b o u t 10 ~ m y c o b a c t e r i a (~ 10 8 c f u ) (Canetti, !959). Among these organisms, which are normally drug-sensitive, there are drug-resistant mutants at a mean frequency of = 10 -6 (Canetti & Grosset, 1961). In the pulmonary cavity, a large bacillary population is located in the thin liquid caseous layer that covers the inner part of the cavity wall. These bacilli are extracellular and multiply actively because of the favourable oxygen tension and nutritive substances found in the cavity. In addition to the large population in the cavity, there are at least two other bacillary populations, one inside macrophages and another inside solid caseous foci, Both o f these populations are limited in size because

Received September 26, 1995.

e n v i r o n m e n t a l c o n d i t i o n s are u n f a v o u r a b l e f o r growth (Grosset, 1980). In the mid-1940s, when streptomycin (SM) was first introduced as chemotherapy for cavitary pulmonary tuberculosis, it was administered alone, with the result that, in 3 months' time, 80 % o f patients w e r e harbouring streptomycin-resistant organisms (Medical Research Council Investigation, 1948). The explanation o f such a phenomenon is simple: before treatment = ! 0 1- 10 2 streptomycin-resistant mutants were already present in the tuberculous c a r ity along with the 10 8 sensitive organisms, and these mutants were selected by the use of streptomycin. Soon it was understood that there was no hope o f curing cavitary tuberculosis with any single antimicrobial drug because it was impossible to prevent the selection of drug-resistant mutants under these

SOLVING THE DILEMMA OF ANTIMYCOBACTERIAL

circumstances. Suppression of resistant mutants became possible when para-aminosalicylic acid (PAS) (Lehmann, 1946) and isoniazid (INH) (Bernstein et al., 1952) became available in 1946 and 1952, respectively (Medical Research Council Investigation, 1950; Medical Research Council, 1962). In the early 1950s, the rule was to treat patients with a combination of available drugs. Because each drug was active against the mutants resistant to other drugs, the selection of drug-resistant mutants was prevented in the majority of cases (Medical Research Council, 1962). For chemotherapy to be a success, it must not only prevent drug resistance but also kill all, or almost all, of the drug-sensitive organisms to prevent their subsequent multiplicat,on and a resultant relapse after cessation of treatment. Because a small number of drug-sensitive organisms survived despite chemotherapy with the three-drug combination of INH+SM+PAS, 18-24 months of treatment were qecessary to permit the host defenses to eliminate persisting organisms. Despite such prolonged treatment, the relapse rate after discontinuation of treatment was -- 10% (Medical Research Council, 1962). A radical change occurred when rifampicin (RMP) became available (Grumbach and Rist, 1967). RMP was effective not only against actively multiplying organisms but also against the resting or persisting organisms responsible for relapses after treatment was stopped. RMP, in combination with INH and SM, effeeted the cure of almost 100% of patients in a treatment period of 9 months, i.e., half the time required with the three-drug combination of INH+SM+PAS (British Thoracic and Tuberculosis Association, 1976: Trial 6, 9, 12, 1977). A few years later, British Medical Research teams rediscovered the bactericidal activity of pyrazinamide, a very potent drug against organisms located in an acid environment, especially inside macrophages (Mackaness, 1956; East African/British Medical Research Councils, 1972); this property further increased the possible effectiveness of chemotherapy. These findings led directly to the recommendation by numerous health authorities (American Thoracic Society and the Centers for Disease Control, 1986; British Thoracic Society, 1984; Soci~t6 Franqaise de Pneumologie, 1984) of the 6month short-course of chemotherapy for tuberculosis that is presently used and becoming routine practice in many countries (Algerian Working Group/British Medical Research Council Cooperative Study, 1984; Chanlet, 1983; Farga et aL, 1983; American Thoracic Society, 1994). Problems with tuberculosis treatment in industrialized countries

Although standard 6-month chemotherapy is almost 100% effective whe~ adequately prescribed

