multidrug-resistant tuberculosis (mdr-tb): epidemiology ... · pharmacotherapy, relapse of clinical...
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Texila International Journal of Clinical Research
Volume 6, Issue 1, Aug 2019
Multidrug-Resistant Tuberculosis (MDR-TB): Epidemiology, Causes, Pathophysiology, Diagnostic Approaches, Preventive Interventions, and Treatment Challenges/Opportunities – (An Evidence-Based Narrative
Literature Review)
Article by Khalid Rahman PhD Clinical Research, Texila American University
E-mail: [email protected]
Abstract
Background: MDR-TB (Multidrug-resistant tuberculosis) reportedly proves to be the greatest public
health issue on a global scale. The mutation tendency of Mycobacterium tuberculosis substantially
elevates its resistance against the recommended pharmacotherapeutic interventions. Limited
information on the MDR-TB diagnostic approaches and treatment options is primarily responsible for
its extensive progression across resource-limited regions. The frequently reported adverse effects of the
standard therapies barricade their long-term use by the MDR-TB patients.
Aim: The presented narrative review attempts to consolidate and strengthen the clinical evidence
for improving the MDR-TB diagnosis and treatment decisions in health care settings.
Methods: The author performed an evidence-based analysis of the causative factors,
pathophysiology, diagnostic techniques, and treatment options/challenges for MDR-TB through the
systematic exploration of databases including Google Scholar, PubMed/Medline, and Cochrane
Library. The utilization of these databases was effectively undertaken to explore the peer-reviewed
MDR-TB-related articles based on meta-analysis, systematic review, retrospective study, randomized
controlled trial, and narrative literature reviews.
Findings: The study findings revealed MDR-TB epidemiology, etiology, diagnostic approaches,
preventive measures, pathogenesis, treatment adversities, and therapeutic potential in the context of
controlling the prevalence of drug-resistant tuberculosis and related comorbidities.
Conclusion: The study findings advocate the need for improving the overall MDR-TB investigation
and treatment process to control the elevated prevalence of MDR-TB among the suspected patients.
The study outcomes advocate the requirement of multidisciplinary coordination between clinicians and
researchers to effectively improve the medical decision-making quality for enhancing the therapeutic
outcomes of MDR-TB patients.
Keywords: MDR-TB, Drug-resistant, tuberculosis, diagnosis, pathophysiology, treatment.
Introduction
Multidrug-resistant tuberculosis (MDR-TB) continues to be the greatest challenge that increasingly
elevates the overall health care burden across the globe [24]. MDR-TB reportedly occurs under the
impact of increased bacterial resistance against conventional treatment interventions, including
rifampicin and isoniazid [14]. Alternatively, MDR-TB patients require second-line therapy in the
context of improving their clinical manifestations. Mycobacterium tuberculosis is reportedly the most
commonly reported pathogen that elevates the prevalence of tuberculosis, particularly in children and
adolescents [6]. The significant risk factors of MDR-TB include the inappropriate response to first-line
pharmacotherapy, relapse of clinical manifestations, medication non-compliance, Mycobacterium
tuberculosis re-exposure, epidemic outbreak, and HIV comorbidity [24]. 3% of entire tuberculosis cases
are based on multidrug-resistant tuberculosis. The second-line treatment for MDR-TB not only elevates
the health care cost but also increases the risk of potential toxicity. Furthermore, limited information on
drug susceptibility testing for tuberculosis barricades the appropriate drugs’ selection process [29]. This
eventually elevates the risk of MDR-TB among predisposed patients. The configuration of person-
centered therapeutic approaches is, therefore, highly necessary to minimize the overall recovery time
while maximizing the therapeutic outcomes in MDR-TB cases [25]. The global data on MDR-TB
1
DOI: 10.21522/TIJCR.2014.06.01.Art003
ISSN: 2520-3096
reveals the reported occurrence of 8014 XDR-TB (extensively drug-resistant) cases across 72 nations.
