1. Dr. Abdullah Jan. Pathan MBBS, TDD, DTM&H

DTCD, MRIT, FCCP

Director-cum-Chest Specialist

Diseases,

Kotri, Sindh.   

Dr. Abrar Ali Khan MBBS, DTCD, MCPS

Senior Medical Officer

Institute of Chest Diseases,

Kotri, Sindh – Pakistan         

* Received for publication:   August 5, 1995

Revision accepted:                 November 5, 1995

ethionamide and cycloserine for the further         

nine months phase among 32 patients of Pri         

vate ward at Institute of Chest Diseases Kotri

Sindh.

The aims of our work were to determine the effectiveness of this regimen with regard to         

bacteriological conversion and relapse and             

to assess it’s side effects. The results of our        

four years of experience with this regimen are

presented herein.

      Thirty two cases of chronic tuberculosis of an averageage 33 years +SD9.2 with a male to female ratio 9.6:1and history of tuberculosis varying from 3-10 years (Table-I) were admitted (SHRZE) for an average duration of 7.03 (SD+4.08) months and remained positive for acid epilepsy/psychiatric disorder, alcoholism fast bacilli in their sputa on direct microscopy and           

INTRODUCTION

The importance of reserved

drugs for tuberculosis is Institute of Chest

increasing because of high

Drugs resistance to

Isoniazid and rifampicin

Due to rampant misuse

of anti-tuberculosis drugs

And over the counter-sale

in developing countries.

Their use is limited by availability and high   cost We have evaluated a 12 Months regimen    comprising Of kanamycin, ethionamide and

 Cycloserine   

drug susceptibility pattern. It was found that 29 out of 32 cases (90.6%) were resistant to three or more drugs (Table-II) TABLE – II : 32 Patients not responding to 2SHRZE + 5HRZE showed following drug resistance pattern*

PATIENTS AND METHODS

·        Drug resistance pattern by concentration method on LJ media.

Incidentally not a single patient

·         

in the private ward on retreatment regimen had any associated medical diso diabetes mellitus, hepatic disease,rder like or renal disease.

TREATMENT PROTOCOL

It consisted of kanamycin, ethionamide and

cycloserine for three months followed by

 Shot course chemotherapy for TB

hospital (Table III); two of them died while others left the hospital against medical advise. One death was because of bleeding stress ulcers and hepato-renal failure; other was because of tuberculosis it failed to respond to treatment. Total failure cases were five (22.0%) who for a mean treatment of 5 months didn’t convert. Three patients did not complete second phase

culture with no clinical improvement and consistent

or worsening radiographic shadows. They were     

treated with reserve drugs after determining   

pretreatment                                           

ethionamide and cycloserine for another        

nine months.

Ethionamide ½ gram daily in the morning.

Cycloserine  ½ gram daily in the morning.

Kanamycin ½ gram daily deep in tragluteally

Initial three month’s treatment was supervised in hospital, thereafter it was looked after in out-patient department.

MONITORING OF BACTERIOLOGY

Single morning specimen was examined under direct microscope and culture on every tenth day for 3 months thereafter every month for another 9 months. The patient was called every 6^th month for follow-up for the next 12 months.

MONITORING DTUG SIDE EFFECTS

Pretreatment base-line investigations like liver function tests, urea/creatinine, complete blood count and urinalysis were performed in every patient. Monitoring of drug toxicity was mainly clinical. When symptoms suggestive of drug toxicity developed the drugs were discontinued until the results of investigations. On recovery from symptoms the patient was challenged without delay with single drugs beginning with ethionamide 125mg on first day and 375mg second day, then cycloserine alone 125mg on first day and 250 mg on second day, finally knamycin 125mg on first day and 500 mg on second day. If hypersensitivity reaction took place to the challenge dose, then one tenth of the challenge dose was used initially, doubling it every twelve hours until full dosage was reached. When a reaction supervened during desensitization, the procedure was resumed with a lower dose and continued more slowly⁵.

