The Continuous and Concurrent Use of Streptomycin, Para-Aminosalicylic Acid, Isoniazid Plus Early Surgery in the Treatment of Tuberculosis

The

Continuous

and

Concurrent

Para-Aminosalicylic Surgery ALBERT

R.

Acid,

in the M.D.,*

ALLEN,

GUY

The

development in

tuberculosis. found to tory; of

action

drug

of

while

strains

action

decreased, Pitts,

as Tempel,

are

seen

but

developed

in

others in streptomycmn present and

by

Miller,

Sands,

the

five

large

of

regimen

all

directly

these and

Mackaness

and

11 patients

of

four

with

and

During

the

tuberculosis by

year

admitted had been

beginning

therapy.

regarding

June

All

had

sections. these

range

from

0-10 years 10-20 20-30 30-40 40-50 50-60 60 and over

....

“

“ “

“

“

-

*Medlcal Selah,

Director

clinically

beneficial

by effects

resistance

positive.

had

D’Esopo3

the use 1, 1952,

and

of continuous we began

para-ammnosalicylic from

admission

our acid

to

discharge

tuberculosis.

but

101

cultures

following

cases

101 treated none had or

table

of

proved

with received

the

tuberculosis three previous

a diagnosis

shows

background

drugs, anti-

substantiated material

patients.

Discharged Patients Still Hospitalized Deaths TOTAL Age

the survival is further

Methods

these

positive

The

still

independent

used the

of

both been the labora-

concentration be

bacterial

extrapulmonary

1, 1952,

to our hospital. Of hospitalized elsewhere

pathological

When

were

continuously

and

the together bacilli

had established acid. On June

or

have in

used tubercle

Weiser2

main

treatment

to

streptomycin,

pulmonary

M.D.

Is the

the

appears

definite

that

Material were nine

in

with

are

and

months

administering

concurrently

patients

K. YU,

organisms

Smith.’

Fitzpatrick

the

JAMES

hydrazide organisms

isoniazid

two drugs extracellular

of

and

therapy

varies the

end

Early

Tuberculosis

tubercle

acid tubercle

government hospitals and para-aminosalicylic

isoniazid

to

shown by

of

isonicotinic action on of

of drug concentration. When time of both intracellular

Plus

M.D.

antimicrobial and

Streptomycin,

Washington

streptomycin the

of

E. MARCY,

resistant

continuous

Streptomycin have a bactericidal

the the

of

using

of

Isoniazid

Treatment Selah,

problem

Use

and

Superintendent,

60 36 5

Male Female White Non White

62 39 76 25

14 8 15 19 18 9 18

Extent of Disease Minimal Tuberculosis Moderately Advanced Far Advanced Extrapulmonary Primary

4 38 38 9 12

Central

Washington.

41

Washington

Tuberculosis

Hospital,

42

ALLEN, The

adults

a week,

received

children

twice

a week.

on the tablet,

basis and

sodium

Isonicotinic

children

form

of

the

Upon positive days,

using

with

tance

to

grams

of the the

the

as

disease by

choscopy

reveals

when by

six

and

months

of the

third

patients

month

sputum three

contents

the

our

opinion

destroyed

have

not

tissue converted

are

are

for resis-

intervals.

is

hospital

tomographs

kept

Roentgeno-

It

who

in

was not successive

month

the

into

went

Gastric

clearing.

were

physically

develops.

represents

All

were

at three

No

they

culture Is whether bacterial

if it

some

healing.

and

tituted

a delaying

patients,

the

25

Twenty

and

patient factor

the

cavity

to

etc.) and be salvaged

swelling, for

(4)

then

three

have

of been

resection were

wall.

considered

taken

and

bron-

positive (2)

for when

three there

or

accept

without

any

when portions by decortication.

surgery

Is

again.

This

our

bronchial

prolonged

delayed

two

bronchitis

patients.

In

period

of the lung If bronchos-

this

to has

series

have

been using

following

performed. sections

table

of

Surgery

Culture

contains

After

surgery, disease,

summaries

Before

Surgery

Culture

of Specimen

1 Pneumonectomy

Negative

Negative

5 Lobectomies

Negative

Negative

1 Lobectomy 1 Lobectomy

Negative Positive

Positive Positive

Negative

Negative

Positive Negative

Positive Negative

5 Segmental

Resections

3 Segmental Resections 2 Wedge plus decortication

of

obvious

surgery. Pulmonary

three cons22

done.

cultured The

has been antibiotics, with

likely

is bronchoscoped

with

specimens

patient of the

destruction

is not

(alcoholics, adhesions may

thoracotomles from

of

patient

bronchoscopies

pathological

(1) the all three

areas

the

redness

months

usually

or

admission

Antero-posterior

localized

(3)

of hospitalization bound down

the

end

is present showed

surgery when after receiving

extensive

stenosis,

copy

the

determine

and

weight.