The incident cases of tuberculosis majorly include MDR-TB patients who experience substantial
predisposition towards XDR-TB. The WHO (World Health Organization) findings reveal the
inappropriate treatment pattern among the patients affected with XDR-TB and MDR-TB. For example,
30% of XDR-TB and 54% of MDR-TB patients fail to effectively comply with the desired
pharmacotherapy that eventually elevates their risk for comorbidities and mortality [16].
The evidence-based clinical literature does not delineate any globally accepted or standard
therapeutic intervention for the complete recovery of MDR-TB patients. The physicians require
formulating the treatment regimen following the intensity of relapse, clinical manifestations, and the
patient’s overall health status. Ethambutol, pyrazinamide, and elevated dosage of isoniazid include the
first-line drugs that require oral administration for treating XDR and MDR tuberculosis [2]. The second-
line MDR-TB treatment group–(A) drugs include levofloxacin/moxifloxacin (fluoroquinolones),
bedaquiline, and linezolid. The elevated dosages of these drugs in many clinical scenarios helps to treat
MDR-TB complications. The second-line MDR-TB treatment group–(B) drugs include clofazimine,
cycloserine, and terizidone. However, second-line MDR-TB treatment group–(C) drugs include
ethambutol, delamanid, pyrazinamide, imipenem-cilastatin, meropenem, amikacin,
prothionamide/ethionamide, and p-aminosalicylic acid [14]. World Health Organization (WHO) does
not recommend the prioritization of second-line injectable drugs for rifampicin-resistant MDR-TB
cases. However, Group–(A) drugs require prioritized oral administration for extended therapy. The
clinicians require carefully selecting the appropriate drug combinations based on the MDR-TB patients’
clinical manifestations and prognosis in the context of improving the therapeutic outcomes.
Furthermore, prospective clinical trials require evaluating comprehensive treatment approaches for
minimizing the prevalence and adverse outcomes of MDR-TB. The presented narrative review
effectively explores the etiology, causes, pathophysiology, diagnostic approaches, preventive
interventions, and treatment modalities for MDR-TB while considering the existing therapeutic
challenges. The presented evidence-based findings will not only prove conducive to the configuration
of innovative MDR-TB treatment regimen but also improve the clinical decision-making process in the
context of minimizing the recovery time and relapse rate of multidrug-resistant patients.
Methods
The narrative review was undertaken through the systematic exploration of evidence-based databases
including Google Scholar, PubMed/Medline, and Cochrane Library. The following keyword
combinations were effectively utilized through Boolean Operators.
1. “MDR-TB” AND “Causes”
2. “MDR-TB” AND “Pathophysiology”
3. “MDR-TB” AND “Diagnosis/Diagnostic Imaging”
4. “MDR-TB” AND “Prevention”
5. “MDR-TB” AND “Treatment”
The research articles’ selection criteria were based on consecutive reviews, retrospective studies,
systematic reviews, meta-analysis, randomized controlled trial, and narrative literature reviews. The
author selected the research studies between the span of 2010 to 2019. The articles unrelated to MDR-
TB and the articles that solely focused on the MDR-TB comorbidities were summarily excluded from
the narrative review. The following PRISMA flow diagram effectively elaborates the articles’ selection
process.