RESULTS

INCOMPLETE THERAPY:

Six patients (18.7%) did not complete three months initial phase of protocol therapy in

Abdullah J. Pahtan & Abrar A. Khan

TABLE – IV : Side effects of drugs in 26 patients

Initial phase of 3 months therapy in the hospital. The mean duration for sputum conversion was 44.9 days SD+24.1 (range 24-124 days). An over all success was achieved in 18 patients (78.2%) during the follow-up of one year.

SIDE EFFECTS OF DRUGS:

Life-threathening side effects were noted in three patients. Haemotologic (neutropenic leukopenia) in one patient; cause couldn’t be assigned. Ethionamide inducted hepatitis in two patients. Suicidal behavior in another patient who also died later on because of tuberculosis after being on this therapy for five months. Gastrointestinal upsets were noted in 18 patients who were managed by giving ethionamide with meals with or without prochlorperazine/metoclopramide (Table IV). It was observed that once gastrointestinal intolerance was controlled, it was achieved for the entire period of protocol regimen and no one required any change in therapy thereafter. Coming a problem for control programmes all over the world. ^1,2,3,4 MDR tuberculosis in effect means patients with combined drug resistance to isonizaid

And rifampicin with or without resistance to other drugs.⁷ Presently the main brunt of tuberculosis epidemic is on Pakistan in EMRO region.⁸ The drug resistance in patients if Indian sub-continent origin including resistance to five or six drugs was found higher (8.5%) as compared to patients of other ethnic origin in a south-east English study.⁴ Likewise in Pakistan secondary drug resistance to isoniazid and rifampicin is also found very high. In one series 37% cases of relapse and treatment failure were resistant to three drugs² while 16.4% bacteriological conversion to five drugs (SHRZE) was found in our own study³. The rapide bacteriological conversion which is the mainstay of antituberculosis activities is achieved by protocol therapy on smear microscopy in 80.7% cases and on culture in 76.9% cases. This is further corroborated by a low relapse rate (5.5%) making the regimen effective and promising, it’s follow-up is still continuing.

We have used low does of ethionamide and cycloserin⁹ to avoid toxic effects as much as possible. Following per oral one gram of ethionamide, the peak serum level achieved in three hours is 20 microgram . ml.¹⁰ The minimum inhibitory concentation (MIC) and minimum bactericidal concentration (MBC) for my cobacterium tuberculosis are 0.3-1.25 microgram/ml and 2,5 microgram/ml respectively.¹¹ Hence with 0.5 gram ethionamide the speak levels achieved are quite higher than MIC and MBC required for bacteriocidal activity against m. tuberculosis. Likely blood level of cycloserine 3 to 4 hours after a single dose of 250 mg are 15-35 microgram/ml,¹² while the inhibitory concentration required for M. tuberculosis is 5-20 microgram /ml.¹³ Hence with 0.5 gram cycloserine quite higher concentration are achieved to inhibit the

Abdullah J. Pathan & Abrar A. Khan

reserve drugs for tuberculosis should not be freely available in the market and should be sold only on the prescription of chest physicians that too in institution as they are the only arms in the pharmaceutical arsenal effective against multi-drug-resistant bacilli. We recommend that government of Pakistan should allow reserve drugs of tuberculosis on reasonable prices but be sold only on the prescription of chest physicians.

REFERENCES

1.      Song L.A review of the resistance to antituberculosis drugs and the related problems during the past 30 years in China. Am Rev Resp Dis 1990; 141: 447.

2.      Macor, G,; Arosse, We,; Cordolla, G. et al. Primary drug resistance to TB drugs study and analysis of secondary drug resistance rate of C/S tests routinely performed on failure and relapes case. SAARC Conference on TB & Respiratory Diseases Lahore 1993; P-34.

3.      Pathan, A.J.; Memon, M.Y,; Khan A.A. Drug resistance in pulmonary tuberculosis at institute of Chest Diseases Sindh, Kotri. SPECIALIST Pakistan 1992 9(1): 75-79

4.      Grange, J.M,; Yates, M.D. Re-emeragence of tuberculosis. BMJ Pakistan 1993; 3 (4) 162.

Of 9 months therapy as they refused to continue treatment because of it’s high cost and again became smear positive during median follow-up of 83 days.