patients

media. original

adults,

and

on

groups

is done. recommend or more

are

on

from

candidates.

to

to their

they

the

Petragnani’s The

isoniazid

after

as of

all patients whose contents cultured and

disease

daily to

soon

age

nearest 50 mg. Ten grams of

of patients

most

discharge.

obtained

resulting

as

months

hospital gastric

remaining

cultures surgical

We months

or were

group

twice

to all to the weight.

given

1954

intramuscularly

administered

according

this

cultures

long-standing

scarring

their

three

subsequent

chest

gram

1/2

was

privileges

of

until

streptomycin

old

on

Lowensteins

monthly

was

down

used

the their

intramuscularly

received

solution

lavatory

to had

July,

sulfate

age

scaled

was

full

modified

are cultured comparison

that

use

admission on smear

Even

in

up. At the end room to eat.

YU

of body weight adjusted the patient gained in

was

therapy

to

to be dining

of hydrazide

kilo as

dosage

collapse

encouraged

or

acid

of 4 mg. per also adjusted

AND

of streptomycin

12 years

para-aminosalicylate

for

able the

1 gram

under

MARCY

of

Vol.

ANTIBIOTICS

XXVI

AND

EARLY

SURGERY

IN

TUBERCULOSIS

Extrapulmonary Surgery 5 Genito-urinary tuberculosis 3 Nephrectomies. 1 Bilateral resection of the epididymis plus right moderately advanced pulmonary tuberculosis. 1 Ureteral transplant to the large bowel; 1 kidney

43

orchiectomy;

patient

functionless,

has

marked

involvement of the bladder with stenosis of the ureter where it enters the bladder; also has moderately advanced pulmonary tuberculosis. 5 with Bone Involvement 2 TuberculosIs of the knee which have been fused. 1 Tuberculosis of the fibula with a sinus tract that was saucerized and the tract excised; also has moderately advanced pulmonary tuberculosis. 2 Fusions of the spine, one with pulmonary tuberculosis, the other with a sinus tract from lumbar 5 and the sacrum.

Early

surgery

clearing

had

is taken

possible place

because at

the

occurring during the first had subsided within three the

bronchus

would

negative

for

tubercle

surgical

death,

no

and and

when

spread

or

our

Time

in

patient

have

are

resistant

months

treatment two been

of which

these

patients

and on

closed

change

bronchitis so that

have

there

disease

was

of the

the acute of admission

become

has

the

been

opposite

with

primary

acute was

to

no side,

suture

to

the

and

following

isoniazid,

table.

53

21

8

5

5

2

2

55.2

21.9

8.3

5.2

5.2

2.1

2.1

3 mo.

resistant

at

Six

six

Both

onset

isoniazid of and

months have

4 mo.

at

had

five the period four months,

over

of

6 mo.

treatment

resistant time three

have

been

5 mo.

bacilli

re-

at

the was Both

organisms

and

are

now

6 mo.

and

before conversion at five months.

developed

resected

Over

that negative.

Drugs:

and

Toxicity: eosinophllia

reaction

subsided,

continued

the

to

comparable

2 mo.

for

isonlazid.

in

is

1 mo.

convert.

and converted

of our patients used streptomycin

is shown

streptomycin

positive to

Reaction

Streptomycin temperature dosage

was

five

who

the

cultures

of Conversions

onset of prolonged;

Toxic

of

Converting

Percentage One

reactivation

maximum most

and, time

of

surgery

in the condition et al, when they

Months

quired

with

Evaluation:

conversion

Number

All

following fistula

General improvement described by Pitts,

and

months, period; from

resected.

bacilli

roentgenologically,

of six

three month or four months

only one bronchopleural a small thoracoplasty.

Bacteriological that

heal

shown

end

for

Two

dermatitis occurred on

they four

and

were six

the

given months

medicamentosa 28th day

with treatment.

of

elevated After

dihydrostreptomycmn

and

until

without

their

discharge

the

any further difficulty. Two with renal tuberculosis developed toxic nephrltis with elevation of blood urea nitrogen which returned to normal level within two weeks after stopping streptomycin.

44

ALLEN, Para-aminosalicylic

occurred In any further symptoms. Isoniazid She

was

a

Toxicity:

had been to administer

receiving it

Toxicity:

Only

has

one

epileptic

isoniazid. The

following

the

60

of months received:

table

is

discharged positive,

of

therapy

2

Far

Advanced

Advanced

that

of Conversion

Patients

10

1.7

17 (Three

periods

moderately ilar, both

The

regardless

1.67

248.3

2.7

4

172.1

10

Days

207

No.