CHEMOTHERAPY

1l

and taken by highly motivated persons who represent the majority of patients in developed countries, its effectiveness is substantially reduced when the drugs are delivered or taken inappropriately. This is the case for many patients in developing countries (Grzybowski and Enarson. 1978) and for those of the developed countries who live in socioeconomic conditions close to those prevailing in the developing world: many out-of-work and homeless persons, many HIV-infected individuals and drug addicts, and recent immigrants who have poor access to medical care. For these patients, because of the difficulties of diagnosis, drug supply and supervision of therapy, and also sometimes because of their social distress and the discouragement of some health-c~e providers, chemotherapy of tuberculosis is often a real disaster. More than 50% of patients are not cured, the tubercle bacilli become resistant to the drugs used, and because patients usually live in cro~vded conditions, their drug-resistant organisms may well be transmitted to their contacts. Such a situation raises four major concerns for tuberculosis management: social responsibility of the policy makers, the adequate delivery of chemotherapy, the treatment of drug-resistant tuberculosis, and prevention of the spread of drug-resistant organisms. To limit ,and. hopefully, reduce the current problems with tuberculosis treatment in industrialized countries, the following recommendations can be made.

Political commitment to assure effective treatment to all who need it

The difficulty of chemotherapy for tuberculosis in the developed wodd is not its implementation in the standard population but the dramatic deficit in the access to care and to drug supply and delivery of the most unfavoured groups of the population. Because the effective way of interrupting transmission of the tubercle bacilli in a population is prompt and effective chemotherapy of all existing sources of infection, good chemotherapy will benefit all of society and not only patients (Hopewell, 1994). To ensure good chemotherapy of tuberculosis for most deprived patients is therefore in the interest of all. If we limit our concern to treatment, we know well what should be done for these patients because it is exactly ~,hat has been done in all or almost all developed countries during the past 100 years and was strengthened 50 years ago when antituberculosis drugs became available: all means of diagnosis and treatment of tuberculosis, including institutional therapy, were free of charge and furthermore, in many countries, the patient's salary was assured during the whole course of treatment to overcome the potential conflict between the requirements of treatment and the financial support of the patient's

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13th FORUM IN MICROBIOLOGY

family. What was considered essential for the success of tuberculosis control in the 1950s when tuberculosis was endemic remains essential in the 1990s for all patients, especially those living in highly endemic areas. It is the duty of public health officers to make the policy makers understand the problem; because the problems are political and not medical, the solution is political. The need for some specialized clinics The role of specialized tuberculosis clinics in the delivery of chemotherapy in the present era of integration of care deserves careful consideration. Although there is no doubt that integrated care is beneficial for most parents and for the treatment of most diseases, it is important to remember that, in all developed countries, past successes in the control of tuberculosis have been obtained through strictly vertical programmes and that, in endemic countries where the tuberculosis control programme has been integrated, the control of tuberculosis has often been unsuccessful. Of course there are many other convincing reasons apart from integration that explain the failure of tuberculosis control programmes in such countries; nevertheless the advantages of tuberculosis clinics in highly endemic areas should not be underestimated. If patients suspected of having tuberculosis are referred to them, they can provide complex tuberculosis-related medical and social services. They can become engaged in directly observed therapy (DOT), which is of paramount importance for the success of chemotherapy and cannot be implemented by general serr'~ees because it is too t i m e - c o n s u m i n g and usually requires specialized staff (Hopewell, 1994; Frieden et aL, 1994). In addition, among their tasks tuberculosis clinics may assure not only treatment of HIVinfected tuberculosis patients but also all sorts of health counselling that these patients usually need. The active search for new drugs New antimicrobial drugs at~ needed - first, to shorten the present 6-month duration of chemotherapy, which is a serious obstacle to its effective implementation, and second, to treat patients with drug-resistant tubercle bacilli, especially those with bacilli resistant to the major antituberculosis drugs isoniazid and rifampicin. Often these patients also have organisms resistant to streptomycin, ethambutol and other drags, and only potentially toxic and poorly effective antituberculosis drugs remain active. Thus, new highly bactericidal dru~s, as active as isoniazid or rifampicin, are needed for effective treatment (Bates, 1995). The scientific prospects for developing new antituberculosis drugs

