2.5 Ethambutol in the Treatment of Patients With Chronic Pulmonary Tuberculosis

8/7/2019 2.5 Ethambutol in the Treatment of Patients With Chronic Pulmonary Tuberculosis

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February 1971 S . A . M E D I C A L J O U R N A L 171

MATERIAL AND METHODS

Forty-six Bantu an d one Coloured pat ient were treatedfor per iods of 3 - 19 months. They were hospitalized atRietfontein (Johannesburg), Zonderwater (Cullinan), Tshepong (Pretoria), an d George Stegmann (Saulspoort). Allwere chronic cases according to the usual definition,i.e. their strains showed resistance to the best drugs;moreover, they ha d bilateral pUJnonary tuberculosis, andwere above the age of 15 years. All had had previousthe rapy with primary and/ or secondary antituberculosis

drugs. They w e n ~chronic excreters of M. tuberculosis.Th e 47 pat ient s were d iv ided into two distinct groups:

Group I , compris ing of 23 pat ients, received ethambutol(EMB) an d isoniazid (INH) only. These were patientswho ha d already received many reserve drugs an d excretedINH-resistant organisms. Th e clinicians, however, expectedsome therapeut ic value from the administration of IN Ha nd h op ed to make the bacterial population fully catalasenegative an d t hu s a tt enu ate d. It is generally accepted,,lIthat IN H may have a beneficial effect in pat ients withprimary IN H resistance, an d Freerksen" showed in experiments on a ni mal s t hat INH ca n ac t like a secondarydrug on INH-resistant s trains . Canet ti et al." recently

stated that when drug resi stance has emerged dur ingchemotherapy n. further response should be expected, an dthis is t rue even fo r INH.

Apart from IN H and EMB, 7 of the 23 patients wereoiven addit ional drugs, namely PAS in 4 cases, strepto~ y c i nin 3 cases, kanamycin in I case, capreomycinin 4 cases, an d pyrazinamide in 1 case. Their strains,however, had shown in vitro resistance to these drugs.Th e strains of the 23 patients were all fully sensitiveto EM B and 3 showed ill v i/ro resistance to IN H at thelevel of 01 p.g/ml only. In their case, the IN H wasexpected to have therapeutic effect.

Group 11, compris ing 24 pat ients, received ethambutol,plus I or 2 other antituberculosis drugs to which the irs trains showed sensi tivity in vitro. Participating physicians were free to use a drug of their choice, and inmost cases t he drug sensitivity pattern was known at thestart of the tri al. The test was done using the absolute

ETHAMBUTOL IN THE TREATMENT OF PATIENTS WITH CHRONICPULMONARY TUBERCUWSIS*

M G . B. R. DE MUElENAERE, M . B . , CH.B. (PRET.), M.MED.PATH., H . H. KLEEBERG, DR.MED.V:ET. (GIESSEN).J. ' MACKINTOSH, M.B. , B.CH. (RAND), E. BEHYNA, M . D . (BUDAPEST), AND E. G L A T T H A A ~ ,M . B . ~CH.B. , . D . P. H .

(PRET.), Me di cal Research Counci lT u b e r c u l o s i ~

Research Group, Onderstepoon; Rletfontem /fosPltal,Johannesburg; Zondenvater Hospital, Cullman; an d Tshepong S A N TA Settlement, Pretolla

associated and usually reversible on discontinuation ofthe drug.

Th e emergence of resistance to ethambutol appears tobe slow. On monotherapy the following figures weregiven: 41 ~ ~ within 3 - 6 months: 37% within 3 - 5 months,'an d 58% after 6 m on th s. ' W he n given in combinationwith other effective drugs, the makers report 68% of 380chronic cases as drug-resistant."

The purpose of our study was the ev alu at io n of theefficacy an d acceptability of prolonged ethambutol treatment in chronic multi-resistant cases of pulmonary tuberculosis. Emphasis was placed on the bacteriological statusand follow-up results.

e ar e now 13 basically different antituberculosis drugs7 derivatives of these drugs in use in South Afr ica.

s becomin a increasingly difficult fo r th e n on -e xp er tdecide on '" the correct dosage and combination ofe drugs, especially once the initial treatment hasd to convert the spu tum.

