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Tuberculosis

Chemotherapy—How Long?

MoRE than twenty years ago it could be claimed that chemotherapy offered the possibility of 100% success in the treatment of tuberculosis; and since then additional antimycobacterial drugs have become available, of which one, rifampicin, is now

accepted, where cost is not a limiting factor, as a first-line drug. Yet in large areas of the world tuberculosis is still a frequent cause of illness and death. The failure of poorer parts of the world to benefit from advances in knowledge is due to interacting economic, social, and medical factors. Effective treatment requires the administration of antimycobacterial drugs in combinations known to limit the rate of emergence of resistant organisms, for long enough to reduce the number of viable bacilli to a level at which the patient’s own defences can deal with the residual population. In practical terms, this calls not only for provision of the essential drugs but also for an organisation to ensure that all patients take them regularly. In developing countries the cost of these services is a serious burden, and the search is on for regimens effective after shorter periods of treatment; ideally at least part of the course would consist of intermittent rather than daily treatment, so as to reduce the number of necessarily supervised doses. Studies directed to this end have been reviewed by Fox.l Since the number of possibly useful combinations of drugs and of periodicity and duration of administration is large, and these can be assessed only by comparative clinical trials under field conditions, progress is inevitably slow. The efficacy of twiceweekly administration of suitable drug combinations has been well established. Lately, attention has been directed to intensive treatment with combinations of bactericidal drugs to reduce rapidly the bacterial population, either throughout a short total period of treatment, or as the initial phase to be followed by a less intensive, usually intermittent phase. In a study in Singapore2regimens of streptomycin (S) plus isoniazid (H) plus rifampicin (R) plus pyrazinamide (Z) for the first two months, followed by either 2 or 4 months’ continuation treatment with either HR or HRZ were compared. All 330 patients with drug-sensitive bacilli, and all but 1. 2.

Fox, W. Proc. R. Soc. Med. 1977, 70, 44. Singapore Tuberculosis Service/British Medical Research Council. Am. Rev. resp. Dis. 1979, 119, 579.

1 of 33 with bacilli

initially resistant to S, H, or initial good response. There was only one bacteriological relapse among 164 patients treated for a total of 6 months, but among 154 who received only 4 months’ treatment 12 relapsed. Although pyrazinamide adds to the effectiveness of SHR in the initial intensive phase of treatment,3 those receiving it in the continuation phase showed no advantage. Thus, the preferred regimen among those studied seems to be SHRZ for 2 months, followed by HR for 4 months. Although this completes treatment within 6 months, it entails daily treatment with expensive rifampicin throughout; and while possible in Singapore, with wellorganised clinics and good financial resources, it would be difficult to implement where these do not exist. Those regimens which depend upon continuation phases not including rifampicin, with twice-weekly dosage, have so far required at least 9 months’ treatment to avoid an unacceptable number of relapses.4 Another approach to reduction of costs that has been little explored is the possibility of defining a group of patients for whom briefer periods of chemotherapy can be expected to be efficacious. Such individualisation of treatment, if the criteria for it are simple and call for no extra investigative procedure, might be formally introduced with advantage into current practice everywhere, but especially in developing countries. Patients in whom the diagnosis of pulmonary tuberculosis seems likely on clinical and radiological grounds, but in whom microscopy of sputum reveals no acid-fast bacilli (A.F.B.), are frequently started on chemotherapy on a presumptive diagnosis, for which bacteriological confirmation may or may not be obtained subsequently. On p. 1361 we publish the first report of a study in Hong Kong designed to provide answers to questions about the most costeffective way of managing such patients, who are believed to constitute as many as half those treated for pulmonary tuberculosis in Hong Kong (and probably a similar proportion in some other areas). Patients regarded by physicians of the Hong Kong Chest Service as having active pulmonary tuberculosis on radiographic grounds but with five negative microscopical examinations for A.F.B. in sputum were randomly allocated to two main groups. One of these was treated only after activity of the disease had been confirmed either bacteriologically or by radiological or clinical evidence of extending disease (selective chemotherapy group). The other received immediate chemotherapy with one of 3 regimens: SHRZ daily for 2 months; SHRZ daily for 3 months; or a standard regimen of S, H and both, made

a

3. Fox, W., Mitchison, D. A. ibid. 1975, 111, 325. 4. East African/British Medical Research Council. ibid. 1978, 118, 39.

