The results of treatment in patients with cultures resistant to streptomycin, isoniazid and PAS: A five-year follow-up

Tuhnrtr, /.om/., (I%7). 4H, 27

riiK fucsiJixs ()i< TRKAriMKNr IN rMiKNis w n u ('Ui;ri)ui:s KKSISI A N i r o SlkKPTOMVClN, ISONIA/JI) AND PAS: A MVIvYKAU r()IJX)W4JI» iiy j . ToiisiiK, \i. .IAU(IK'\

M. Zn.i.NiCA, M, JANc'tKovA-MAKovA"

from fhr TtilH'iriili>M\\ Hcuuiiifi iusutufi', l'in)>iu', ('/rc/uishn-iilyiu SUMMARY

riic lajc rcsulis, live years al'ier (be slnii oT Irealincnl, arc jtivcn in IX?. palienis with I'aratlvaneecl (silx-reulosis and cullures ivsislanl In strcpfdinyciii, isojiia/id and PAS. 'I'liiilynine had clienu)llu:rapy and early stn'^ical irealnicni and H\ had cli-.^iiolherapy alone (surgical (realniciK was used in four afler a re!a))se), I he Inllovvin); dru^^s were nsed; elhioiianiide (0-5 j ^ twice ilaily), pyra/niann'de (0'5 [i three limes dady), eycloserine (()'25 1^ three limes ihaily), vioniyein (1 )», daily oi 2 i\, twice a week), {'ifly-iive of the
Kl'SOMH

f.cs resnitals (ardlfs du irailemcnl de 122 maladcs allcinfs dc ttd)crculosc avanccc el portenrs de bacillcs rcsislants a la sireploniycine, a risonia/ide el an I'AS, sonl doniids avec nn rccul dc 5 ans aprcs le dehtil du Irailemcnl. Trenie-neuf oni iVf^u dc la chindolhcrapic associi^c a nn iraitemcnt chirnrgicai prccoce, tandis (pic H3 n'oni rcQu cjuc dc'la chirnioihcrapic (unc cure chiriirgical a 6le faitc pour 4 rnalades aprcs recluilc)- Jxs drogues suivanlcs onf 6ie utilisccs; c'lhionamidc (0,5 g.. 2 fois par jour), pyraxinaniide (0,5 g, 3 (bis par jour), cycloserine (0,25 g., 3 fois par jour), viomycinc (! ^. par jour ou 2 g,, 2 fois t)arsc!r)ainc), Cinquantc-cinq maladcs sur Ics 83, out etc ti^ail6s iniiallcmcnt par Irois dcs drogues sccondaircs pendant trois mois an minimum, cicn moycnnc 12 mois; (c Irailcmcnt a alors etc poursuivi par deux drogues, Cinquanlc-lrois maladcs (91 %) sont dcvcnus ucgalifs a ht ' Present address: Univensity Chcil Di.scascs ))cparnT}cnl,.iihi:)V5ik^ 100, JJrno, C/tx:hQslovakia,

culture. Chez deux malr.des le trailement a et6 inefficace d'embl6e. Tous deux ont regus unedes drogues (viomycine) de fagon intermittenle, et comrae oa s'en est aperpu plus tard, la concentration d'etliionamide dans le serum, que ce soit aprcs administration orale ou rectale du medicament n'atteignait pas un niveau suffisant. Fiuit malades (14%) ont rechutc tardivement. lis ne prenaiefit pas leurs drogues regulieremcnt. Pour 4 d'entrc eux, ies cultures sont devenues resistantes aux drogues secondaires. Qnq malades sont redevenus de nouveau negatifs par la pousuite du traitement (deux d'entre eux apres chirurgie). Dix malades sont morts, dont six apres que leur expectoration soil devenue conjitamment ntSgative. Vingt- huit malades n'ont regus initiallement que deux drogues. Onze sculenicnt (40%) sont devenus negatifs, dont trois apres une reprise du traitement par trois drogues. Dixneufsont morts, et pour 1.6 alors que lour expectoration elait encore positive. II n'y avait pas de difference significative entre le groupe ayant re^u trois drogues et cclui n'en ayant regiu que deux, quant a la severite de la maladie et quant aux autrcs facteurs en rapport avec elle. Les difficulles du traitement par des drogues secondaires sont souiignees. Cependant des .• resultats a long-terme satisfaisanis peuveni etre obtenus si les quclques regies fondamentales simples de (oute bonne chimiotherapie sont respectees, et si les malades ont la volenti de cooperer. RESUMHN