Per Time

194.2

cent

77 90

and discharged

the

of

far

advanced group

their

extent

of

patients

hospital

their

admitted

tuberculosis 60 and

of

stay

is

the

of

93

-

160.9

convert

2.05

in Hospital

185.3

to

1.67

152.3

Averages

Received

--

required

Positive

200.2

Isoniazics

time

No.

20

5

length

of

Days

P.A.S.

of

PATIENTS Average Months

27

RECEIVED

advanced In the

hospital.

DISCHARGED Average No. Hospital

group

months

Streptomycin

The

number

discharged

2.88 months

Average

-

hospitalized

243.5

Final DRUGS

of

by

2

5

Extrapulmonary with Pulmonary)

but

average

the

No.

isonlazid.

administering still

disease,

SIXTY

month

Primary

patients

of

to

convulsions

continue

PATIENTS IN HOSPITAL Average Rate

1

prostration

reaction

36

1954

from 24 to 49 days and recurrence of the same

to

the

amount

Patients

Minimal

of

the

of

marked

of

possible

extent

No. Stage

it was

to

THIRTY-SIX

drug in

recurrence

regard

and

and

unfavorable a

a summary

July,

fever

with

REMAINING

Moderately

had

drugs

YU

the resulted

had

who

anti-convulsant

AND

Chills,

four who attempt

known

Increasing

and

Acid

MARCY

with

minimal,

are surprisingly 36 remaining

generally

about

In the

simthe same

disease.

Discussion When

we

compare

acid and Isoniazid,

isonlazid there

first

months

of

four all

three

is

our with little of

drugs

therapy.

seems

conversion rate The question

and the Is raised:

cultures

end

ment

by of

the

bacterial

results

of

using

the results difference to

Beyond be

emergence Why three

resistance

streptomycmn,

of Pitts, between

of

that

time,

greater

accounts

however,

therapeutic

of fewer do not all

months?

para-aminosalicylic

et al, using streptomycin the two programs during

resistant patients

Bacterial for

the value

resistance eight

of

a higher

of organisms. their gastric or

the

combination with

strains convert

and the

14

the who

developdid

not

Vol.

ANTIBIOTICS

XXVI

convert

during

became

negative

to

the

the

tuberculous

following

hysterectomy

normal We have

activity

in

There

to

always

been

our

been

to

farm

weights

of

or

and

uterus

was

given,

of

to

bronchitis

supply

had

marked

became

negative

her

patients.

Once

were

and

blood

14,

she

maintain

they

45

poor

the

and

possible

though

other

hemoglobin they

became

permitted

previous

additional

foundry

work of this of these

but

our

patients

161

days

of

out of an average no readmissions

and

and

carpentry.

group

have

There

received

of 207 days it would seem

in

the

an

no

labor,

these the

every

hospital

their

of

and

of

If

dosage

194

185

after

roent-

leaving should

days

days one

for

discharge

evidence

average

hospital.

this

of

maintained

acid

that

upon

physical

no chemotherapy since three drug combination

para-aminosalicylic

has

returning

examine

out

been

had the

hard

We

has

have long

been

immediately

to

been

the

exertion

have

activity back

have

and

specimens.45 have been

physical we

gone

patients

have

since

and

have

symptoms.

bacteriologist

pathological specimens

reactivation,

occupations Many

and some more. All no

of

the

found on pathological

authors,

cause

hospital.

have

between

cultures from our

change. These patients We do not know how

tomycin,

acute

had

last

positive

even

the

their the

work,

genological the hospital. be

reports

from

three months six months

The

fibroid

disagreement

considered

patients

doing

so

the negative of culture

the

discharge

it

had

Two

silicosis. a

TUBERCULOSIS

Three

subsided.

intermittantly

great

regarding the results

similar

to

IN

hospital.

has

clinician Since

to

due

remained

the

months.

when

seen

they

SURGERY

bronchitis due

loss

level. not

negative,

three

the

area

blood

at

first

when

continuous

EARLY

AND

of

of

strep-

isoniazid

year

are

there

is adequate.

SUMMARY

1)

When

usage

we

of

the

streptomycmn,

drugs

used

with

a higher

of

compare

streptomycin-isoniazid

combination

para-aminosalicylic

concurrently

and

conversion

acid

continuously

rate

and

have

the

and a greater

emergence

of

with

isoniazid,

our

the

three

therapeutic

fewer

value

resistant

strains

organisms. 2)

centage 3) only sistant

It

is

possible

to

of patients

maintain

because

Surgery after four to safe but it is desirable organisms.

