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2.5 Ethambutol in the Treatment of Patients With Chronic Pulmonary Tuberculosis

2.5 Ethambutol in the Treatment of Patients With Chronic Pulmonary Tuberculosis

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13
February
1971
S.A.
MEDICALJOURNAL
171
MATERIAL
AND
METHODS
Forty-six
Bantu
and
one
Colouredpatient
weretreatedforperiods
of
3-
19
months.
They
werehospitalized
at
Rietfontein(Johannesburg),
Zonderwater
(Cullinan),Tshe
pong
(Pretoria),
and
George
Stegmann(Saulspoort).Allwerechroniccasesaccordingtotheusualdefinition,i.e.
their
strainsshowedresistancetothebestdrugs;moreover,they
had
bilateralpUJnonarytuberculosis,
and
were
above
theage
of
15
years.All
hadhad
previoustherapywith
primary
and/
or
secondaryantituberculosisdrugs.
They
w e n ~
chronicexcreters
of
M.
tuberculosis.
The
47patientsweredivided
into
twodistinct
groups:Group
I,comprising
of
23patients,receivedethambutol(EMB)
and
isoniazid
(INH)
only.Thesewerepatientswho
had
alreadyreceived
many
reservedrugs
and
excreted
INH-resistant
organisms.
The
clinicians,however,expectedsometherapeuticvalue
fromthe
administration
of
INH
andhoped
to
make
thebacterial
population
fullycatalasenegativeandthusattenuated.
It
is
generallyaccepted,lI
that
INH
may
haveabeneficialeffect
in
patientswith
primary
INH
resistance,
and
Freerksen"
showedinexperiments
on
animalsthat
INH
can
act
likeasecondarydrug
on
INH-resistant
strains.Canetti
et
al."
recentlystated
that
when
drugresistance
has
emergedduring
chemotherapy
n.
further
responseshould
be
expected,
and
this
is
trueeven
forINH.Apart
from
INH
andEMB,
7
of
the23patientswereoivenadditionaldrugs,
namely
PASin4cases,strepto
~ y c i n
in3cases,
kanamycin
inIcase,capreomycinin4cases,
and
pyrazinamidein1case.
Their
strains,however,
hadshown
invitro
resistance
to
thesedrugs.
The
strains
of
the
23
patientswereallfullysensitive
to
EMB
and3showed
illvi/ro
resistance
to
INH
at
thelevel
of
0·1
p.g/mlonly.
In
theircase,the
INH
wasexpectedto
have
therapeuticeffect.
Group
11,
comprising24patients,receivedethambutol,plusIor2
other
antituberculosisdrugs
to
whichtheirstrainsshowedsensitivity
invitro.
Participatingphysicianswerefreetousea
drug
of
theirchoice,
and
inmostcasesthe
drug
sensitivity
pattern
was
known
at
thestart
of
thetrial.
The
testwasdoneusingtheabsolute
ETHAMBUTOLINTHETREATMENTOFPATIENTS
WITH
CHRONICPULMONARYTUBERCUWSIS*
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.),
MedicalResearchCouncil
T u b e r c u l o s i ~
Research
Group,
Onderstepoon;
Rletfontem
/fosPltal,Johannesburg;
Zondenvater
Hospital,Cullman;
and
Tshepong
SANTA
Settlement,
Pretolla
associatedandusuallyreversibleondiscontinuationofthedrug.
The
emergence
of
resistance
to
ethambutol
appearstobeslow.
On
monotherapy
thefollowingfiguresweregiven:
41
~ ~
within
3-6
months:
37%
within
3-
5months,'
and
58%
after
6
months.'When
given
in
combinationwith
other
effectivedrugs,the
makers
report
6·8%
of
380
chroniccasesasdrug-resistant."
The
purpose
of
ourstudy
wastheevaluation
of
theefficacy
and
acceptability
of
prolonged
ethambutol
treatment
in
chronicmulti-resistantcases
of
pulmonary
tuberculosis.
Emphasis
was
placed
on
thebacteriologicalstatus
and
follow-upresults.[here
are
now
13
basicallydifferentantituberculosisdrugs
lDd
7
derivatives
of
thesedrugs
in
use
in
SouthAfrica.
