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Biomedical subjects

D A Mitchison

Publications and source records attributed to D A Mitchison.

At least 91 records · Page 5Linked to original sources
PubMed1987

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.

Antitubercular Agents↗
PubMed1986

Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis.

The response to short-course chemotherapy of patients with pulmonary tuberculosis caused by drug-resistant Mycobacterium tuberculosis was examined in 12 controlled trials carried out during the past decade in Africa, Hong Kong, and Singapore. Among those with initial resistance to isoniazid and/or streptomycin, failures during chemotherapy were encountered in 17% of 23 patients given a 6-month regimen of isoniazid and rifampin and in 12% of 264 patients given rifampin only in an initial 2-month intensive phase of their regimen. The proportion of failures fell as the number of drugs in the regimen and the duration of treatment with rifampin were increased, to reach 2% of 246 patients receiving 4 or 5 drugs including rifampin in 6-month regimens. The sterilizing activity of the regimens, whether these included rifampin or pyrazinamide, was little influenced by initial resistance, because the sputum conversion rate at 2 months was similar to that in patients with initially sensitive bacilli, and the relapse rates after chemotherapy were only a little higher. The response in the 11 patients with initial rifampin resistance was, however, much less good, failure during chemotherapy occurring in 5 and relapse afterwards in a further 3 patients. This review demonstrates the value of rifampin in preventing failure caused by the emergence of resistance during treatment and the greater sterilizing activity of rifampin and pyrazinamide compared with that of isoniazid and streptomycin.

Antitubercular Agents↗
PubMed1986

Recombinant interferon-gamma and chemotherapy with isoniazid and rifampicin in experimental murine tuberculosis.

Viable bacterial counts in the lungs and spleens of mice infected intravenously with Mycobacterium tuberculosis, strain H37Rv were reduced by intravenous recombinant murine interferon-gamma (IFN-gamma) 1000-5000 u, but not by 200 u. Reduction in counts was greatest when IFN-gamma was given 1 day before infection and was not increased by additional doses in the preceding 2 days. The effect was complete in 1 day and was not increased by successive doses during the next week. Giving IFN-gamma in multilamellar liposomes further reduced the spleen viable counts, but this appeared due to the liposomes themselves and not to encapsulation of IFN-gamma within them. Only a minimal reduction in organ viable counts, not statistically significant, occurred when IFN-gamma was given 5 days after infection. Although IFN-gamma alone and isoniazid 25 mg/kg alone reduced the organ viable counts, combined treatment with IFN-gamma and isoniazid was no more bactericidal than isoniazid alone. Similarly, the bactericidal activity of rifampicin 25 mg/kg was not increased by simultaneous administration of IFN-gamma. There seems little likelihood that IFN-gamma would increase the efficacy of the early stages of the chemotherapy of tuberculosis.

Animals↗
PubMed1986

Effects of recombinant interferon-gamma and chemotherapy with isoniazid and rifampicin on infections of mouse peritoneal macrophages with Listeria monocytogenes and Mycobacterium microti in vitro.

The effect of recombinant murine interferon-gamma (IFN-gamma) on the growth of Listeria monocytogenes for 4 h and Mycobacterium microti for up to 3 days in monolayers of peritoneal macrophages from BALB/c mice was examined by serial viable counts of cell-associated bacteria. Macrophages pretreated with 10 u IFN-gamma per ml were bacteriostatic and with 100 u or 1000 u per ml were bactericidal against L. monocytogenes. Addition of IFN-gamma 3 days before infection caused monolayers to be bactericidal against M. microti mainly during the first 15 min after infection. This was just evident with 10 u IFN-gamma per ml and greater with 100 u or 1000 u per ml. If IFN-gamma was added when phagocytosis of M. microti was complete, about 2 h after infection, its action was only bacteriostatic, the viable counts remaining stationary while those of unexposed monolayers increased. IFN-gamma 100 u per ml added before infection did not alter the bactericidal activity of rifampicin 10 mg/l, nor did it alter the killing curves for isoniazid 1 mg/l or for rifampicin 10 mg/l if added after completion of phagocytosis.

Animals↗
PubMed1985

Activity of the combination of fludalanine and cycloserine against mycobacteria in vitro.

The initial steps in the incorporation of alanine into the bacterial cell wall include the conversion of natural to D-alanine by a racemase followed by the coupling of 2 D-alanine molecules by a synthetase to yield a dipeptide. A combination of fludalanine (3-fluoro-2-deutero-D-alanine), an analogue of D-alanine that irreversibly inactivates the racemase, and cycloserine, which inhibits the synthetase, has been found to be more active against a wide range of non-mycobacterial organisms than either fludalanine or cycloserine alone. When tested against 16 strains of slowly growing mycobacteria including M. tuberculosis, the combination was no more active than cycloserine alone. However the cycloserine minimal inhibitory concentration (MIC) of the combination against the rapidly growing species M. phlei and M. fortuitum was much lower than the MIC of cycloserine alone, particularly with low ratios of fludalanine to cycloserine, and was within the range attainable by therapeutic cycloserine plasma concentrations in man, suggesting its possible use in the treatment of disease due to M. fortuitum.

Alanine↗
PubMed1983

Amikacin in the treatment of pulmonary tuberculosis.