are good because of the accumulated knowledge of the biology of the mycobacterial cell, the high quality of the research, and several promising leads. The economic prospects are less bright because of the present limited funding by industrialized countries, the high cost (about US$150 million) of developing a new antituberculosis drug and the scarce financial resources of the countries with the great majority of pauents. There are at least two reasons for optimism. First, although the problem of multidrug-resistant tuberculosis is prominent in developing countries, it also exists in industrialized countries and is a challenge for physicians, scientists and, hopefully, politicians in these countries. It should result in concerted funding and scientific efforts by industrialized countries. Second, the search for new drugs active against Gram-positive and Gram-negative bacteria is continuing, and some of the newly developed drugs - the fluoroquinolones - are also active against M. tuberculosis. Therefore, systematic screening for antituberculosis activity of all newly developed antimicro.'-;al drugs, especially those that are lipophilie and active against Gram-positive organisms, is a priority. It would not be fair to minimize the present efforts to develop effective immunotherapy. These efforts should be encouraged by adequate funding. Measures to limit the diffusion of multidrug-resistant tubercle bacilli Since strains of M. tuberculosis with secondary multidrug resistance will continue to be selected despite the efforts to assure effective treatment of all newly detected cases, physical measures should be taken to limit their transmission to immunodeficient as well as immunocompetent contacts. The precise recommendations already made in this respect (Centers for Disease Control, 1992) should be followed as strictly as possible.

Current problems with tuberculosis in developing countries The global failure of tuberculosis control in the Third World Only those tuberculosis patients who received regularly an adequate combination of active drugs during a~. adequate length of time are cured (Grzybowski, 1993). Already, in the multicentre trial conducted by the International Union Against Tuberculosis (IOAT) b e t w e e n 1958 and 1960 (Etude intemationale sur refficacit6 de la chimiothErapie, 1964), 15% of the patients were lost to follow-up during the course of their treatment and could not be considered as cured. The overall rate of success of

SOLVING THE DILEMMA OF A N T I M Y C O B A C T E R I A L C H E M O T H E R A P Y

the tested treatment was therefore 85 %, i.e. much lower than the 100% rate observed among those infected with fully susceptible organisms, who complied with their treatment and had no drug sideeffects. In developing countries, where the resources are limited and the difficulties in organizing regular drug supply and drug delivery are unlimited, the rate of success among treated patients is often far inferior in routine conditions than that observed in the multicentre trial conducted by IUAT. For example, in a recent study (Datta et aL, 1993) conducted ;n SouLh India to assess the real efficacy of a district tuberculosis programme, only a little more than 40% o f patients took 80% or more of the prescribed drugs, while a slightly larger group took less than 50% of chemotherapy (table !). The fatality rate was e x t r e m e l y high, with o v e r 25 % o f the patient~. dying, while another 25 % remained bacteriologically postive. Resistance to antimicrobial agents was c o m m o n among the latter cases, with 50-60% of them e x h i b i t i n g resistance to INH and 12 % to rifampicin. As emphasized by S. Grzybowski (Grzybowski, 1993), these results are no better than would have been the case if no treatment whatsoever had been given. The causes o f such a disaster are multiple, but most likely related to non-compliance of the health staff with regulations governing treatment, and noncompliance o f patients with taking their medication, What holds true for the surveyed district of South India holds true as well for other regions o f the world with similar conditions, i.e. tbr a majority of developing countries. In addition to the difficulties in organizing the regular treatment o f the identified patients, it may be assumed that in the majority of developing countries only 40-50% o f new cases of tuberculosis are identiled and put on treatment (Centers for Disease Control, 1993). The~e patients are not treated mainly due to lack o f drug~ and also lack of diagnostic facilities. This explains why for the year 1990, the estimated incidence was 7.5 million, and an estimated 2.5 million deaths occurred from tuberculosis worldwide (Centers for Disease Control, 1993), As shown in