major ant ituberculosis drug should be highly effecacceptable to the pa ti en t, non-tox ic an d reasonably

p. Th e price is impor tant in a country w h e r ~a ~ o ~ tpatients ar e treated at Sta te expense. Only Isomazld

streptomycin have in the past fulf il led the aboveditions for major drugs. A new major drug shouldbe suitable fo r self-medication an d for intermittent

apy and produce no cross-resistance to well-establisheds.he l iterature o n e th am bu to l hydrochloride is alreadynsive and most of the above conditions seem to belled. Its relatively high pri ce makes its i nt rod uct ion

first-line drug problematic. As a second-line drugeems to be eminently suitable in view of the inacability of most of the pr esently available reserves. To o often treatment is stopped by the docto r o rsed by the patient because of toxic symptoms; and

happens especial ly with treatment containing ethioide, pyrazinamide an d cyc!oserine. When all threegiven together they have a substantial degree of

city. In routine secondary treatment these drugs showisappointingly moderate rate of success. Th e o t h ~ r

reserve drugs-rifampicin, kanamycin. capreomyclDviomycin-are very expensive, costing about 300

s as much as isoniazid .South Africa Dormer' undertook a trial with etham

l in 47 cases of chronic pulmonary tuberculosis an dlton' described the chemistry, in vitro and in vivo

vity, pharmacology an d adverse react ions of this d rug.main features are its high specific activity againsttuberculosis, M. bovis and othe r species of mycobac. Of 35 South African wild strains of M. tuberculosisd bv us on Lowenstein-Jensen medium, all were

sen'sitive to 15 p.g/ml, an d 25 s trains also to 0' 7ml ethambutol. Twenty strains of M. bovis wered in the same way an d all but two were fully sensitive7 p.g/ml. Seven of the sensitive s trains were i son iaesistant M . bovis.e drug's act ion is of a degenerat ive type. Th e bacidal phase is preceded by a phase of bacillary multi

a tion last ing several days.. .. Dickinson et al: proveduinea-pigs that if the daily doses ar e accumulated,mittent d ru g i nt ak e is superior to daily dosage. Adstration by mouth is on a once- dail y schedule, and

absorpt ion and excretion occur rapidly. I ts acceptay to the pat ients an d the rar ity of side-effects makesui table for self-medication. I ts o cu la r toxicity is dose-,

r ec ei ve d: 9 September 1970.


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172 S . - A . M E D IE S E T Y D S K R I F 13 Februarie 1971

concentration method an d Lowenstein-Jensen medium atthe following levels: PAS at 05 an d 10 fLg/ml, INH at01 an d 5 fLg/ml, streptomycin at 5 an d 50 fLg/ml, thiacetazone at I an d 10 fLg/ml, ethionamide at 20 an d 30fLgfml, cycloserine at 10 an d 30 fLg/ml, viomycin at 20an d 30 fLg/ml, k an am yc in a t 10 an d 20 fLg/ml, capreomycin at 30 an d 50 fLg/ml, pyrazinamide at 20 an d 100fLg/ml, and EMB at 5 an d 10 !Jog/m!.

PA S was given in 12 cases, kanamycin in 10 cases,capreomycin in 4 cases, cycloserine an d pyrazinamide in2 cases each, an d ethionamide in I case, al l at routinedosages.

Additional drugs given despite in vitro resistance wereas follows: IN H in 17 cases, thiacetazone in 5 cases,PAS, streptomycin an d capreomycin in 2 cases each,an d cycloserine, e th ionamide and kanamycin in I caseeach.

In both groups the dose of e thambutol was 25 mg/kg /da y in I dose pe r os fo r the first 2 or 3 months. Subsequently 15 mg/kg/day was given f or a no th er 9 or 10

months. Th e dose of IN H was usually 600 mg/day.During hospitalization the intake of drugs was controlled,bu t after discharge it was no t possible to ensure selfmedication.

All patients showed bilateral pulmonary tuberculosiswith far-advanced disease and/ or extensive destructionon X-ray. One or multiple cavities were visible in 31 ofthe patients. Their weigh t was recorded, and laboratorytests such as haemoglobin value, SGPT, SGOT, anderythrocyte sedimenta tion rate were carried out. Th e history, previous treatment an d clinical condi tion were verys imil ar for both groups. Fourteen pat ients were femalesan d 33 were males. Th e age var ied from 20 to 76 years,with a mean of 41 years. Together they ha d ha d 94

previous admissions, which is an average of 2 admissionspe r patient. Admitted or known previous treatment variedfrom 2-!- to 125 months, with an average duration of 49months per patient. Th e average weight was 110 Ib (50 kg),vary ing fro m 68 to 148 Ib (30 - 67 kg). Th e clinicalcondition was poor in 17 cases, fair in 11, an d relativelygood in 6 cases. During hospitalization X-rays were takenevery month and, as fa r as possible, th e ES R an d weightwere measured. Eye examinations fo r visual acu ity werea!so performed monthly. After bacteriological conversionan d discharge, patients were referred to outpatient clinics.Satisfactory clinical data on all pat ients concerned couldonly be obtained fo r the first 4 months of treatment.Th e clinical status at that t ime is given in Table I.