2
Texila International Journal of Clinical Research
Volume 6, Issue 1, Aug 2019
Prisma flow diagram
3
DO
I: 1
0.2
15
22
/TIJ
CR
.20
14
.06
.01.A
rt0
03
ISS
N:
2520
-30
96
Res
ult
s
Lit
eratu
re
Su
mm
ary
Tab
le
Au
tho
r
Stu
dy
Ty
pe
Ob
ject
ive
Met
ho
ds
Parti
cip
an
ts
Inte
rven
tio
ns
Ou
tco
mes
R
eco
mm
en
da
tio
ns
Chang a
nd
Yew
(2013
)
Narr
ati
ve
revie
w
The
au
thors
effe
ctiv
ely
reco
mm
end
ed
pre
ven
tiv
e and
ther
ap
euti
c
ap
pro
ach
es f
or
the
syst
emati
c
manag
emen
t of
dif
ficu
lt t
o t
reat
MD
R-T
B a
nd
XD
R-T
B
The
rese
arc
her
s
per
form
ed a
lit
eratu
re
revie
w b
ase
d o
n M
DR
-
TB
/XD
R-T
B
epid
emio
logy,
pre
ven
tive
inte
rven
tions,
and c
om
pre
hen
sive
ther
apeu
tic
appro
ach
es
NA
T
he
rese
arc
her
s
evalu
ate
d
infe
ctio
n c
ontr
ol
stra
teg
ies,
alt
ernati
ve
ther
ap
euti
c
regim
en,
and
adju
nct
ive
ther
ap
euti
c
ap
pro
ach
es f
or
min
imiz
ing t
he
occu
rren
ce
of
MD
R-T
B/X
DR
-
TB
and r
elate
d
clin
ical
com
pli
cati
ons
- T
he
rese
arc
her
s
and c
lin
icia
ns
requ
ire
dev
elop
ing n
ov
el
ther
ap
euti
c
ap
pro
ach
es i
n t
he
conte
xt
of
imp
rov
ing t
he
clin
ical
manag
emen
t o
f
MD
R-T
B a
nd
XD
R-T
B c
ase
s
- T
he
reco
mm
end
ed
MD
R-T
B/X
DR
-
TB
pre
ven
tio
n
and t
reatm
ent
ap
pro
ach
es
requ
ire
form
ula
tio
n
thro
ug
h i
n-v
itro
inte
rven
tions
an
d
a c
om
bin
ati
on o
f
pyra
zinam
ide,
lin
ezo
lid,
iso
nia
zid
(ele
vate
d d
osa
ge)
,
- T
he
clin
icia
ns
requ
ire
consi
der
ing v
ari
ou
s
fact
ors
inclu
din
g
adju
nct
ive
surg
ery,
dosi
ng s
ch
edu
les
of
seco
nd-l
ine
dru
gs,
and
MD
R-T
B/X
DR
-TB
man
ifes
tati
ons
in t
he
conte
xt
of
imp
rov
ing t
he
ther
ap
euti
c ou
tco
mes
- D
rug r
esis
tance
pro
gra
ms,
DO
TS
(sh
ort
cou
rse
ap
pro
ach
), a
nd
HIV
/po
ver
ty e
radic
ati
on
mea
sure
s are
so
me
of
the
reco
mm
end
ed
stra
teg
ies
to e
levate
th
e
cure
rate
s of
the
pati
ents
aff
ecte
d w
ith M
DR
-TB
and X
DR
-TB
4
Tex
ila I
nte
rnati
onal
Jou
rnal
of
Cli
nic
al
Res
earc
h
Vo
lum
e 6
, Is
sue
1,
Au
g 2
019
and
flu
oro
qu
ino
lon
es
Gil
pin
,
Koro
bit
syn,
and W
eyer
(2016)
Narr
ati
ve
revie
w
The
au
thors
evalu
ate
d v
ari
ous
dia
gn
ost
ic
mo
dali
ties
to
faci
lita
te e
arl
y
iden
tifi
cati
on o
f
MD
R-T
B/X
DR
-TB
The
auth
ors
explo
red
clin
ical
lite
ratu
re i
n t
he
conte
xt
of
