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Year : 2002  |  Volume : 36  |  Issue : 4  |  Page : 211-213
Challenge of therapeutically refractory and multidrug resistant tuberculosis in orthopaedic practice

VIMHANS, Ring Road, Lajpat Nagar, New Delhi, India

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How to cite this article:
Tuli S M. Challenge of therapeutically refractory and multidrug resistant tuberculosis in orthopaedic practice. Indian J Orthop 2002;36:211-3

How to cite this URL:
Tuli S M. Challenge of therapeutically refractory and multidrug resistant tuberculosis in orthopaedic practice. Indian J Orthop [serial online] 2002 [cited 2020 Feb 20];36:211-3. Available from:
With 36 million HIV positive cases world-wide, increasing number of human beings with immune compromised state, possible pathogenesis by atypical mycobactria (alone or in combination with typical mycobacteria), abuse of broad spectrum antibiotics (many of which have potential antitubercular action), and longevity of human race with concomitant morbidities (diabetese and other endocrinopathies, use of immunosuppressive drugs in organ transplantations and malignancies) the incidence of multidrug resistant cases in likely to increase many fold. The incidence at present varies between 7 to 15%. Currently available chemothetaputic agents alone are not enough to heal such cases. Being essentially a disease of the economically poor countries no new drug specifically for tuberculosis has been introduced for clinical use during the last 30 years.

The population with AIDS and immune compromised states are likely to get infected with atypical tuberculous bacilli, and many of these strains show resistance to a large number of antitubercular drugs. Such patients are also a potential source for spread of multidrug resistant strains of tuberculous bacilli to other members of society. Another cause of development of resistant cases is failure of compliance of prolonged multidrug therapy. According to WHO estimates it is only 25% of cases who complete the prescribed course of therapy, the 75% defaulters again harbour mycobacteria with acquired resistance. [1]

Strictly speaking multidrug resistance (MDR) is defined if the infecting organism is resistant to isoniazid and rifampicin (with or without resistance to other antitubercular drugs). Unfortunately in orthopaedic tuberculous infections positive cultures for acid fast bacilli are obtained (under best of circumstances) in less than half of cases. In clinical practice if the disease is not showing a healing response within 4 to 5 months despite multidrug therapy one should consider such cases as "resistant" or therapeutically "refractory" cases. The destructive process increases, sinuses and ulcer continue to discharge, fresh cold abscesses may appear, additional active tubercular foci may develop. If an operation was performed the operative wound would undergo dehiscence.

The favourable healing response is judged by improvement in general health, body weight, fever, and laboratory findings. However radiological appearance and MR images lag behind the biological healing. It is not uncommon to observe 'deterioration' in the radiographs and MRI when repeated at 2 to 4 months post- treatment. If radiographs and MRI show deteriorating picture even after 5 to 6 months of treatment one should consider the possibility of an alternative pathology or a therapeutically refectory tuberculosis.

By the time a patient is suspected to be a resistant case the treating physician has already tried 'first-line' drugs (streptomycin, isoniazid, ethambutol, rifampicin, pyrazinamide). One has to resort to 'second-line' drugs or potential antitubercular drugs [Table 1]. Most of such drugs are more costly and more toxic. Ideally these drugs should be employed after hospitalization, at least in the initial stages of treatment, for closer observation and management of serious side effects. While treating such patients on domiciliary lines more frequent (one or two month) follow-up and monitoring is mandatory. Attention must be paid to supportive therapy including nutrition and control of concomitant morbidities. Operative debridement, drainage and decompression may be undertaken for absolute indications.

Immune response of healthy human beings to infection by tubercle bacillus has been very effective due to which only about 5% of infected persons develop clinically evident primary (pulmonary) disease, and only a further 5% or so develop post-primary disease late in life. [2] Immunomodulation in conjunction with second-line

  • INH must from part of any mulit-drug therapy.
  • Thioacetazone is contraindicated in HIV positive patients because of risk of severe skin reactions.
  • Avoid more than one hepatotoxic drug in patients where surgical intervention is anticipated.

drugs is recommended for cases who are detected to be resistant to first-line multidrug therapy used for 4 to 5 months.

Attempts are underway for the development of better immunomodulation techniques. However pending such advances the following outline is suggested: 150 mg of levamisol is given at night for 3 consecutive days at weekly intervals for a total of 45 tablets. Four injections are administered once a month. The first and second are 0.1 ml intradermal BCG injections, and the third and fourth are intramuscular DPT (diptheria + pertussis + tetanus vaccine) injections. Clinically a favourable response was observed in 85% of patients. The helper subset of T lymphocytes is central to the cell-mediated immunity against tuberculous infection. These cells carry the CD 4 antigens on their surface (CD4 + lymphocytes). HIV virus enters and infects CD 4 lymphocytes, kills these cells, and progressively leads to a decline in the immunity of the host. Thus nearly 50% of HIV infected patients die of tuberculosis. In patients who were considered therapeutically refectory CD4 + count was analysed to be lowered. [3] The above mentioned immunomodulation regime in conjunction with second-line drugs demonstrated upgradation of CD4 + count after 4 to 6 months of therapy.