Table

I. Results of chemotherapy under a district tuberculosis programme.

Among 4,000 smear-positive patients 4 0 % took _> 80% of medication 4 0 % took less than 50% of medication - - Case-fatality rate: 25 % --Still bacteriologically positive: 25%, of which 5 0 - 6 0 % were resistant to isoniazid and 12% to rifampicin. From M. Datta et aI. (1993).

13

table I!, 78 % of the tuberculosis cases are in three regions of the word, namely southeast Asia, western Pacific and Africa, with a case-fatality rate of 35-40%! Compared with the 50-60% case-fatality rate ebserved before the antituberculosis drug era, the present 35-40% case-fatality rate of tuberculosis in these three regions of the world is not much better. It demonstrated that despite the existence of drugs able to cure 100% of patients when available and used adequately, the control of tuberculosis in the Third World is a complete failure. If active measures are not taken rapidly, one may expect the estimated number of tuberculosis cases worldwide to i n c r e a s e d r a m a t i c a l l y in the next ten years (table liD.

What is needed for improving the present situation ?

To control tuberculosis in the developing countries, the basic goals defined by the World Health Organization (WHO) are to cure at least 85 % of the detected new smear-positive tuberculosis cases and to detect at least 70% of existing cases. To cure the tuberculosis cases, WHO recommends that all countries with a tuberculosis problem provide standardized short-course chemotherapy. In addition, WHO states that priority should be given to achieving high cure rates before improving case finding, because the inverse would contribute to the tuberculosis problem by producing chronic cases and multidrugresistant tuberculosis. in practice, effective tuberculosis control requires a clear government commitment to a national tuberculosis programme based on case detection through predominantly passive case finding, regular drug supply, a strong organization assuring the regular drug intake by the patients and a monitoring system for programme supervision and evaluation. Several points o f the tuberculosis programme deserve careful consideration. First of all, it seems that only a limited number of public health managers understand that successful completion of therapy is the responsibility of the provider that undertakes to treat tuberculosis patients, and chemotherapy cmt be successful only within the framework of the overall clinical and social management of patients and their contacts. I should like to amplify upon that fact: not only should the tools Ibr diagnosis and the drugs be available (including adequate salaries for both medical and paramedical officers), but also their use :~hould be free of charge, and the patients should be in a position to benefit from them. This means that an effective chemotherapy programme requires significant social, financial and operational support as well as reliable provision of diagnostic facilities and drugs, Second. the absolute need for the regular intake

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13th FORUM IN MICROBIOLOG y

Table IL Case-fatality rates of tuberculosis worldwide, 1990. Region

Cases (x 1,000)

Deaths (x 1,000)

Case "atality rate (%)

3,106 1,839 992 641 569 194 196 7,537

1,087 644 393 249 114 29 14 2,530

40 35 40 39 20 15 7 33

Southeast Asia Western Pacific Africa Eastern Mediterranean Americas Eastern Europe Western Europe and others (*) Total

(') Canada,USA, Japan, Australiaand New Zealand. (From: MMWR(1993), 42:961-964).