evalu
ati
ng t
he
mole
cula
r bio
logy
appli
cati
ons
for
MD
R-
TB
ass
essm
ent
NA
T
he
rese
arc
her
s
exp
lore
d
phen
oty
pic
/gen
o
typ
ic a
pp
roach
es
and t
hre
e-ti
ered
labora
tory
net
work
in t
he
conte
xt
of
iden
tify
ing
indiv
idu
ali
zed
dia
gn
ost
ic
inte
rven
tions
for
MD
R-T
B
- T
he
stu
dy
ou
tco
mes
rev
eal
the
requ
irem
ent
of
foll
ow
ing t
he
En
d
TB
ap
pro
ach
to
rap
idly
id
enti
fy
the
MD
R-T
B
pati
ents
- T
he
pati
ents
aff
ecte
d w
ith T
B
man
ifes
tati
ons
mu
st u
nd
erg
o
un
iver
sal
dru
g
susc
epti
bil
ity
test
ing i
n t
he
conte
xt
of
min
imiz
ing t
he
risk
of
MD
R-T
B
trea
tmen
t d
elay
and a
ssocia
ted
com
orb
idit
ies
The
thoro
ug
h
op
tim
izati
on o
f W
HO
-
base
d d
iag
nost
ic
inte
rven
tions
is h
igh
ly
nee
ded
insi
de
the
clin
ical
sett
ings
in t
he
conte
xt
of
contr
oll
ing
the
pre
vale
nce
of
MD
R-
TB
and X
DR
-TB
acr
oss
the
pre
dis
pose
d
pop
ula
tio
ns
Gir
um
,
Mukta
r,
Len
tiro
,
Wondiy
e,
and
Shew
angiz
a
w (
2018)
Met
a-
Analy
sis
The
au
thors
att
emp
ted t
o
evalu
ate
MD
R-T
B
epid
emio
logy
acr
oss
Eth
iop
ia
The
auth
ors
per
form
ed a
syst
emati
c li
tera
ture
searc
h b
ase
d o
n v
ari
ous
data
bas
es i
nclu
din
g
Afr
ican I
ndex
Med
icus,
Cochra
ne
Lib
rary
,
Em
base
, G
lobal
Hea
lth
Data
base
, and
PubM
ed/M
edli
ne
The
random
-eff
ects
model
was
uti
lized
in
The
rese
arc
her
s
evalu
ate
d
7461
subje
cts
aff
ecte
d w
ith
MD
R-T
B/T
B
thro
ugh t
he
syst
emati
c
analy
sis
of
The
rese
arc
her
s
evalu
ate
d M
DR
-
TB
pre
vale
nce
am
on
g s
ub
ject
s
who e
xhib
ited
a
his
tory
of
tuber
culo
sis
trea
tmen
t
- T
he
stu
dy
ou
tco
mes
rev
eale
d a
n
elev
ate
d
pre
vale
nce
of
MD
R-T
B a
mon
g
the
sele
cted
sub
ject
s
- T
he
stu
dy
fin
din
gs
rev
eale
d
mu
ltid
rug-
Dru
g s
usc
epti
bil
ity
ass
essm
ent,
tim
ely
pharm
acoth
erap
y,
and
adv
erse
eff
ects
’
pre
ven
tio
n i
nclu
de
som
e
of
the
sign
ific
ant
stra
teg
ies
to r
edu
ce
the
freq
uen
cy o
f M
DR
-TB
case
s
5
DO
I: 1
0.2
15
22
/TIJ
CR
.20
14
.06
.01.A
rt0
03
ISS
N:
2520
-30
96
the
conte
xt
of
extr
act
ing
data
rel
ate
d t
o M
DR
-TB
trea
tmen
t outc
om
es,
det
erm
inants
, and
pre
vale
nce
thir
ty-f
our
studie
s
resi
stant
tub
ercu
losi
s in
th
e
conte
xt
of
a
seri
ou
s p
ub
lic
hea
lth c
oncer
n
that
requ
ired
imm
edia
te
mit
igati
on
- M
DR