Sputum samples were sent t o O nd er st ep oo rt initiallyat weekly an d later at 2-weekly intervals fo r microscopyand culture. Sensit ivity tests were done at montWy intervals. As is customary today, final eva luation in this studyis based on the bacteriological results. Th e laboratorymethods used have been described elsewhere.'" Afterdischarge from the hospital sputum specimens wereusual ly sent at i rregular intervals varying from one toseveral mon ths, a lthough pa tients were supposed to report to their nearest clinic every 4 weeks. In many casespatients had to be traced in order to obtain spu tum an dwe do not know whether they took the EM B tabletsdaily.

RESULTS

Th e term 'bacterial conversion' means the c ha ng e f ro mpositive sputum culture to negative fo r 3 consecutivemonthly sputa . Where the findings differ from this definition, the leng th of the negative period will be given. Wedefine a case as a relapse when after several consecutivenegative sputa, growth of M. tuberculosis re ap pe ars o n

culture. Th e term 'reconversion ' is used when a pat ient 'ssputum first becomes negative, then positive aga in fo r afew consecut ive samples an d subsequently converts tonegative.

The clinical and radiological assessment after 4 monthsof EMB treatment as given in Table I illustrates theamazing improvement which occur red in many of thesedesperate cases. Th e majority of seriously ill pat ien tshad a dramatic clinical c ha ng e f or the bet ter. Patients ingroup 11, where EM B was combined with other effectivedrugs, showed resolution of infiltration more often thanpatients on EMB and IN H only, bu t failure of infiltrationto c lear was due mos tly to fibrosis.

Th e therapeutic history an d the resistance pattern at

the sta rt of the trial ar e given in Table 11. Five to 6different drugs h ad been used previously, an d in almostall cases the patients' strains were resistant to IN H an dstreptomycin an d several reserve drugs.

Th e bacteriological results as summarized in Tab les II Ian d IV and Fig. I will be descr ibed in more detail. Th esputum of patients in group I, given EMB and IN Honly, converted in 12 cases. Conversion occurred in 4cases in the 1st month , in 5 cases in the 2nd, in 2 casesin the 3rd, an d in I case in the 4th month. No furthercases became negative after 4 months. Th e hi gh er th ecolony count at the start of therapy, the later conversionoccurred. In 3 of the 12 cases we c ou ld o nl y examine 2consecutive negative sputa.

TABLE I. C LIN IC AL AN D RADIOLOGICAL A SS ES SM EN T A FT ER 4 M ON TH S O F ETHAMBUTOL TREATMENTTherapy Clinical s taflls Weight changes Resollltion of Alteration ill size of

infiltration on X-ray cavities 0/ 1 X-ray

Group I (EMB+INH)23 cases

Group I I(EMB+ otherdrugs)24 cases

20 felt, looked and weremuch betterno changedied (pneumonia)died ( l month afterwithdrawal of EMB)

14 felt, looked and weremuch better

9 no information1 deteriorated

16 showed weight increases of 13-163kg (average 62 kg)

7 no information

14 showed weight inincreases of 0-4 - 108kg (average 49 kg)

1 lost 62 kg

9 no information

9 improved (3 slight,4 moderate, 2marked)

10 no change4 no information

18 improved (7 slight,4 m o r l e r ~te, 7

marked)1 deteriorated


13 improved ( l closure.7 much smaller, 5somewhat smaller)


11 improved (4 closures,1 much smaller, 6somewhat smaller)

1 deteriorated



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uary 1971 S . A . M E D I C A L J O U R N A L 173

BLE 11. KNOWN PREVIOUS CHEMOTIIERAPY HISTORY AND llACfERJAL RESISTANCE AT START OF E1liAMBUTOL TREATMENT

IN H SM PAS TH ET H CS CAP PZA V M K MI (EMB + INH) 23 cases

23 18 10 9 6 12 5 ofs received previously 23 1 2 Mean 5 drua sitro bacterial resistance acquired 22 22 16 18 16t 6 4t 5 4 6 Resistant to mean

of 5 clrogs

II (EMB+ IN H + other drugs)

asess received previously 24 24 21 14 15 14 4 16 7 10 Mean of 65 drugsitro bacterial resistance acquired 23 22 11 18 15 10 4 2 4 5 Resistant to mean

of 5 drugsisoniazid; SM = streptomycin; PAS = para-amino salicylic acid; TH = thiacetazone; ET H e th io na m id e ; C S = cycloserine; CAP =

mycin; PZ A = pyrazinamide; V ~ = viomycin; KM = kanamycin.ce 10 I Jlg TH occurs naturally In S ou th A fn ca .tment ca n cause ET H resistance.ce 10 CA P can be caused by use of KM or VM.