Antigens from  Mycobacterium vaccae Scientific Name Search CTC 11659 are currently deriving special attention for immunotherapy of mycobacterial infections in general. There are suggestions that immunotherapy employing a potential new vaccine prepared from mycobacterium vaccae can significantly reduce the incidence of treatment failures and deaths, and help in healing of multidurg resistant tuberculosis. [2] BCG vaccination has been known to provide some degree of immune protection for various mycobacterial infections. Direct BCG vaccination without tuberculin testing is considered safe and acceptable to the persons being vaccinated. BCG vaccination activates macrophages to be more effective killer cells against mycobacteria. Though the mechanism of influence on immune response after mycobacterial vaccination remains speculative however it is considered that macrophages get activated to become more effective killer cells against mycobacteria, probably it switches off the tissue-necrotizing aspects of the Koch phenomenon, and it replaces an inappropriate immune reaction by an appropriate one against mycobacterial infections. [4]

Triple antigens in addition to specific protection against diptheria, tetanus and pertussis and levamisole has in general an immunostimulant effect working through cell mediated machanisms.4 These are considered to increase the number of precursor T-lymphocytes and the number of T-cells. [5],[6] Immunotherapy as administered by our regime probably favorably modulates different levels of the immune system and provides an improved host response to control the disease in multi-drug resistance situation (otherwise a hopeless scenario) where chemotherapy alone is no longer enough.

Tuberculous infection may re-occur at any time during the life-span of patient. Approximately 2% to 5% of patients report back with reactivation within about 20 years after the apparent clinical healing of the first lesion. The causes of re-activation include prolonged use of systemic cortisone therapy, malnutrition, development of diabetes or an immune deficiency state and any surgical procedure or injury to the previously infected area. Dormant tuberculous bacilli, persisting in tissues for years, may start to replicate under such circumstances, or reinfection with a different type of mycobacterium may take place. Such patients require to be treated by newer chemotherapeutic agents, or drugs which were not used or used for the shortest duration or used in the remotest past. The duration of drug therapy recommended is 12 to 18 months.

Present generation of Orthopaedic Surgeons should be cognisant of tuberculous infection that may occur after any surgery in which bio-implants have been used or after treatment of compound fractures. The incidence of such an infection is not high however unexplained dehiscence of wound, persistent seropurulent discharge, formation of ulcers with undermined edges, cavitations in the bones a few weeks or months after operation should arouse the suspicion of such an infection. Histological examination of the curretings from the sinuses, cavities, and ulcers would establish the diagnosis. Acid fast bacilli may be demonstrated in a few cases by Ziehl-Neelson staining or on culture. Atypical mycobacteria may be responsible for infection following compound fractures.The author has observed, analysed and treated 12 cases collected in the last 10 years (1991 to 2001).[7]

With perpetuation of endemic state of tuberculosis in the developing world and currently about 10% annual increase in it's incidence in the affluent countries, the challenge of tuberculous infection is far from contained.

   References Top

1.World Health Organization. Global tuberculosis programme reports, Geneva 1988.   Back to cited text no. 1    
2.Standford JL, Standford CA. Immunotherapy of tuberculosis with mycobarcterium vaccae -NCTC 11659. Immunobiology 1994; 191: 555 - 563.  Back to cited text no. 2    
3.3.Arora A. Behavior of CD4 + and CD8 + T lymphocytes during immunomodulation of therapeutically refectory cases of skeletal tuberculosis (paper presented in SICOT 2002; San Diego, USA).  Back to cited text no. 3    
4. 4.Standford JL, Gange JM. The promise of immunotherapy for tuberculosis. Respirat Med 1994; 88: 4 - 7.  Back to cited text no. 4    
5.5.Rook GA, Hernandez - Pando R. T-cells helper types and endocrines in the regulation of tissue - damaging mechanisms in tuberculosis. Immunobiology 1994; 191: 478 - 492.  Back to cited text no. 5    
6.6.Turett GS, Telzak EF. Normalization of CD4 + T lympbocyte depletion in patients without HIV infection treated for tuberculosis. Chest 1994, 105 : 1335 - 1337.  Back to cited text no. 6    
7.7.Tuli SM. Preliminary observations of the effect of immunomodulation in multidrug resistant cases of osteo-articular tuberculosis. Ind J Orthop 1999; 33 : 83-85.  Back to cited text no. 7    

Correspondence Address:
S M Tuli
VIMHANS, Ring Road, Lajpat Nagar, New Delhi
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