TABLE-III : Protocol therapy not completed among 32 patients

Reason                                             Patients

                                                              (n)

Non-TB death                                       1

TB death                                                1

Lost during hospitalization                    4

Refusal of treatment because of            3

High cost                             

Total                                                       9

FOLLOW-UP AND RELAPSES:

Twenty three patients (88.4%) completed one year protocol treatment. Eighteen (78.2%) among them remained smear and culture negative at the end of nine months contination phase. Post-chemotherapy follow-up ranged from 6 to 26 months (average 12 months). During this follow-up one patient (5.5%) relapsed bacteriologically 8 months after completion of therapy and was rendered negative bacteriologically  on retreatment with same drugs.

OVER ALL SUCCESS OF THERAPY:

Twenty (76.9%) among twenty six smear positive, culture positive patients were rendered bacteriologically negative both on smear microscopy and culture during the

DISCUSSION

Drug resistance acquired to initial chemotherapy of tuberculosis in the form of multiple drug resistance (MDR) is rapidaly be

Short course chemotherapy for TB

Growth of M. tuberculosis. Secondly peak serum level work more effectively than the sustained serum levels in the tuberculosis hence a single daily dose is the most effective mean for best bacteriocidal effect. Thus we used half grams of ethionamide, cycloserine and kanamycin in single daily doses to achieve maximum peak levels for best bacteriocidal effects and also to raise the patients compliance. In our series side effects to single morning dose were low.

One gram kanamycin is commercially available in 4 ml vial which will be an ordeal for patient to get administered in his hip daily or alternately for three months. Hence we reduced it to half gram daily deep in tragluteally. A total of 45 grams kanamycin was given in 90 doses which is thrice the dose that causes toxicity in man¹⁴ but it produced only minor vestiblurar disturbance in three patients in the 8^th, 10^th and 11^th week of therapy and did not require any change in drugs and regressed when the drug was stopped.

Another important observation that was made in this study was the poor compliance of the patients though they were well educated about the problem they had and the danger which they carry to their contacts. In this regard the cost of the drugs was also a factor that worked adversely on our efforts. Presently the cost of 125 mg ethionamide, 250 mg of cycloserine and one gram of kanamycin is rupees 12.50, 15.00 and 78.00 respectively. The total cost of one day doses is Rs. 105.50, hence these are out of reach for even well to do people. In our study therefore three patients refused to continue these drugs because of economic reasons.

One of the factors contributing to secondary drug resistance is physician’s error. In a study³ among smear positive admitted cases at our Institute ninety nine percent were on bad chemotherapy for tuberculosis with regard to dosage, rhythm and duration. Hence

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6- Chadwick, M.V. Sensitivity testing of my cobacteria in : MYCOBACTERIA 1981; P.57-58.

7- Ahmed, T. Resistant tuberculosis. MEDICINE DIGEST 1994;7 (2): 12-16

8- Kochi, A.A.Global overview of TB situation. WHO/TUB/91-158 p.23,40,82,84.

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10- Mandell, GL,; Sande, M.A. Ddrugs used in the chemotherapy of tuberculosis and leprosy. In; Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 7^th Education, p.1208, 1985.

11- Leonid, B.H Pamela, J.L.L. & Marcella, F.Comparison of bacteriostatic and bacteriocidal activity of Isoniazid and Ethionamide against myco. Avium and myco. Tuberculosis. AM.REV.RESPIR. DIS. 1991; 143: 268-270.

12- Lester, T.W. Drug resistant and atypical myco bacterial disease; Bacteriology and treatment Arch, Intren. Med 1979; 139; 1399.

13- Jawetz, E. Antimycobacterial drugs. in: Katzung BG. Basic and clinical phrmacology. 3^rd Edition, p.544, 1987.

14- Sande, M.A. & Mandel, G.L. The aminoglycosides in: Goodman & Gilman’s The Pharmacological Basic of Therapeutics. 7^th Edition. P. 1164-1165, 1985.