D. A. Mitchison

The action of antituberculosis drugs in short-course chemotherapy.

Abstract The mode of action of antibacterial drugs can be considered under 3 headings: prevention of drug resistance, early bactericidal activity and sterilizing activity.

CONTROLLED CLINICAL TRIAL OF COMPLETE OPEN SURGICAL DRAINAGE AND OF PREDNISOLONE IN TREATMENT OF TUBERCULOUS PERICARDIAL EFFUSION IN TRANSKEI

240 patients with active tuberculous pericardial effusion received a 4-drug daily antituberculosis regimen for 6 months and have been studied for 24 months or longer. Those willing were randomly allocated to open pericardial biopsy and complete drainage of pericardial fluid on admission or percutaneous pericardiocentesis as required. All patients were randomly allocated to prednisolone or matching placebo for the first 11 weeks, on a double-blind basis. Complete open drainage on admission abolished the need for pericardiocentesis (p less than 0.01) but did not influence the need for pericardiectomy for subsequent constriction or the risk of death. Among patients who did not have open drainage on admission, 2 (3%) of 76 given prednisolone compared with 10 (14%) of 74 given placebo died of pericarditis (p less than 0.05), 6 (8%) and 9 (12%) respectively required pericardiectomy, 7 (9%) and 17 (23%) repeat pericardiocentesis (p less than 0.05), and 3 (4%) and 7 (9%) open surgical drainage. By 24 months, apart from the 16 who died from pericarditis, all but 3 patients (2%) had a favourable status.

Drug resistance in tuberculosis.

A drug-resistant strain of Mycobacterium tuberculosis is defined as one differing from the tight distribution of wild strains that have not come into contact with the drug concerned. Sensitivity tests are performed by the absolute concentration method, the resistance ratio method or the proportion method. The hypothesis underlying the proportion method is that there are appreciable differences in inoculum size so that there should be an association between the proportion on drug-free medium and the proportion on drug-containing medium. This hypothesis was not supported by a study on ethionamide-resistant strains. It indicated that variation in the proportion on drug-free medium was due to clumping of the bacilli in the inoculum rather than to differences in the number of bacilli. Hence, the use of the proportion method introduces errors in susceptibility testing. While the method can produce reliable results, it is more time consuming than a minimal inhibitory concentration determination, and should not be adopted as a standard method.

In vitro activity of new rifamycins aganst rifampicin-resistant M. tuberculosis and MAIS-complex mycobacteria

Comparisons were made of the in vitro activity of rifampicin, and the rifamycin derivatives, rifapentine, rifabutin, CGP 29861, CGP 7040 and CGP 27557, against rifampicin-sensitive and rifampicin-resistant strains of Mycobacterium tuberculosis and against the Mycobacterium avium/intracellulare/scrofulaceum (MAIS) complex. The new rifamycins had MICs four to eight times lower than those of rifampicin against sensitive M. tuberculosis strains. Of the 35 rifampicin-resistant strains of M. tuberculosis, 31% were sensitive to rifabutin but only 3-11% to the other rifamycins. The proportions of the MAIS strains found to be sensitive were 35% for rifampicin, 50-60% for CGP 27557, rifapentine and rifabutin and 85-92% for CGP 29861 and CGP 7040.

In vitro properties of rifapentine (MDL473) relevant to its use in intermittent chemotherapy of tuberculosis

In a comparison of in vitro properties of rifapentine (RIF) and rifampicin (RMP), the minimal inhibitory concentration of RIF against Mycobacterium tuberculosis in Tween-albumin liquid medium was usually 0.02 micrograms/ml, 2-3 times lower than for RMP; the bactericidal activity against a log phase culture was slightly less than that of RMP and the recovery after pulsed exposures to 1 microgram/ml of RIF or RMP lasting 6, 24 and 96 h was identical for the two rifamycins. These findings are used to interpret published data from the chronic experimental murine tuberculosis model and support the view that in the mouse, the efficacy of RIF in widely spaced intermittent chemotherapy is the result of its long half-life.

Bactericidal activity in vitro and in the guinea-pig of isoniazid, rifampicin and ethambutol.