Se comunican los rcsuhados,>al cabo de 5 anos de tratamiento, de 122 pacientcs con tuberculosis avanzada y bacilos resistentes a EM, INH y PAS. 39 recibieron quimioterapia y tratamiento quirurgico precoz, mientras que 83 recibieron solo drogas (en 4 casos se aplico tratamiento quirurgico despues de una recaida). Se empiearon las siguientes drogas: ethionamida 500 mg., dos veces diarias; pirazinamida 500 mg., tres veces diarias; cicloserina 250 mg., tres veces diarias; viomicina 1 g. diario 6 2 g., dos veces por semana, 55 de lbs 83 enfermos fueron tratados inicialmente con 3 drogas secundarias durante 3 meses como minimo y 12 mesescomo promedio; luego se continuo con 2 drogas. 53 casos se negativizaron al cultivo (91 %). En 2 casos el tratamiento fracaso desde el comienzo; ambos recibian 1 droga (viomicina) en forma intermitente y la concentracion de la ethjonamida en el suero era baja al suministrarla por via oral o rectal, Ocho casos (14%) presentaron una recaida posterior; no tomaban las drogas regularmente. En4 de ellos los bacilos se hicieron resistentes a las drogas secundarias. Cinco casos'volvieron a negativizarse con ulterior tratamiento (2 con tratamiento quirurgico), Muieron 10 casos, 6 de ellos con esputos persistentemente negatives. 28 pacientes recibieron solo 2 drogas desde el comienzo; se negativizaron solamente 11 (40%), incluyendo 3 que recibieron posteriormente 3 drogas. Murieron 19 y en 16 de ellos los esputos persistian positives. No habia diferencias significativa en las caracteristicas de los enfermos que recibian 2 6 3 drogas. Se insiste en las difficultades del tratamiento con drogas secundarias. Sin embargo, se pueden obtener resultados satisfactorios alejados si se cumplen los requisites basicos de una quimioterapia correcta y si el paciente coopera suficientemente. Introduction In 1963 we reported the early results of treatment in a group of 122 patients with cultures resistant to streptomycin^ isoniazid and PAS (Janclk and others, 1963). All the patients have been followedup, most of them for five years. The bacteriological results at the time of the last assessment (March 1966) are given in the present report.

RHSISTANT CULTURHS

29

The Patients During the period from 1959 to 1962 260 patients with cultures resistant to streptomycin and isoniazid or to streptomycin, isoniazid and PAS were treated in and discharged from the Tuberculosis Research Institute in Prague. One hundred and thirty-eight are not included in this investigation because they did not fulfil the following criteria: (a) having cultures of typical tubercle bacilli; (b) previous treatment with streptomycin, isoniazid and PAS; (c) treatment with secondary drugs started at the Institute; (d) treatment continued for three months or longer with one or more of the secondary drugs (24 patients treated for less than three months have been excluded). There remained 122 case records for analysis. The results for groups with cultures resistant to streptomycin and isoniazid and to streptomycin, isoniazid and PAS were analysed separately. No important dilTercnces were found in the condition of the patients before treatment or the results of treatment. The two groups have, therefore, been combined. Ireatnient Eighty-three of the 122 patients were treated initially by chemotherapy alone and 39 had early surgical treatment in addition. The following drugs were used in various regimens: ethionamide — 0-5 g. twice daily pyrazinamide — 0-5 g. three times daily cycloserine — 0-25 g. three times daily viomycin —- 1 g. daily or 2 g. twice weekly Results The great majority of the patients have been followed-up for 60 months from the start of treatment, with an average of 63 months in the 91 who were alive in March 1966. Of the 122 patients (all of whom completed at least three months' treatment), sputum conversion was obtained by the initial planned treatment in 103 (84%) and at the end of the observation period 89 (73%) were alive and had negative cultures (Table 1). CfeMOTHHRAPY ALONR

