retreatment of pulmonary tuberculosis with ethambutol

RETREATMENT OF PULMONARY TUBERCULOSIS WITH ETHAMBUTOL

J. Luis G6mez-Pimienta, Hector Shibayama Hernandez, L. FelipeP6rez Fernandez, Roberto P6rez Herrera,

Olivia Garc:a Oranday National Pneumoiogy Institute,

Mexico City, Mex.

The need for retreatment in pulmonary tuberculosis, either because of the failure of initial therapy, or because of the relapse of those patients who might have been considered “cured,” is an increasingly frequent occurrence. These patients present multiple problems: bacteriologically they are almost all resistant to one or several of the so-called “primary” drugs, while physiolog- ically they frequently have pulmonary hypertension and, anatomically, most of them are bearers of disseminate fibrocaseous changes of an irreversible na- ture. All of them have chronic tuberculosis, epidemiologically very dangerous and incurable in a great proportion of

Specific or curative treatment is frequently impossible. Therefore, the physician is forced to fall back almost always on strictly conservative measures even though these may have a limited scope. This state of affairs has previously been analyzed by one of

I n this paper we shall express our views on the “retreatment” of pulmonary tuberculosis with ethambutol.

Material and Methods

We selected 14 patients, all with cavernous lesions in an advanced state and bilateral nodular dissemination. Drug therapy had failed in 12 of the patients treated elsewhere; one other presented a bronchial fistula that had appeared one year after lobar resection, and the other had a residual cavity subjacent to a thoracoplasty tha t had been quite limited because of physio- logical reasons.

The ages of these patients ranged between 10 and 60 years, and the dura- tion of their pulmonary disease averaged 36 months. Three were women and eleven were men. The clinical status was serious in eight and moderate in the others. Sputum examinations were repeatedly positive in all patients before treatment with ethambutol, and sensitivity tests for the major drugs TNH, SM and PAS showed constant resistance t o one or several of these bacterio- static agents (TABLE 1).

The patients were hospitalized a t the National Pneumology Institute, with the exception of two patients who should not have left, for a minimum of six months, during which time EMB was administered regularly in a dosage of 20 mg./kg. of body weight daily. Concomitant treatment consisted of 10 mg./

882

G6mez-Pimienta et al.: Retreatment of Tuberculosis 883

R R

R R

R R R R

s

Case No.

R R R S S S S

R R S S S S S

R R R S S S S

R S S S S R S S S S

R R R S S S S

R S S S S

R S S S S

R R R S S S S

R R R S S S S

R R R S S S S

s s s s s s R R R S S S S

R R R S S S S

1. . . 2.. . 3. . . 4 . . . 5. . . 6., . 7.. . 8. . . 9. . . 10. , . 11. . . 12. . . 13.. . 14. . ,

TABLE 1 ETHAMBUTOL IN FAR ADVANCED PULMONARY

TUBERCULOSIS WITH RESISTANT GERMS

Drug Sensitivity (ug./ml.)

SM:

3.5 10 1oc

R R R

s s s s s s R R R

R R R

R R R

R R R

R R R

R R R

R R R

R R R

s s s R R R

R R R

PAS:

5 10 1oc

R R R

s s s s s s s s s s s s R R R

s s s R R R

R R R

R R R

R R R

s s s R S S

R R R

3.2 Y 1 5 2 4 8 16

Medication

PAS, INH,, EMB,

SM, PAS, INH, EMB,

SM, PAS, INH, EMB, PAS, INH:, EMB,

PAS, INH, EMB,

SM, PAS, INH, EMB,

PAS, INH, EMB,

SM, PAS, INH, EMB,

SM, PAS, INH, EMB,

PAS, INH, EMB,

INH, EMB,

SM, PAS, INH, EMB,

PAS, INH,, EMB,

SM, PAS, INH, EMB,

Key: R - Resistant; S - Sensitive.

kg. daily of INH, 12 gm. daily of PAS, and 3 gm. weekly of streptomycin sulphate.