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p-aminosalicylic acid daily for 3 months followed by a further 9 months, usually of SH twice weekly. In the selective chemotherapy series, cultures of the initial sputum specimens proved negative in 181 of the 288 patients. These 181 patients provided a yardstick by which the immediate effects of the three regimens of chemotherapy could be assessed. During the 12 months’ reported observation, 34% of them showed bacteriological, and another 8% radiographic, evidence of disease activity. Among those receiving immediate chemotherapy, the only positive bacteriological finding during treatment was the isolation of a resistant strain from 1 patient in the standard chemotherapy group. But after the end of the two short-term regimens, positive culobtained from 20, two of the isolated strains being resistant; and there was radiographic evidence of deterioration in 2 more. As might be expected, most of these relapses occurred in patients whose initial cultures had proved positive; among these, 11% of 173 relapsed, compared with 1.5% of 343 with negative initial cultures. tures were

Several conclusions, some tentative, can be drawn from this report after only 1 year of observation. It is clear that in Hong Kong the diagnosis of pulmonary tuberculosis made on clinical and radiological grounds, even though repeated microscopical examinations of sputum have failed to show A.F.B., is generally correct, and that a high proportion of such patients require treatment. This finding is not necessarily applicable elsewhere, since the diagnostic criteria adopted by physicians and radiologists and the reactions of populations to locally prevalent pathogens may be different. It is to be hoped that evidence on these points will emerge from other centres. The therapeutic results to date suggest that it may be appropriate in treating initially "smear-negative" patients to discriminate between those with positive and those with negative culture results. In those with negative results, 2 or 3 months of intensive daily chemotherapy was followed by a very low incidence of early relapse, but in those with positive results the incidence was higher and at a level that would generally be regarded as unacceptable. Perhaps a reasonable policy on existing evidence would be to start intensive chemotherapy in all cases and stop it at 3 months in those whose initial cultures had proved negative; in those with positive initial cultures, it could be continued in a suitably modified form, probably not including the more expensive drugs and intermittently administered for a further 6 months. But more information is required about the long-term progress of the patients who received very short periods of chemotherapy with satisfactory early response; and it is good to know that the investigators responsible for this important study

promise a five-year follow-up.

Extracranial—Intracranial Anastomosis THE introduction of the into neurosurgery and the

operating microscope development of tech-

niques which permit the anastomosis of arteries as small as 1 mm diameter1 have opened an entirely new field for the treatment of cerebral ischsemia. The cerebral circulation may at first sight seem an unpromising area for this type of surgery because nature has already provided an abundant collateral circulation. The circle of Willis permits flow of blood between the carotid arteries and the basilar; leptomeningeal anastomoses develop over the cerebral hemispheres when circulation through the anterior, middle, or cerebral arteries is impaired; and there is a multitude of potential anastomoses between branches of the external and internal carotid arteries and between the ascending cervical and vertebral arteries. It is this extensive collateral circulation which makes carotid-artery ligation a harmless procedure in most patients; and it also explains why carotid occlusion is sometimes discovered at necropsy when there is no story of a cerebral incident. The occurrence of cerebral infarction indicates, however, that this complex system of collaterals does not ward off all threats to the cerebral circulation. Attempts to supplement these collaterals by surgical means are therefore reasonable. The problem is to know what type of case is likely to benefit. Several groups2-6 have now recorded their results with extra-intracranial anastomosis. The total number of cases is several hundred, but differences in selection criteria make assessment of the place of this operation difficult.

The operation most commonly performed is anastomosis of the superficial temporal branch of the external carotid to a branch of the middle cerebral artery. This is not solely because these vessels are technically most accessible but also because a high proportion of ischaemic events and infarctions occur in that part of the brain supplied by the middle cerebral artery. The ideal case for this procedure is a patient who presents with transient , ischaemic attacks and is found to have a stenosis of the middle cerebral artery. Presentation with transient ischaemia indicates that cerebral tissue has not yet been irrevocably damaged, as is the case with infarction, and stenosis at the origin of the middle cerebral artery cannot be compensated for by shift

Yasargil, M. G. Krayenbuhl, H. A., Jacobson, J. H. Surgery, 1970, 67, 221. Chater, N., Popp, J. Surg. Neurol. 1976, 6, 115. 3. Gratzl, O., Schmiedek, P., Spetzler, R., Steinhoff, H., Margueth, F. J. Neurosurg. 1976, 44, 313. 4. Sundt, T. M., Siekert, R. G., Piepgras, D. G., Sharbrough, F. W., Houser, D.W. Mayo Clin. Proc. 1976, 51, 677. 5. Samson, D. S., Hodosh, R. M., Clark, W. K. J. Am. med. Ass. 1979, 241, 1. 2.

376. 6. Lumley, J. S. P. Br. J. Surg.

1979, 66, 317.

Tuberculosis chemotherapy--how long.

1383 the child grows up, and what is management of women during their reproductive life? apy be modified the as correct Tuberculosis Chemotherap...
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