Treatment with Three Drug^ Fifty-five patients were treated with three-drug regimens, the great majority (47) containing, ethionamide. After three months 31 (56%) oi^ 55 were negative on culture. The proportions after 6, 12 and 24 months were 87 % of 54, 94 % of 52 and 90 % of 51 respectively. In all, 53 (96%) became sputum-negative with the initial treatment, using chemotherapy alone. Relapse—Eight of the 53 relapsed. In each case the treatment had been incorrect; seven 6\d not take the drugs regularly and one stopped treatment too soon after discharge from hospital Two of the eight patients did not tolerate ethionamide well (one had a peptic ulcer). In three, retreatment in hospital with the same regimens (the cultures still being sensitive to {\\Q. drugs) produced sputum conversion. Two became negative after a lobectomy. Rctreatment failed in three cases: two patients died with the sputum positive, 27 and 34 months after the start of treatment (one with an empyema and the other from cor pulmonale); one patient, an alcoholic, became negative after a resection but discharged himself six months later and refused further treatment, the sputum becoming positive on culture again 16 months after resection. In four of the eight, cultures were resistant during the relapse to some of the secondary drugs (to ethionamide only, pyrazinamide only, thiosemicarbazone, ethionamide and cycloserine and in the fourth to PAS, pyrazinamide and viomycin). failure of Initial Chemotherapy—in two patients the sputum remained positive: both died. One woman aged 46 years had inadequate absorption of ethionamide after both oral and rectal adminis-

30

TUBERCLE

TABLE I.—^THE BACTEfiioLociCAL RESPONSE TO TREATMENf OF 122 PATIENTS WITH CULTURES RESISTANT TO THE STANDARD DRUGS AND THE RESULTS OF SPUTUM CULTURE IN THE 91 LIVING PATIENTS (AFTER AN AVERAGE OF 63 MONTHS FROM THE START OF TREATMENT)

|! Chcmoihenipy

Sputum converted by initial treatment ' Bacteriological relapse Retrcatment successful Relreatment failed

3 drugs

1 or 2 days

\

Total

55 (700%)

!

28(700%)

i

83(700%)

.j

53(9(5%)

! i

|

64(57%)

;l ij

i 1

11 8 3

19(75%)

j

j 8 1 5 * ' 1 3 ^

. ; !

Sputum not converted by initial treatment

1 2**('^%)

i

Alive Sputum negative

! i

45 44(6^0%)

' j

Deaths Tuberculous Non-tuberculous

i

10 ^

;

6

11 (-^0%) 3 3t 0

\if\m%^ 1 9 8(29%)

;

54 52(6i%)

1

29 20 9

19 16 !

3

I

•! Chemotherapy ^ 1 unci \ 11 early surgery j

; I

Total

39(700%)

I

122(700%)

39(700%)

i ;

103(6'-^%)

1 31 3 '; 0

i ; i

14 '^ 3

i

0(0%)

1 i

I

37 37(95%)

91 89(75%)

; ; !

31 20 11

^

2 0 2

19(7<5%)

* 2 patients were treated surgically. t 1 patient was treated surgically. § 2 patients died with sputum still positive and one had a lobectomy but had a positive sputum 16 months later **• Both patients died while the sputum was still positive. t t 16 died while the sputum was still positive.