LE Ill . BACTERIAL STATUS AT END OF LABORATORYINVESTIGATJONS

Group IIGroup I EM B + other

treatment EMB mnnotheraoy drugsrage length (treated 11 months) (treated 9 months)

No. % No. %

ion 12 52 16 67rsion 3 13 0 0

3 13 1 4ly posi- 5 22 7 29

l patients 23 100 24 100

INFECTIOUSNESS OF PATIENTS' SPUTA AT 3-MON'lHLYINTERVALS

Time lapse after start of EM Btreatment

.. ..

,:::: OS'":: s::.. c c

.. .. .., ~ l:: l::~ ~ "S s::s::: s:: s:: c '" 00C


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174 S . - A . M E D IE S E T Y D S K R I F 13 Februarie 1971

Th e resistance pattern to other antituberculosis drugsin strains isolated f ro m p at ie nt s in group II was verysimilar to the pattern for pat ients in group I. But, contrary to group I pat ients, no resistance to EM B emerged.Two patients on kanamycin an d 1 on PA S acquiredresistance to the drug concerned.

DISCUSSIONA comparison of the results obtained in the 2 differentgroups shows a higher rate of conversion an d a lowerrate of relapse in t he g roup on EM B treatment combinedwith other effective drugs than in the g roup that receivedEMB and IN H only. This was to be expected as allwe re c hr on ic cases of tuberculosis with poly-resistanceof the excreted organisms. Th e use of one effective drugalone in cases of advanced pulmonary tuberculosis willlead to emergence of resistance to that drug. Th e totalconversion rate however is nea rly the same in both groupsif reconversion is added. I t is 65% for EMB 'monothe rapy 'an d 67'% fo r combined EM B therapy.

In group I, which was vir tual ly on EMB monotherapy,th e rate of relapse was higher than in group n. In the3 cases of reconversion on EMB monotherapy, resistanceto 5 j-Lg/ml EM B emerged in their last posit ive culturesduring the relapse period, i.e. in the 4th, 5th an d 6thmonths respectively. Reconversion to negative occurredwithout a change in therapy.

As regards th e cases which per sisten tly exc ret ed M.tuberculosis, none of those on combined EM B treatmentdeveloped drug resistance, while 4 of the 5 cases on EM Bmonotherapy showed a resistance to 5 j-Lg/ml EM B after7 - 12 months of t re at me nt . T hi s indicates that thesepatients continued to take the drug as outpatients.

Th e most likely explanations fo r the maintenance of

sensitivity to EMB is that our in vitro method was no tsensitive enough to detect resistance. After this tr ial wechanged t he lowes t concentration of EM B incorporatedin the medium to 2 j-Lg/ml. However, Gyselen et al. 15

using 2 j-Lg/ml of ethambutol for in vitro tests also foundthat, contrary to experience with other drugs , the failureto convert to negative was as a r ule no t ac comp an ied bydemonstrable drug resistance. Th e in vitro difference between sensitive an d res is tant s trains is very small . 13

I t should be emphasized that all but 1 of the 28 successfully treated cases converted within the first 4 monthsof EM B treatment. Usual ly convers ion was earl ie r whenthe number o f cul tivable bacil li was low at the start. Th ebacteriological relapses in group I on EMB mono-the rapy occur red after 3, 6, 7, 10, 12 an d 14 monthsrespectively, but most of these pat ients were desperatecases an d no miraculous results could be expected. Inthis t ria l the only known relapse after c om bi ne d E MBtreatment occurred during th e 17th month.

Ou r over-all results are comparable to those publishedelsewhere. On EM B monotherapy the rate of conversionafter 6 months is 51'% fo r 163 chronic cases describedin the literature; in this trial it was 50%. Fo r a 12-monthperiod the rate from the literature is 35% 'of 98 casesan d in ou r study it was 46%. Ou t of a total of 163 cases28% were reported to be persistent excreters 6 monthsafter starting E MB, an d t he sa me figure was obtained in

our series. Th e 3 months on combined EM B treatment

evaluat ion of 191 published chronic cases shows conversion in 130 patients, i.e. 68,% compared with 58% conversion in ou r 24 patients.