Besides the clinical observations, patients were studied radiologically at least once a month, including tomograms. Laboratory studies included blood chemistry, hematology, urinalysis, sputum examination, and monthly sputum culture. An ophthalmologic examination was performed every two weeks.

Results

Clinical, x-ray, and bacteriologic results are summarized in TABLE 2. Tolerance was satisfactory except in one patient who had mild intestinal upsets. One patient became worse both clinically and radiologically, and one died from cor pulmonale.

Results of sensitivity tests for EMB and PAS after their administration for six months are shown in TABLE 3.

884 Annals New Y ork Academy of Sciences

Case No.

l . . . . . 2 . . . . . 3 . . . . . 4 . . . . . 5. . . . . 6 . . . . . 7 . . . . .

8 . . . . . g . . . . .

10. . . . . 11. . . . . 12. . . . . 13. . . . . 14. . . . .

Results Six Months Later

Radiol. Clin. Bact . Tolerance

+ + + + Positive Well Tolerated + + Positive Well Tolerated f Positive Well Tolerated

+ + + + Positive Well Tolerated + + Positive Well Tolerated + + Positive Well Tolerated + + Positive Transient - Gast ro -

+ + Positive Well Tolerated (-) (-) + Positive Well Tolerated

+ + Positive Well Tolerated

Intestinal Intolerance

+ + Negative Well Tolerated + + + Negative Well Tolerated - - Positive Death from Cor Pulmonale

+ + + + Positive Well Tolerated

Key: - = worse - + = no change + = slight improvement

+ + = significant improvement

Because of technical difficulties, blood levels were determined for only seven patients (TABLE 4). The chemical method employed did not give us satisfactory results, and for the biological method we had recourse to a modification of the method described in the Veteran’s Administration Armed Forces Cooperative Study on the Chemotherapy of Tuberculosis (Tubercu- losis Laboratory Methods, Washington, D. C., 1958), in that we discontinued administration of streptomycin, isoniazid and PAS during the 48 hours previ- ous to the laboratory procedures.

Discussion

The overall therapeutic problem presented by those patients with chronic tuberculosis requiring retreatment is very complex anatomically, physio- logically, and clinically, as well as bacteriologically. Even if we had available a nontoxic therapeutic agent with an antibacterial action strong enough to achieve a bacteriologic cure, we would still be very far from attaining a complete cure for the patient.

I n fact, as a result of hernodynamic and anatomo-pathologic mechanisms, the most frequent causes of death among tuberculous patients are cor pulmonale and h e m ~ p t y s i s . ~ These complications bear witness to the fact that

G6mez-Pimienta et al.: Ret rea tmen t of Tuberculosis 885

Case No.

TABLE 3 DRUG SENSITIVITY SIX MONTHS AFTER TREATMENT

Control Ethambutol Ethambutol Medium

+ INH +PAS Ethambutol

Drugs, pg./ml. in Lowenstein Medium 1

1. . . 2. . . 3 . . .

4. . .

4+ 2Colonies - - - - 2+ + + 4+

4+ 4Colonies - - - - + + - 4+

4+

2+ - - - - - 2 i + - 4+

- - - - - - - - -

I I I 11 5 I lOl2Ol5 pg./ml. each I 5 pg./ml. each1 1 I 10 I

5. . . 4+

6. . . 4+

7... -

a. . . 3+

- - - - - 3Colonies - -

- - - - - - - -

- - - - - 4+ 4+ 4+

Inoculum: 0.01 mg. (wet weight) in 0.1 ml. Read 15 days after incubation at 37°C.

- = Negative + = Growth of 50 to 200 Colonies.

++ = Intermediate growth (over 200 Colonies). +++ = Dense growth but no confluence.

++++ = Confluent growth with surface of medium completely covered.

the disease persists and that no antibacterial agent, no matter how effective it may seem, can have any action whatsoever on it. I n other words, the only thing that we may expect to achieve with an antituberculosis drug, particularly in chronic cases, should be the bacillary negativity of the sputum and perhaps the disappearance of the tuberculin sensitivity. This sensitivity is a biological witness that specifically attests to the persistence of the infection.