tration, and cultures resistant to cycloserine appeared during treatment with ethionamide, 1 g. daily cycloserine, 0-75 g. daily and viomycin twice weekly. She died from cor pulmonale 32 months after starting treatment. The second patient, a man aged 54 years had far-advanced silico-tuberculosis. He had the same treatment as the first patient and died from cor pulmonale after eight months. Deaths—there were 10 deaths, four in patients with a positive sputum (two during initial treatment, two during treatment of a relapse), and six from non-tuberculous causes: cor pulmonale with sputum negative in two and other causes in four. DwatiGH of Treat men t-^Th\riy-nine of 53 in whom the initial treatment produced sputum conversion were alive in March 1966. Twelve had received three drugs throughout the duration of chemotherapy and the other 27 had had two drugs only during the later stages. The average duration of treatment was 24 months and of treatrnent with three drugs 12 months. Results at the End of the Fo//ow-up Period—of the 55 patients, 45 wei"e alive and 44 (80 %) had negative cultures (39 from the initial treatment and five after re-treatment). Treatment With Less Than Three Drugs Twenty-one patients were treated with regimens of less than three drugs, 18 with ethionamide and one other drug, and seven with only one drug. Eleven(40%) became sputum-negative with the initial treatment. Relapse—Three patients had a bacteriological relapse. All became negative after three-drug regimens had been started in hospital (one also had a thoracoplasty).

RKSISTANT CULTURES

31

failure of InUial Chcmotherapy^-Stv^niccn patienis remained spmujn-posiiive, ]n five rliere was only one elTeclive drug used; and Tour iiad incorrect treaiment prescribed, being given tirugs to which the cultures were resistant, hi five of the 17, cultures resistunt to one or more of the secondary drugs were isolated during treatment. Deaths—There were 19 deaths, 16 in patients with a pcsiiive sputum (with, cor pulmonale) and three iii patienis with a negative sputum (from cor pulmonale in two and bronchial carcinoma In one), DuraUon of Treat menl^^Aghx ofllie i 1 in whom the initial IreaUnent produced sputum conversion were alive in March 1966. Six had received two drugs and iwo OJily one drug. The average duration . of treatmenl was 29 months. Results at the End of the fo/hw-up Period—0( Ihe 2S patients only nine were ahvr and eight had negative cultures. CK!^:MOTtmRAPY AND E A R L Y

SURG[:RV

In 39 patients the initial planned treatmcDi was chemotherapy and surgery. All became spuiumnegaiivc. Three rclapsi^d. two 18 monlliS and one 30 months after the surgical treatment. Jn all tiiree the chemotherapy had beep, given for only short periods after surgical treatment (thice nionths in two cases and seven months in one). Tw'o became sputuni-negalive with further chemotherapy and OJ>e with cheiriothcrapy and a thoracopiasty. There was no difference in results between those who had three-drug regimens and those who had two-drug regimens. At the end of the period otToUow-iip 37 were alive, all with negative cnUurcs,, Two had died from non-luhercuious causes. Discussion in 1963 we demonstrated that good early resuUs can be obtained with secondary drugs in patients with cultures resistant to the primary drugs. Most of the 122 patients have now been observed for five years. The results are stili good, There were no important differences bciv\^een the group treated with three drugs and the group treated with one or two, in the age of ihe patients or in the extent and scvci-jty of the disease. Ninety-six per cent of the 55 treated with three drugs became sputum-negative on culture, compared with only 40% of 28 treated with less than three drugs (seven of whom had only one drug and in some of the others the drugs were incorrectly prescribed. At the end of the follow-up period the proportions wiiLh negative cultures were S0% and 29% respectively. The differences can be reasonably attributed to the Ircatment given. It is of interest that two of the patients With persistently negative cultures developed aspergi Nomas, demonstrated by x-ray. bacteriological and serological examinations. Most of the patients who had chemotherapy only were unsuitable for surgical treatment because of extensive lung involvement. Our results suggest that, W a three-drug regimen of chemoiherapy can be used and the patient is wiUing to co-operate and can tolerate the drugs for as long as two years, surgical treatment is not required. We reserve such treatment for patients wiio have cuJtares sensitive to less than three drugs which they are able to tolerate, la our experience surgical treatment can be successfully covered by two drugs only. We have to convince patients who have cultures resistant to the primary drugs that, even tliough it is impossible to restore the destroyed lung tissue, it. is possible to achieve a non-infectious state if ihey will co-operate fully in the treatment. This state caii persist for a long time. Their fives are made easier; there is less risl<: to themselves of relapsing and to others of becoming infected by resistant tubercle bacilli. I^BFERriNCB JANCIK, E.. Zhi-iiT^KA. M., Tov&iiK. J., & MAKOVA, M . 0963). 7'uhercle, Lond., 4-*, 443.