Itis
becomin
a
increasinglydifficultforthenon-expert
[0
decideon
'"
the
correct
dosage
andcombinationof
thesedrugs,especiallyoncetheinitialtreatmenthasfailed
to
convertthesputum.A
major
antituberculosisdrugshould
be
highlyeffec
tive,
acceptable
to
thepatient,non-toxic
and
reasonablycheap.
The
price
is
importantin
a
country
w h e r ~
a ~ o ~ t
all
patients
are
treated
at
Stateexpense.OnlyIsomazldandstreptomycinhaveinthe
past
fulfilledthe
above
conditionsfor
major
drugs.Anew
major
drug
should
alsobesuitable
for
self-medication
andfor
intermittenttherapy
andproduce
no
cross-resistance
to
well-establisheddrugs.Theliterature
onethambutol
hydrochlorideis
already
extensiveand
mostof
the
above
conditionsseem
to
befulfilled.Itsrelativelyhighpricemakesitsintroductionasafirst-line
drug
problematic.Asasecond-linedrugitseemstobeeminentlysuitable
in
viewoftheinacceptability
of
most
of
thepresentlyavailablereservedrugs.
Too
often
treatment
is
stopped
by
the
doctoror
refusedbythepatientbecause
of
toxicsymptoms;
and
this
happens
especiallywith
treatment
containingethionamide,pyrazinamide
and
cyc!oserine.Whenallthreearegiventogethertheyhaveasubstantialdegree
of
toxicity.
In
routinesecondary
treatment
thesedrugsshowadisappointingly
moderaterate
of
success.
The
o t h ~ r
fourreserve
drugs-rifampicin,
kanamycin.
capreomyclDand
viomycin-are
veryexpensive,costing
about
300times
as
muchasisoniazid.In
South
Africa
Dormer'
undertook
atrialwith
etham
butol
in
47
cases
of
chronic
pulmonary
tuberculosis
andCharlton'
described
the
chemistry,
invitro
and
invivo
activity,
pharmacology
and
adversereactionsofthisdrug.Its
main
featuresareitshighspecificactivityagainst
M.
tuberculosis,
M.
bovis
andother
speciesof
mycobac
teria.
Of
35
South
African
wildstrains
of
M.
tuberculosis
testedbv
us
on
Lowenstein-Jensenmedium,allwerefullysen'sitive
to
1·5
p.g/ml,
and
25
strainsalso
to
0'7
fLg/ml
ethambutol.
Twenty
strains
of
M.
bovis
weretested
in
the
same
way
and
all
but
two
were
fullysensitiveto
0·7
p.g/ml.Seven
of
thesensitivestrainswereisoniazid-resistant
M.
bovis.
The
drug'saction
is
of
adegenerativetype.
The
bactericidalphase
is
preceded
byaphase
of
bacillarymultiplicationlastingseveraldays....
Dickinson
et
al:
proved
in
guinea-pigs
that
ifthedailydoses
are
accumulated,intermittent
drugintake
is
superior
todailydosage.Administration
bymouth
is
onaonce-dailyschedule,
and
both
absorptionand
excretion
occur
rapidly.Itsacceptability
to
thepatients
and
therarity
of
side-effectsmakesitsuitableforself-medication.
Itsocular
toxicityisdose-,
'Da,e
received:9
September
1970.
 
172
S.-A.
MEDIESETYDSKRIF
13
Februarie
1971
concentrationmethod
and
Lowenstein-Jensen
medium
at
the
followinglevels:
PASat
0·5
and
10
fLg/ml,
INH
at
0·1
and
5fLg/ml,streptomycin
at
5
and
50
fLg/ml,thia
cetazone
at
I
and
10
fLg/ml,ethionamide
at
20
and
30
fLgfml,
cycloserine
at
10
and
30fLg/ml,viomycin
at
20
and
30fLg/ml,
kanamycinat
10
and
20fLg/ml,capreo
mycin
at
30
and
50
fLg/ml,
pyrazinamide
at
20
and
100
fLg/ml,
andEMB
at
5
and
10!Jog/m!.