In view of the above remarks, it can be stated that the use of ethambutol resulted in a decrease of bacilli in the sputum but not negativity. No significant changes were observed in tuberculin sensitivity. We consider it pertinent to stress that only by employing exhaustive bacteriologic research measures, as we did (21 sputum examinations and 15 consecutive cultures) in each patient, is it possible to demonstrate the persistence of bacteriologic results, because otherwise one would speak of negativation. See TABLES 5 and 6.

886

3.. . . . .

4.. . . . .

Annals New York Academy of Sciences

2 None: Same as the control


TABLE 4 BIOLOGIC DETERMINATION OF ETHAMBUTOL BLOOD LEVELS

Ethambutol Serum Blood Levels : pg./ml.

v......

CASE 1 Modified Biologic Method


I

NO. Concentration at 2 hrs.

in wg./ml. Concentration at 24 hrs.

l . . . . . . I 2 I None: Same as the control ~~

2 . . . . . .1 4 I None: Same as the control

5 . . . . . . 1 4 I None: Same as the control

6.. . . . . 4 I None: Same as the control

With regard to radiologic improvement, it should be emphasized that the only shadows that disappeared were those caused by exudative lesions. For this reason, and particularly with respect to antituberculosis campaigns, one should insist on the need for taking x-rays from different angles and using various techniques in order to ascertain the cure of lesions with irreversible anatomic damage, such as cavities, bronchiectases, and bronchial stenoses. The persistence of these irreversible foci of infection, in our opinion, consti- tutes the primary cause of relapses in tuberculosis.

I n our experience, ethambutol in a dosage of 20 mg./kg. daily was well tolerated without any toxic effects or clinical manifestations of intolerance that might have justified withdrawal of the drug. The toxic effects that have been reported are very likely related to the dosage employed. Blood levels, as found by us after two hours, did not exceed 4 pg./ml., and it could well be that the persistence of bacilli in the sputum as well as the absence of signs and symptoms of toxicity could be explained by the failure to reach sufficiently high levels of blood concentration.

Clinically, improvement was evident in most of the patients: body weight increased, fever disappeared, and there was a considerable lessening of ex- pectoration. One patient died of cor pulmonale and there was only one patient whose pulmonary tuberculosis became worse.

TAB

LE 5

B

AC

TER

IOLO

GIC

STU

DY

OF

PAT

IEN

TS

UN

DE

R T

RE

AT

ME

NT

WIT

H E

THA

MB

UTO

L FO

R SIX M

ON

THS

Cas

e N

O.

1.

..

.-

. I

Sput

u

12

3

- -

4..

..I -

I. . .

. ++

++

8.

. , .

-

- -

- -

2 B

aar

-

- -

- -

++++

++

++

2 -

Baa

1

Pet

rdf

Cul

ture

M

ediu

m

I D

irec

t E

xam

inat

ion

I Pe

trof

f C

ultu

re M

ediu

m

Ace

tyl-

Cys

tein

e C

ultu

re M

ediu

m

Sput

um:

Day

21

31

4

5 3

Baa

r

-

+ -

IBA

r 1 -

Baa

r

-

21

Baa

r ++

-

3 B

aar

+

__

17

Baa

r ++

_

_

-

14

Baa

r ++

-

3 B

aar

+

__

26

Baa

r ++

-

Baa

r ++

8 2

Baa

r I -

1 Baar

~ ++++

++

++

++++

++

++

baci

lli

xill

i in

?he

en

tire

SE

X&

-

3 B

aar

+

5 -

1 - 1 Baa

r 3

Baa

r +

- I Bir

l

-

3 B

aar

+ -

++++

__

++++

__

++++

il̂

B

aar

Baa

r ++

++

++++

++

++

3 B

aar

+ -

-

8 B

aar

+ -

-

+ 1

1

++ =

10

or

mor

e ac

id-f

ast

baci

lli

in t

he e

ntir

e sm

ear

+++

= 10

or

mor

e ac

id fa

st b

acil

li i

n m

any

imm

ersi

on f

ield

s ++

++ =

aci

d-fa

st b

acil

li i

n an

y fi

eld

obse

rved

-

= ne

gati

ve

TA

BL

E 6

R

ESU

LT

S O

F C

UL

TIJ

RE

S FR

OM

PA

TIE

NT

S A

FTE

R S

IX M

ON

THS'

TR

EA

TM

EN

T W

ITH

ET

HA

MB

IJT

OL

-_

_

______.--

'-]-p

c.lt.