Serial viable counts on Mycobacterium tuberculosis exposed in vitro to isoniazid, rifampicin and ethambutol in Tween-albumin liquid medium showed no bactericidal synergism between isoniazid and rifampicin and no influence of ethambutol on the bactericidal activity of isoniazid or isoniazid plus rifampicin. Guinea-pigs with moderately advanced experimental tuberculosis were treated fro 11 weeks with either (1) ethambutol, (2) isoniazid, (3) isoniazid plus ethambutol, (4) isoniazid plus rifampicin, (5) isonaiazid plus rifampic in plus ethambutol, or (6) no chemotherapy. The amount of tuberculous disease was scored and the spleen cultured in groups killed at intervals from 0--7 1/2 months after the end of chemotherapy. The regimens containing rifampicin were no more bactericidal during treatment than the corresponding regimens without rifampicin, but the onset of relapse after chemotherapy was delayed for at least 2 months following the rifampicin-containing regimens. Ethambutol alone did not protect guinea-pigs, nor did it influence the response to isoniazid or to isoniazid plus rifampicin. It was concluded that rifampicin may act selectively on a small proportion of the bacterial population and that it may be unnecessary to prescribe it for long periods in short course chemotherapy in man. Ethambutol does not appear likely to contribute to the sterilizing activity of short course regimens though it may prevent the emergence of drug resistance.

Comparison of strains of Mycobacterium tuberculosis from British, Ugandan and Asian immigrant patients: a study in bacteriophage typing, susceptibility to hydrogen peroxide and sensitivity to thiophen-2-carbonic acid hydrazide.

Strains of Mycobacterium tuberculosis were obtained from 65 patients with pulmonary tuberculosis resident in Uganda, and from pulmonary and extrapulmonary tuberculosis in 42 British patients of European ethnic stock and in 67 Asian immigrants, often from Uganda, resident in Britain. The bacteriophage-type patterns of the African, British and Asian strains were different. The pattern for the Asian strains resembled that found previously in patients from South India, suggesting that there has been little interchange of organisms between the Asian community and the African and British communities alongside whom they have lived. The patterns for pulmonary and extra-pulmonary tuberculosis were similar. Strains of bacteriophage type 1, mainly obtained from Asians, were characterized by a greater susceptibility to the bactericidal activity of hydrogen-peroxide and/or a greater sensitivity to thiophen-2-carbonic acid hydrazide than strains of other types.

PHARMACOLOGY OF SOME SLOW-RELEASE PREPARATIONS OF ISONIAZID OF POTENTIAL USE IN INTERMITTENT TREATMENT OF TUBERCULOSIS

Abstract The pharmacology of three slow-release preparations of isoniazid (I.N.H.) have been studied for their potential use in the once-weekly treatment of tuberculosis. The I.N.H. in the matrix preparation was almost completely absorbed, yet the rate of absorption should allow a dose of at least 30 mg. per kg. body-weight to be given to slow and rapid inactivators of I.N.H. without acute toxicity. Such a dose should be therapeutically effective in once-weekly regimens. Effective and safe once-weekly chemotherapy might also be achieved in rapid inactivators by giving 15 mg. per kg. ordinary I.N.H. with 15 mg. per kg. of the enteric-coated preparation studied, but this regimen would not be safe in slow inactivators.

In vitro observations on the suitability of new rifamycins for the intermittent chemotherapy of tuberculosis.

The bactericidal activity of six new rifamycin derivatives--rifabutin (RBU), FCE 22250 (F22), rifapentine (RPE), CGP 29861 (C29), CGP 7040 (C70) and CGP 27557 (C27) and rifampicin (RMP)--have been measured against log phase and, as a better test of sterilising activity, against stationary phase cultures of Mycobacterium tuberculosis, H37Rv. The order of activity of 1.0 and 0.2 mg/l rifamycin against log phase cultures was RMP greater than RPE & C27 greater than RBU & C29 greater than C70. The order of activity of 1.0 and 0.4 mg/l, adjusted for stability of the rifamycin, against stationary phase cultures was F22 & RMP greater than RBU greater than RPE greater than C27 & C29 greater than C70. Viable counts were done during and after pulsed exposures of 6, 24 or 96 h to C29 and RMP. The curves were similar though C29 was less bactericidal and the lag period before recovery was 1-2 days longer. F22, having high bactericidal activity against stationary organisms and a long half-life, was considered likely to be the most effective sterilising drug.

VIRULENCE IN THE GUINEA-PIG AND SENSITIVITY TO PAS AND THIACETAZONE OF TUBERCLE BACILLI FROM SOUTH INDIAN PATIENTS WITH PULMONARY TUBERCULOSIS.

Summary Isoniazid-sensitive strains of tubercle bacilli, obtained pretreatment from 280 South Indian patients, were tested for their virulence in the guinea-pig and for their sensitivity to PAS; strains from 209 of these patients were also tested for their sensitivity to thiacetzone. Strains of low virulence more often had a high proportion of PAS-resistant mutants and were more ofter resistant to thiacetazone than those of high virulence. There is suggestive evidence that Indian strains can be divided into two groups, the smaller group, comprising about one-quarter of the strains, resembling strains from British patients and the larger group characterized by a lower virulence, a higher susceptibility to hydrogen peroxide, a higher proportion of PAS-resistant mutants and thiacetazone resistance.