PAS
wasgivenin
12
cases,
kanamycin
in10cases,
capreomycinin
4cases,cycloserine
and
pyrazinamidein
2
caseseach,
and
ethionamidein
I
case,all
at
routinedosages.
Additional
drugsgivendespite
in
vitro
resistancewereasfollows:
INH
in
17
cases,thiacetazonein5cases,
PAS,
streptomycin
and
capreomycin
in
2caseseach,
and
cycloserine,ethionamideandkanamycinin
I
caseeach.
In
both
groups
the
dose
ofethambutol
was
25
mg/kg/day
in
I
dose
per
os
for
thefirst2
or
3months.Subse
quently
15
mg/kg/day
wasgiven
foranother
9
or
10
months.
The
dose
of
INH
wasusually600
mg/day.During
hospitalizationtheintake
of
drugswascontrolled,
but
after
dischargeitwas
not
possibletoensureselfmedication.Allpatients
showed
bilateral
pulmonary
tuberculosiswithfar-advanceddisease
and/
or
extensivedestruction
on
X-ray.
One
or
multiplecavitieswerevisiblein
31
of
thepatients.
Their
weightwasrecorded,
andlaboratory
testssuchashaemoglobinvalue,
SGPT,SGOT,and
erythrocytesedimentationratewerecarriedout.
The
history,previous
treatment
and
clinicalconditionwereverysimilarfor
both
groups.
Fourteen
patientswerefemales
and
33
weremales.
The
agevaried
from
20to76years,witha
mean
of
41
years.
Together
they
had
had
94previousadmissions,
which
is
an
average
of
2admissions
per
patient.
Admitted
or
known
previous
treatment
varied
from
2-!-
to
125
months,
with
an
average
duration
of
49
months
per
patient.
The
averageweightwas110
Ib
(50kg),varyingfrom
68
to
148Ib(30-67kg).
The
clinical
condition
was
poor
in
17
cases,
fairin
11,
and
relatively
goodin
6cases.
During
hospitalizationX-rayswere
taken
every
monthand,
as
far
aspossible,
theESR
and
weightweremeasured.
Eye
examinations
for
visualacuitywerea!so
performed
monthly.
After
bacteriologicalconversion
and
discharge,patientswere
referred
to
outpatient
clinics.Satisfactoryclinical
dataon
allpatientsconcerned
couldonly
be
obtained
for
thefirst4
months
of
treatment.
The
clinicalstatus
at
that
timeisgiven
in
TableI.
Sputum
samplesweresent
toOnderstepoort
initially
at
weekly
and
later
at
2-weeklyintervals
for
microscopy
and
culture.Sensitivitytestswere
done
at
montWyintervals.As
is
customarytoday,finalevaluationinthisstudy
is
based
on
thebacteriologicalresults.
The
laboratory
methodsusedhavebeendescribedelsewhere.'"
After
dischargefromthehospital
sputum
specimenswereusuallysent
at
irregularintervalsvarying
from
one
to
severalmonths,althoughpatientsweresupposed
to
re
port
totheirnearestclinicevery4weeks.
In
many
casespatients
had
tobetraced
inordertoobtainsputum
and
we
donot
knowwhethertheytook
the
EMB
tabletsdaily.
RESULTS
The
term'bacterialconversion'
means
the
changefrom
positive
sputum
culture
to
negative
for
3consecutive
monthly
sputa.Wherethefindingsdiffer
from
thisdefinition,thelength
of
thenegative
period
will
be
given.
We
defineacaseasarelapsewhen
after
severalconsecutivenegativesputa,growth
of
M.
tuberculosis
reappearson
culture.
The
term'reconversion'isused
when
apatient's
sputum
firstbecomesnegative,thenpositiveagain
for
afewconsecutivesamples
and
subsequentlyconverts
to
negative.
The
clinicalandradiologicalassessment
after
4
monthsofEMB
treatmentasgivenin
Table
Iillustratestheamazingimprovementwhichoccurredin
manyof
thesedesperatecases.
The
majority
of
seriouslyillpatients
had
a
dramatic
clinical
changefor
thebetter.