Table llI. Estimated number of tuberculosis cases worldwide. Year

Cases (× 1,000)

1990 1995 2000 2005

7,537 8,768 (+ 16.3 %)<*) 10,222 (+35.6%) t*) 11,875 (+57.6%)(*)

~'~Increase since 1990. (From MMWR(1993), 42:961-964).

of drugs should be emphasized, as should the importance, in many settings, of the close supervision of drug delivery and intake. The important matter is not that the treatment be ambulatory or institutional but that regular intake of drugs be ensured wherever the patient is treated. For example, in regions where the population is scattered, some kind of institutional treatment, like Styblo's "hostellization", might well be a solution, whereas in large cities, intermittent, fully supervised ambulatory treatment might be the solution of choice. Third, an important issue is the method used for the diagnosis of tuberculosis. In an industrialized country, the standard procedure for diagnosing pulmonary tuberculosis is the X-ray screening of symptomatic patients followed by sputum smear and culture from those patients with X-ray abnormalities. In many other areas of the world, microscopic examination of sputum is the only available tool. As infectious cases of pulmonary tuberculosis are usually smear-positive, microscopic examination o | sputum may permit their diagnosis. However, to detect one case of tuberculosis the microscopist has

to scan numerous smear-negative specimens from symptomatic, although not tuberculous, patients. The diagnosis of tuberculosis by smear only is therefore a time-cnnsuming, not very motivating procedure, highly dependent upon the quality of sputum collection and smearing and the skill and patience of the microscopist. For these reasons, a simple and inexpensive screening procedure for those patients who should be submitted to smear examination is highly desirable. Finally, the cost-effectiveness of the promising new microbiological techniques - rapid detection of growth, use of genetic amplification and other molecular techniques - should be carefully determined before recommending the use of these techniques in developing as well as in industrialized countries.

The impact of infection with the human immunodeficiency virus (HIV) Tuberculosis has the peculiarity of being an infectious disease under the control of cellular immunity. If cellular immunity progressively vanishes as a result of HIV replication in the human Tlymphocytes, then the subjects with latent tuberculosis infection are at a higher risk of developing active tuberculosis disease. As the HIV epidemic is in rapid extension, especially in those regions of the world where the prevalence of tuberculosis infection is high, an increasing number of tuberculosis cases worldwide axe HIV-attributable (table IV). In addition, the side-effects of drugs are more frequent in HIV-positive tuberculosis patients than in HIV-negative patients (Sepkowitz et al., 1995). Thus HIV infection contributes not only to the increasing number of tuberculosis cases but also to the increasing difficulty in treatment of these cases.

SOLVING THE DILEMMA OF AN'FIMYCOBACTERIAL CHEMOTHERAPY

T a b l e I V , E s t i m a t e d i m p a c t o f H I V infection on tuberculosis incidence worldwide.

Year

HIV-attributable cases o f tuberculosis <') (%)

1990 1995 2000

4.2 8.4 13.8

t'~ Assuming that 95 % of HIV-associated tuberculosis cases are attributable to HIV infection. (From MMWR 0993), 42:961-964).

T h e future o f tuberculosis t r e a t m e n t

Effective treatment intervention should be undertaken rapidly to prevent a significant increase in new c a s e s o f t u b e r c u l o s i s w i t h i n the next ten y e a r s . A c c o r d i n g to W H O information (Centers for Disease C o n t r o l , 1993) there will be an e x p e c t e d 10 million n e w cases b y the year 2000 and 12 million b y the year 2005 (table III). To prevent such a disaster the solutions are not m e d i c a l or sc:entific but s o c i o - e c o n o m i c ( M u r r a y e t a l . , 1 9 9 1 ) ; in o t h e r w o r d s , political, as illustrated b y the s i g n i f i c a n t d e c r e a s e in tuberculosis eases b e t w e e n 1992 and 1994 in N e w Y o r k City as a result o f better rates o f completion of treatment and expanded use of directly observed therapy (Frieden et al., 1995),