4) Sixty occupations, They have

this of the six

few

regimen toxic

months because

of it

of

this prevents

patients have been discharged and regardless of the amount of activity shown no roentgenological change,

charge

weights

cultures

as

or

gained,

and

some

therapy

reactions.

have

on

The

three the

cost

a

drug regimen development

returned to their these occupations have maintained

already

high

had

per-

is negligible. is of

not re-

previous require. their dis-

negative

gastric

out-patients. RESUMEN

el

1) Cuando comparamos la uso de estreptomicina-PAS-Isoniacida,

combinaciOn

de estreptomicina-isonlacida se observa que el uso

de

las

con tres

46

ALLEN,

drogas porciOn cepas 2)

simult#{225}neamente m#{225}selevada resistentes. Es posible

centaje El costo 3)

La

drogas,

germenes 4) Se han ciones previas ciones su

despues

sOlo

de

al

No

salir

g#{225}strlcos

negativos

a

seis

mayor menor en

de

este

porque

un

prode

elevado

a que

por-

da

lugar.

regimen

previene

de

tres

el desarrollo

que han regresado de actividad que

cambios

1954

con una emergencia

tOxicas

meses

y algunos,

pacientes

y

tratamiento

enfermos el grado

mostrado

July,

reacciones

es deseable

aumentado

en

de

pocas

que

YTJ

terapeutico esputos

de

las

sesenta en cuenta

han

o han

valor

cuatro

sino

resistentes. dado de alta sin tener

AND

regimen de

de

es segura,

requieren.

peso

este

a causa consideraciOn.

cirugia no

tiene un conversiones

de

mantener

de enfermos no es de

MARCY

a sus tales

radiolOgicos,

han

han

a tener

llegado

ocupaocupa-

mantenido cultivos

externos. RESUME

1)

En

comparant

l’isoniazide

et

l’isoniazide, simultan#{233}ment peutique, 2) de

La

des de

auteurs d’une

pour

part

de

la

streptomycine

streptomycine que

associ#{233}e

associ#{233}e au

ces ont

trois plus

une

l’expectoration,

reactions

produits, grande

P.A.S.

et

une

plus

faible

a

non

maintenus d’entre tubages

ce

ont

d#{233}veloppement #{233}t#{233} autoris#{233}s quel

#{233}t#{233} constat#{233} chez au

poids

eux suivis gastriques

qu’ils

que eux

avaient

poursuivre

longtemps Le

m#{233}dicamenteux,

perdu

ant#{233}rieures,

de

#{233}lev#{233}e de malades.

traitement

seulement

#{233}viter le

n’a

de

permet

proportion

ses

a

de

risques

quitter soit

aucune

a

a la consultation negatives.

outre

a

et

radiologique,

sortie

ou

ont

jusqu’a

l’ont

elle

retourner

degr#{233} d’activit#{233}

evolution leur

en

r#{233}sistants. l’hOpital

le

l’interven-

mais

bacilles

prix

qu’elles ils

augment#{233}, present

des

REFERENCES 1 Mackaness, G. B. and Smith, N.: “The mycin, and Terramycin on Extracellular Rev. Tuberc., 67:322, 1953.

2 Pitts, Weiser, culosis,”

F.

a a

administr#{233}s valeur th#{233}ra-

et provoquent

toxiques une

n#{233}gligeable. a six mois

malades Il

et certains cultures de

vite

pour

occupations

exigeaient. sont

plus des

Solxante

leurs

la

constatent fa#{231}oncontinue,

traitement

chirurgicale 4)

de

germes.

revient en est 3) Apr#{233}squatre

souhaitable

se

et

discretion

mode

tion

a

les

d’une

part

n#{233}gativent

r#{233}sistance ce

l’utilisation d’autre

W., Tempel, 0.: “Isoniazid

C. W., Miller, and Streptomycin

Bactericidal Action and Intracellular F.

L., Sands, J. H., in the Treatment

of Isoniazid, StreptoTubercle Bacilli,” Am. Fitzpatrick, of Pulmonary

M.

J. and Tuber-

J.A.M.A., 152:886, 1953. 3 D’Esopo, N. D.: “Long Term Streptomycin Therapy Program Without Collapse,” Read at the 18th Annual Meeting, Am. College of Chest Phys., June 8, 1952. 4 Dubos, R. J.: “Viability of Tubercle Bacilli In Vivo With and Without Chemotherapy,” Am. Rev. Tuberc., 67:874, 1953. 5 Medlar, E. M., Bernstein, S. and Steward, D. M.: “A Bacteriological Study of Resected Tuberculous Lesions,” Am. Rev. Tuberc., 66:36, 1952.