Patients
ingroup
11,
where
EMB
wascombinedwith
other
effectivedrugs,showedresolution
of
infiltration
moreoften
than
patients
onEMBand
INH
only,
but
failure
of
infiltrationtoclearwasduemostlytofibrosis.
The
therapeutichistory
and
theresistance
pattern
at
thestart
of
thetrial
are
given
inTable
11.
Fiveto
6differentdrugs
hadbeen
usedpreviously,
and
inalmost
allcasesthepatients'strainswereresistant
to
INH
and
streptomycin
and
severalreservedrugs.
The
bacteriologicalresultsas
summarizedinTables
III
and
IVand
Fig.
I
willbedescribed
inmore
detail.
The
sputum
of
patients
ingroup
I,given
EMBand
INH
only,convertedin
12
cases.Conversion
occurredin
4cases
in
the1stmonth,
in
5casesinthe2nd,
in
2casesinthe3rd,
and
in
I
case
in
the4th
month.
No
further
casesbecamenegative
after
4months.
The
higherthe
colony
countat
the
start
of
therapy,the
later
conversionoccurred.
In
3
of
the
12
caseswe
couldonly
examine2consecutivenegativesputa.
TABLE
I.
CLINICALAND
RADIOLOGICAL
ASSESSMENTAFTER
4
MONTHSOF
ETHAMBUTOLTREATMENT
TherapyClinicalstafllsWeightchangesResollltion
of
Alteration
ill
size
of
infiltration
on
X-raycavities
0/1
X-ray
Group
I
(EMB+
INH)
23
casesGroup
II
(EMB+
otherdrugs)
24
cases
20
felt,lookedandweremuchbetternochangedied(pneumonia)died
(l
monthafterwithdrawalofEMB)
14
felt,lookedandweremuchbetter9noinformation1deteriorated
16
showedweightincreasesof1·3-16·3
kg
(average
6·2kg)
7
no
information
14
showedweightinincreases
of
0-4
-
10·8
kg
(average
4·9
kg)
1
lost
6·2
kg
9
no
information9improved
(3
slight,4moderate,2marked)
10
no
change4
no
information
18
improved
(7
slight,
4
m o r l e r ~
te,
7
marked)
1
deteriorated2
no
change3
no
information
13
improved
(l
closure.7muchsmaller,
5
somewhatsmaller)2nochange8
no
information
11
improved
(4
closures,1muchsmaller,6somewhatsmaller)
1
deteriorated4
no
change8
no
information
 
ebruary
1971
S.A.
MEDICALJOURNAL
173
TABLE
11.
KNOWNPREVIOUSCHEMOTIIERAPYHISTORY
AND
llACfERJALRESISTANCE
AT
START
OF
E1liAMBUTOLTREATMENT
INH
SM
PAS
TH
ETH
CS
CAPPZA
VM
KM
,up
I(EMB
+
INH)
23
cases
23
18
10
96
12
5of
rugs
receivedpreviously
23
12Mean5
drua
s
I
vitro
bacterialresistanceacquired
222216
18·16t6
4t
546Resistanttomeanof5
clrogs
,up
II
(EMB
+
INH
+
otherdrugs)
~
cases
'rugsreceivedpreviously
2424
21
14
15
14
4
16
7
10
Meanof
6·5
drugs
1
vitro
bacterialresistanceacquired
23
22
11
18·
15
10
4245Resistant
to
meanof5
drugs
=
isoniazid;
SM
=
streptomycin;
PAS
=
para-amino
salicylicacid;
TH
=
thiacetazone;
ETH
ethionamide;CS
=
cycloserine;
CAP
=
preomycin;
PZA
=
pyrazinamide;
V ~
=
viomycin;
KM
=
kanamycin.
'istance
10
I
Jlg
TH
occurs
naturally
In
SouthAfnca
.
.
treatment
can
cause
ETH
resistance.
:islance
10
CAPcan
be
caused
by
use
of
KMor
VM.
"ABLE
Ill.
BACTERIALSTATUS
AT
END
OF
LABORATORYINVESTIGATJONS
Group
II
GroupI
EMB
+
other,
of
treatment
EMB
mnnotheraoydrugs
rlVerage
length(treated
11
months)(treated
9
months)No.
%
No.