References

Algerian Working Group/British Medical Research Council Cooperative Study (1984), Con~oiled clinical trial comparing a 6-month and a 12-month regimen in the treatment of pulmonary tuberculosis in the Algerian Sahara~ Am. Rev. Respir. Dis., 129, 921-928. American Thoracic Society (1994), Treatment of tuberculosis and tuberculosis infection in Adults and Children.Am, J. Respir. Crit. Care Med., 149, 1359-1374. American Thoracic Society and the Centers for Disease Control. (1986), Treatment of tuberculosis and tuberculosis infection in adults and children. Am. Rev. Respir. Dis,, 134, 355-363. Bates, J.H. (1995), Tuberculosis chemotherapy. The need for new antituberculosis druss is urgent. Am. J. Respir. Crit. Care reed., 151,942-943. Bemstein, J., Lott, W.A., Steinberg, B.A. & Yale, H.L. (1952), Chemotherapy of experimental tuberculosis V. Isonieotinic acid hydrazide (Nydrazid) and related compounds, Am. Rev, Tuberc., 65, 357-64. British Thoracic Society (1984), A controlled trial of 6 months chemotherapy in pulmonary tuberculosis. Final report: results during the 36 months after the end of chemotherapy and beyond. Br. J. Dis. Chest.° 78, 330-336. British Thoracic and Tuberculosis Association (1976),

15

Short-course chemotherapy in pulmonary tuberculosis: a controlled trial. Lancet, 2, 1102-1104. Canetti. G. (195q), Modifications des populations des foyers tuberculeux au cours de la chimiothtSrapie antibacillaire. Ann. Inst. Pasteur., 97, 53-79. Canetti, G & Grosset, J. (196t), Teneur des souches sau~ rages de Mvcobacterium tuberculosis en variants r~sistants ~ i'isoniazide et en variants r~sistants "~ !a streptomycine sur milieu de Ltiwenstein-Jensen. Ann. Inst. Pasteur, 101, 28-46. Centers for Disease Control (1992), Management of persons exposed to muitidrug-resistant tuberculosis. MMWR, 41, 59-71. Centers for Disease Control (1993), Estimates of future global tuberculosis morbidity and mortality. MMWR, 42, 961-964. Chaulet, P. (1983), La chimioth~rapie de la tuberculose en 1983, Bull. Int. Union Tuberc., 58, 26-36. Datta. M., Radhamani, M.P., Selvaraj, R., Paramasivan, C.N., Gopalan, B.N., Sudeendra, C.R. & Pmbhakar, R. (1993), Critical assessment of smear-positive pulmonary tuberculosis patients after chemotherapy under the district tuberculosis programme. Tube,de Lung Dis., 74, 180-186. East African/British Medical Research Councils (1972), Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet, l, 1079-85. Etude lnternationale sur l'efficacit6 de la chimioth6rapie (1964), Bull. Int. Union. Tuberc., 44, 81-202. Farga, V., Valenzuela, P., Mendoza, F., Tones, E., Icekson, 1., Grinspun, M,, Fernandez, M., Corradini, A., Martinez, M., Velasco, I. et al. (1983), Trials in Chile. Bull. Int, Union Tuberc,, 58, 102-107. Frieden, T.R., Fujiware, P.l., Hamburg, M.A., Ruggiero, D,, Henning, K.J. (1994), Tuberculosis Clinics. Am. Z Respir. Crit. Care Med., 150, 893-894. Frieden, T.R, Fujiwaxa, P.!,, Washko, R.M. & Hamburg, M,A. (1995), Tuberculosis in New York City - Turning the tide. Special article. N. EngL J. Med., 333, 229-233. Grosset, J. (1980), Bacteriologic basis of short-course chemotherapy for tuberculosis. Clin~ Chest. Med., I, 231-41, Grumbach, F. & Rist, N. (1967), Activit6 antituberculeuse exp6rimentale de la rifa~,picine, ddriv6 de la rifamycine SV. Rev. Tuberc. Pne,.m., 31,749-762. Grzybowski, S. & Enarson, D A. (1978), Results of pulmonary tuberculosis paEents under various treatment program conditions. Bull. Int. Union Tuberc., 53, 7075. Grzybowski, S. (1993), Drugs are not enough. Tubercle Lung Dis., 74, 145-146. Hopewell. P.C. (1994), The baby and the bath water. The case for retaining categorical services for tuberculosis control in a reformed health care system. Am. J. Respir. Crit. Care Med., 150, 895. Lehmann, J. (1946), Para-aminosaticylic acid in the treatment of tuberculosis. Lancet., 1, 15-16. Mackaness, G.B. (1956), The intracellular activation of pyrazinamide and nicotinamide. Am. Rev. Tuberc., 74, 718-28. Medical Research Council Investigation (1948), Streptomycin treatment of pulmonary tuberculosis. Br. Med. J., 2, 769-782.