..M.d

..m

Ace

tyl-

Cys

tein

e ---edium

Pet

roff

(NaO

H 4

%)

(Kub

ica

et a

l. )

I

Sput

um:

days

Sp

utum

: da

ys

~

~~~

1 2

3 4 1

Col

ony

l.

..

-

z...

. -

~~

1 3

..

..

-

1 Cot

ony

Col

ony

-

4.

. . .

- C

ont.

- ~

3.. .

. - =

Neg

ativ

e.

+ =

Gro

wth

of

50 t

o 200

Col

ouie

s

+++

= D

ense

gro

wth

but

no

conf

luen

ce.

++ =

Int

erm

edia

te g

row

th !

over

200

Col

onie

s).

++++

= C

onfl

uent

gro

wth

wit

h su

rfac

e of

med

ium

com

plet

ely

cove

red

Con

t. =

Con

tam

inat

ed.

Cul

ture

Med

ium

Pet

roff

(N

aOH

4%

)

Gas

tric

Lav

age:

day

s

Con

t. C

ont.

C

ont.

"-

Col

ony

~

50

Col

onie

s ++

++t+

-+

G6mez-Pimienta et al.: Ret rea tmen t of Tuberculosis 889

Summary

Ethambutol in a dosage of 20 mg./kg. of body weight daily was employed in the retreatment of 14 patients hospitalized a t the National Pneumology Institute. All had advanced pulmonary tuberculosis with bilateral nodular lesions and cavitation. All patients received isoniazid and PAS concurrently, and four had streptomycin, at a dosage of 10 mg./kg. daily, 12 gm. daily and 3 gm. weekly, respectively.

The drug was well tolerated, as shown by both clinical observations and pertinent laboratory studies. No effect on vision was noted in any patient, and blood concentration levels did not exceed 4 pg./ml.

Clinical improvement was observed in all but one patient, who died from cor pulmonale. Radiologically, exudative lesions disappeared, but in no patients did cavitation or bronchial alterations disappear. The reduction of bacilli in the sputum was significant, but exhaustive research showed that, with the exception of two cases, complete reversal to negativity did not occur.

In our opinion, ethambutol, like other so-called “secondary” drugs as well as those qualified as “primary” drugs, has only a limited action within the therapeutic problem of chronic tuberculosis. Therefore, t o clarify its method of use and indications, its toxic effects must be carefully watched out for, and its antibacterial action evaluated.

References

1. HOLM, S., K. N . RASMUSSEN & K. WIENGE. 1960. Relapses among patients with pulmonary tuberculosis in Copenhagen in the years 1945 to 1958. Acta. Tuberc. Scandinav. 38: 235.

2. AMSLER, R. 1963. Factors in increasing development of chronic pulmonary tuberculosis. Sem. Hop. Paris 3 9 334.

3. G6MEZ-PIMIENTA, J. L. 1956. Quick treatment of pulmonary tuberculosis. Bruxelles-Medicale 45: 1851.

4. G6MEZ-PIMIENTA, J. L. & R. S. ARGUELLO. 1964. Treatment of pulmonary tuberculosis with resistant germs. Bulletin of the Nat. Inst. of Pneum., Mexico City. 1: 1.

5. 6.

MACLEOD, W. M. 1962. Death from tuberculosis. Brit. Med. J., 1: 1379. KUBICA, G . P., W. E. DYE, M. L. COHN & G. MIDDLEBROOK. 1963. Sputum Diges-

tion and decontamination with N-acetyl-cysteine-sodium hydroxide for culture of mycobacteria. Am. Rev. of Resp. Diseases, 87: 775-779.

retreatment of pulmonary tuberculosis with ethambutol

Documents