Sensitivity tests on strains from 11 patients with pulmonary tuberculosis, previously treated with kanamycin and/or capreomycin, showed incomplete cross-resistance between amikacin and capreomycin but complete cross-resistance between amikacin and kanamycin. Treatment with amikacin of 4 patients with multiply resistant strains resulted in no response as assessed by sputum smears and cultures, but resistance emerged to amikacin, kanamycin and capreomycin. Amikacin has no role in the treatment of tuberculosis as it cannot be given as an alternative to kanamycin, has no advantages over it and is more expensive.

Adult↗
PubMed1983

Use of the Phoenix system for bacteriology.

A dedicated microbiology data processing system with remote batched job entry to an obsolete computer, has been superseded by the inclusion of bacteriology in an on-line interactive clinical pathology system which had previously incorporated chemical pathology and haematology. The original Phoenix system has been adapted to allow for the entry of bacteriology data using mnemonic codes and to deal with the problems caused by the longer processing time of bacteriology specimens. Particular advantages of the new system include the immediate linkage of all specimens for each patient and an easy recall and display of results in the laboratories and on the wards.

Bacteriology↗
PubMed1983

Selective Kirchner medium in the culture of specimens other than sputum for mycobacteria.

Over a two-year period, 2949 non-sputum specimens were cultured on two slopes of Löwenstein-Jensen (LJ) medium, two bottles of Kirchner liquid medium, made selective by adding polymyxin B, carbenicillin, trimethoprim and amphotericin B, and a selective 7H11 agar slope. Pus and CSF were inoculated into this set without prior treatment, but other specimens were decontaminated with sulphuric acid. Tissues and fluids were also inoculated without decontamination into additional selective media. The use of the selective media as well as the LJ slopes increased the yield of specimens with cultures of tubercle bacilli from 34 to 53 and decreased specimens with all media contaminated from 34 to 2. Results almost as good, 52 positive specimens and five totally contaminated, would have been obtained by the addition of a single selective Kirchner bottle to the two LJ slopes, and this is recommended for routine use.

Bacteriological Techniques↗
PubMed1983

Examination of operation specimens from patients with spinal tuberculosis for tubercle bacilli.

Operation specimens from 52 Hong Kong patients considered to have tuberculosis of the spine were sent at -78 degrees C to London where they were cultured on two Löwenstein-Jensen medium slopes, a slope of 7H11 medium made selective with antibiotics and in two bottles of selective liquid Kirchner medium. Cultures of M tuberculosis, usually with only scanty colonies, were obtained from 37 of the patients. Pus and caseous matter yielded more positive cultures and more numerous colonies than other specimens, but eight of the 37 patients yielded positive cultures only from tissues lining abscess walls or from bone or intervertebral disc specimens. Cultures in Kirchner medium were never contaminated and twice as many were positive as cultures on the slopes; nine patients had cultures positive only on Kirchner medium. It is recommended that (i) a variety of operation specimens, always including pus or caseous material in volumes of at least 1 ml, should be sent for bacteriology; (ii) specimens should be cultured in selective Kirchner medium, with or without Löwenstein-Jensen slopes; (iii) cultures should be incubated for a minimum of 8-9 wk.

Culture Media↗
PubMed1982

The use of murine monoclonal antibodies without purification of antigen in the serodiagnosis of tuberculosis.

A serum diagnostic test for tuberculosis has been devised on the basis of competitive inhibition by human sera of the binding of 125I-labelled murine monoclonal antibodies (Mabs) to a solid-phase bound pressate of M. tuberculosis. Five monoclonal antibodies binding to distinct antigenic determinants of the organism were used as structural probes which conferred their stringent combining site specificities to the polyclonal mixture of human antibodies. Sera from patients but not from healthy controls competed effectively with the binding of 125I-labelled Mabs to M. tuberculosis-coated polyvinyl plates. This inhibition technique eliminated the need for elaborate purification of antigen used in previous serological methods. Some Mabs gave considerably more positive results than others. The best combination of tests used 2 Mabs and yielded a positive result in 71% of 41 patients with smear-positive pulmonary tuberculosis. This approach is applicable in principle to the serodiagnosis of other human bacterial diseases.

Animals↗
PubMed1982

Role of lipid content and hydrogen peroxide susceptibility in determining the guinea-pig virulence of Mycobacterium tuberculosis.

Among isoniazid-sensitive strains of Mycobacterium tuberculosis, strong associations were found in 56 strains of phage type A and I from India, Burma and East Africa between attenuation in the guinea-pig, a low content of strongly acidic (SAL) and sulphatide (SL) lipids, the presence of the attenuation indicator (AI) lipid and phage type I, suggesting that lipid content might mediate attenuation. However, 22 strains of phage type B and I from Iran and Britain also had low contents of SAL and SL but were highly virulent. Although the finding of a strong association in all 78 strains between attenuation and H2O2 susceptibility in vitro supports other evidence that attenuation is often due to increased susceptibility to H2O2 secreted by macrophages, an alternative mediator of virulence probably exists since 8 of the strains were attenuated and also resistant to H2O2. Identification of South Indian attenuated strains for epidemiological purposes by in vitro tests would be best achieved by the presence of AI, H2O2 susceptibility and, if the strains originated in or near India, by phage type I.

Animals↗