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Medical Research Council Investigation (1950), Treatment of pulmonary tuberculosis with streptomycin and para-aminosalicytic acid. Br. Med. J., 2, 1073-1086. Medical Research Council-Tuberculosis Chemotherapy Trials Commitee (1962), Long-term chemotherapy in the treatment of chronic pulmonary tuberculosis with cavitation. Tubercle, 43, 201-267. Murray, C.J.L., Dejonghe, E., Chum, H.J., Nyangulu, D.S., Salomao, A. & Styblo, K. (1991), Cost effectiveness of chemotherapy for pulmonary tuberculosis

in three sub-Saharan African countries. Lancet, 338, 1305-1308. Sepko~vitz, K.A., Raffaili, J., Riley, L., Kiehn, T.E. & Armstrong, D. (1995), Tuberculosis in the AIDS era. Clin. MicrobioL Rev., 8, 180-199. Soeidtd Fran~aise de Pneumologie (1984), Recommandations pour le traitement de la tuberculose en France. Rev. Fr. MaL Respir., 1, 59-62. Trial 6, 9, 12, (1977), General report: overall methods and results. Rev. Ft. Mal. Respir., 5 (Suppl. 1), 3-63.

Treatment of disseminated Mycobacterium avium complex disease: a clinician's perspective C.A. Benson (*) Section of lnfectious Disease, Rush Medical College, Rush University, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois (USA)

Introduction Disseminated disease due to organisms o f the M y c o b a c t e r i u m avium c o m p l e x ( M A C ) h a s emerged as a common, debilitating and potentially fatal infectious complication of advanced human immunodeficiency virus (HIV) disease. While disseminated disease due to MAC can occur in other immunocompromised hosts, only 13 well characterized cases were reported in the English literature prior to the onset of the HIV epidemic (Horsburg et aL, 1985). Earlier attempts to treat MAC in both HlV-infected and uninfected patients described the use o f multiple c o n v e n t i o n a l a n t i m y c o b a c t e r i a l drugs and were often unsuccessful in eradicating the organism or reducing clinical symptoms ( B e n son, 1994; Inderlied et al., 1993). Following the development of the newer macrolide clarithromycin end the azalide azithromycin, a decade o f accumulated clinical experience and research culminated in the 1993 publication o f the United States Public Health Service Task Force recommendations for

the treatment o f disseminated MAC infections in patients with AIDS (Masur et al., 1993). T h e s e published guidelines form the basis for treatment regimens used by clinicians in the U.S. today and axe outlined below. T r e a t m e n t recommendations of the United States Public Health Service Task Force Patients with disseminated MAC infection should be u'eated; initial treatment should consist o f a combination of at least two antimycobacterial drugs to prevent or delay the emergence of resistance (Masur et aL, 1993). Oral clarithromycin is the preferred first agent; oral azithromycin may be an effective alternative first agent, although published data demonstrating its microbiologic activity and clinical experience with its use in humans are more limited. Ethambutol is the suggested second drug. For patients with more severe M. avium disease manifestations, some expert~ would add a third or fom-th drug to this initial regi-

Received September 26, 1995. c°) Address for correspondence: Constance A. Benson, M.D., Associate Professor of Medicine, Section of Infectious Disease, Rush Medical College, 600 S. Paulina Street, Suite 143 Academic Facility, Chicago, Illinois 60612, USA.