%
rersion
12
52
16
67
.nversion3
13
0
0
pse
3
13
14stently
posi-
5
22
7
29
·e
Totalpatients
23
100
24
100
:.
IV.INFECTIOUSNESS
OF
PATIENTS'SPUTAAT
3-MON'lHLY
INTERVALS·
Time
lapseafterstart
of
EMB
treatment
..
..
,::::
OS
'"
::
s::
..
cc
....
..,
~
l::l::
~
~
"S
s::
s:::
s::
s::
c
'"
00
C
<:l
<:l
E
........
l::
E
E
'"
"""
......
,...,
'Q
0\
....
....
....
version
to
negative
28
2217
13
10
6mversion01020
pse
10331istentlyposiiive
19
14
950ltal
No.
of
patientst
47
37
27
21
16
7
ups
I
and
11
combined.
Averagetime
under
bacterio!ogical
observa·
10
months.
rapid
decrease
in
the
number
of
patients
\vasdue
to
d i ~ c h a r g e
and
Ire
to
report
tocli?:.ics.
here
were
3casesofreconversionin
group
I.
Their
uresinitiallyshowed25-50colonies.
The
firstcaselmenegativewithinthe1st
month,
thenscanMlyposi-again
from
the3rdto
7th
months,
and
subsequentlyltiveduringthe8thto14thmonths.
The
2ndcasebecamenegativewithinthe
1st
month,waspositiventhe12thto14thmonths
and
reconvertedduring15thmonth,asituationwhichpersisteduntilthe
end
thestudy.The
3rd
casebecamenegativeinthe
3rd
1th,waspositiveduringthe7th
to
12thmonths,
and
negativesputa
from
the13thto19thmonths.·hreecases
in
group
Ishowedarelapsewhichappearedingthe6th,10thand14th
months
respectively.
In
first
case
treatmentwasstoppedafter4months
due
:ransfer
toanother
hospital.Thestrainsisolated
after
relapsesweresensitive
to
5p.g/ml
EMB
in
vitro.
Fivecasesshowedpersistentlypositivecultures.
The
.train
fromone
of
thesepatients
didnot
developresistanceto5p-g/ml
EMB.
The
other4casesdevelopedpartialresistanceto5p-g/ml
EMBafter
9,8,
10
and
12
monthsrespectively.
No
significantcmangesinthelevel
of
resistanceto
other
drugsoccurredduring
the
period
of
observation.
B6.CTERIAL
STATUSin
RaATION
to
DURATION
ofTHERAPY
ill
g
z
w
~
~ 1
[lIJRATJ0:--J
in
MONTHS
of
CHEMJTHERAPY
Fig.
1.
Bacterialstatusinrelationtodurationofthcmpy.
The
24casesingroup
IT,
whoreceived
EMB
combinedwithothereffectivedrugs,showedconversionin
16
patients,persistentlypositivesputain
6,
relapsein
1,
and
intermittentlynegativesputain
another
case.
The
conversionoccurredin2casesafter1month,
in
8cases
after
2,
in3cases
after
3,
and
in
1case
after
8months.
The
groupcontains2cases
from
whom1
or
2colonies
were
isolatedafteraperiod
of
negativesputa.
Theycan
beregardedasconverters.
Another
patient
had
ahighlypositivesputum
after
1
month,
wasnegativeafter2months,
then
moderatelypositiveduringthe
3rd
to
6th
months,
and
inthe7th
month
4colonieswereisolated.
In
the8th
month
hissputumwasagainnegative.
Three
of
thepersistentlypositivecasesshowedmoderatetonumerouscoloniesonculturethroughout.
Another
casewashighlypositiveuntilthe3rdmonth,
and
thentheexcretiongFaduallydecreasedto
11
colonies
at
6months.
Two
patientsshoweda
marked
decrease
of
organismswithseveralsinglecolonyisolates
for
aperiod
of
afew
months
beforeexcretinghighernumbers
of
organismsagain.Thesecouldhave
been
calledrelapses.The
one
caseshownasarelapsein
Table
lIT
wasnegativeduring
the
1st
year
of
therapy
but
producedapositivesputum
at
the17thmonth.

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