Although clinical an d radiological assessment of ourseries is only complete fo r the first 4 months, i t is evidentthat improvement was usually rapid an d significant. Theclinical change was often dramatic in pati ent s wh o werevery ill. T he impro ved status was usually maintained.Radiological changes were difficult to evaluate becauseof the extent of the disease. One patient on EMB monotherapy who remained persistently positive an d showedEM B resistance, died after an intercurrent pneumonia.

Th e str iking therapeut ic response was coupled with ahigh degree of acceptability of the drug an d the absenceof hypersensitivity an d side-effects. As fo r toxic reactions.we have on record only 1 patient wh o complained ofweakening of vision after 4 days of t re at me nt w it h 25mg/kg EM B per day. Th e dosage was reduced to 15mg/kg/day an d his vision r et ur ne d t o n or ma l.

Th e follow-up study was greatly hampered by the

number of patients who disappeared before completionof treatment an d could no t be traced.

SUMMARY

Ethambutol was used in the re-treatment of extensive chronicpulmonary tuberculosis. Most patients' bacterial strains wereresistant to all major drugs. During the first 2 months 25 mg/kg was administered per os, thereafter 15 mg/kg body-weight.In group I, 23 patients were treated with ethambutol plusisoniazid (INH), which was virtually a monotherapy becauseof r e s ; s t ~ n c eto isoniazid. In group n, 24 patients were treatedwith ethambutol plus 1 or 2 other effective secondary drugs.

Ethambutol brought about rapid and significant clinical andalso radiological improvement. Reversal of infectiousness wasachieved in 6 5 ~ ~in group I and 67% in group n. I n groupI, 13 % of patients relapsed, and in group n the rate was 4 %.

A great proportion of patients disappeared due to the lengthof the trial. Sputum conversion was usually obtained withinthe first 3 months.

Ethambutol was found to be a very effective drug in there-treatment of chronic tuberculosis, and quite suitable forlong-term administration. Ethambutol in the dosage used wasvery well tolerated and caused no significant ocular side-effects.I t shOUld always be given in combination with 1 or moreeffective antituberculosis drugs.

Some of the ethambutol used was kindly supplied byLederle Laboratories, Division of Cyanamid International.

REFERENCES

1. Dormer, B. A . ( 19 68 ): Med. Proc . 14, 72.2. Cha rll On, R . W. (1968): Ibid., 14, 74.3. Grumbach, F. (1969): Tubercle (Ed inb .) , 50, suppl. March, 12.4. Forbes, M. , Kuck, N. A. an d Peets, E. A. (1962): J . B ac !. , 84. 1099.5. Dickinson, J. M. , Ellard, G. A. an d Mitehison, D. A. (1968):Tuberc'e (Edinb.), 4 9, 351.6. Oka, S ., K on no . K. , Kudo. S., Munakata, K. , Yamaguchi, S. and

Oizumi, K. (1965): A me r. Re v. Re sp . Dis. , 91, 762.7. Leading Art icle (1966) : Tubercle (Edinb. ) , 47, 2 93.8. Pyle, M. M. , Pfuetze. K. H. , Pearl ma n , M. D. , De La Huerga, J.

and Hubble, R . H. (1966): Amer. Rev. Resp. Dis., 9 3, 4 28 .9. Medical Research Department, Cyanamid International (1968): Myam-

b ut al i n I ni ti al Tre at me nt a nd R e- tr ea tm en t of Pulmonary Tuberculosis.10. Devadatta. S. Bhatia, A. L .. Andrews, R. H . Fox, W ., Mitchison.

D. A .. Radhakrishna, S., Ramakrishnan, C. V., S el ko n, J. B. andVe'u, S. (1961 ): B ul l. W ld Hlth Or g . 25 , 807.

11. Tripathy, S. P., Menon, N. K ., M it ch is on , D . A . . N ar ay an e, A. S. L. .Somasundaram, P. A., Stoll , A. an d Velu, S. (1969): Tuberc'e(Edinb.), 50. 25 7.

12. Freerksen, E . (196 9): Prax. Pneumol., 23, 450.13. Canelli, G .. F ox, W. , K ho me nk o. A ., M a hl er , H. T . . M en on . N. K. .

Mitchison, D. A., Rist, N. an d SmeIev, N. A. (19 69 ): BulL Wl d HlthOrg., 41, 21.

14. K leeberg, H . H ., Koo rnh of, H. J. and P al mh en , H . (1970): Laboratory Manual of Tuberculosis Methods. Pretoria: Department of Health.

15. Gyse'en, A. . Verbi s! , Loo Cosemans. Joo LaCQuer, L. M. and Vandenbergh E. ( J9 68 ): Amer. Rev Resp. Dis., 98, 933.

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2.5 Ethambutol in the Treatment of Patients With Chronic Pulmonary Tuberculosis