-TB
-
rela
ted c
o-
morb
idit
ies
inclu
din
g r
edu
ced
base
lin
e w
eig
ht,
HIV
sero
posi
tiv
ity,
mal-
ab
sorp
tion,
and t
reatm
ent
adv
erse
eff
ects
pre
do
min
antl
y
elev
ate
th
e
mort
ali
ty r
isk o
f
the
aff
ecte
d
pati
ents
Koch,
Cox,
and M
izra
hi
(2018)
Narr
ati
ve
revie
w
The
au
thors
per
form
ed a
syst
emati
c
ass
essm
ent
of
TB
path
og
enes
is i
n t
he
conte
xt
of
iden
tify
ing r
eal-
tim
e tr
eatm
ent
chall
eng
es
encou
nte
red d
uri
ng
- T
he
auth
ors
exp
lore
d
evid
ence-
base
d c
linic
al
lite
ratu
re f
or
evalu
ati
ng
dru
g r
esis
tance
pro
ne`
Myc
obact
eriu
m
tuber
culo
sis
(Mtb
)
gen
es a
nd T
b t
reatm
ent
dru
gs
- T
he
rese
arc
her
s
dev
elop
ed v
ari
ous
evid
ence-
base
d t
ools
in
NA
T
he
rese
arc
her
s
use
d o
nli
ne
tools
in
clu
din
g
PhyR
esS
E,
TB
Pro
file
r, P
oly
TB
, R
eSeq
TB
,
and
TB
Dre
am
DB
for
evalu
ati
ng
tuber
culo
sis
The
earl
y
det
ecti
on o
f
MD
R-T
B c
ase
s
and p
rom
pt
init
iati
on o
f
ap
pro
pri
ate
seco
nd-l
ine
ther
ap
y a
re h
ighly
nee
ded
for
imp
rov
ing t
he
- T
reatm
ent
cust
om
izati
on f
or
MD
R-
TB
case
s is
hig
hly
nee
ded
base
d o
n t
he
infe
ctin
g p
ath
og
en’s
stra
in t
yp
e,
het
ero
gen
eity
lev
el,
and
resi
stant
patt
ern
- S
hort
ened
pharm
acoth
erap
euti
c
mea
sure
s w
arr
ant
6
Tex
ila I
nte
rnati
onal
Jou
rnal
of
Cli
nic
al
Res
earc
h
Vo
lum
e 6
, Is
sue
1,
Au
g 2
019
the
manag
emen
t of
MD
R-T
B
the
conte
xt
of
extr
act
ing
data
rel
ate
d t
o s
ingle
nucle
oti
de
poly
morp
his
ms
of
Mtb
gen
es a
nd o
ther
sim
ilar
muta
tions
dru
g r
esis
tance
patt
ern
ther
ap
euti
c
ou
tco
mes
.
imp
lem
enta
tio
n f
or
effe
ctiv
ely a
chie
vin
g a
long
-ter
m c
ure
for
MD
R-T
B
Podany a
nd
Sw
indel
ls
(2016)
Narr
ati
ve
revie
w
The
au
thors
exp
lore
d n
ovel
ap
pro
ach
es t
o
reco
nfi
gu
re t
he
standard
ized
TB
trea
tmen
t
inte
rven
tions
for
pre
ven
tin
g t
he
occu
rren
ce
of
TB
/MD
R-
TB
/XD
R-T
B
The
auth
ors
evalu
ate
d
evid
ence-
base
d c
linic
al
lite
ratu
re t
o e
xp
lore
the
standard
ized
TB
trea
tmen
t dru
gs’
new
ly
dev
elop
ed/p
rop
ose
d
appli
cati
ons
in t
he
conte
xt
of
impro
vin
g t
he
ther
apeu
tic
outc
om
es
NA
-
The
au
thors
exp
lore
d t
he
TB
dru
g
dev
elop
men
t
his
tory
bet
wee
n
192
1 t
o 2
01
3
- T
he
au
thors
exp
lore
d t
he
scop
e of
ther
ap
euti
c (o
r
TB
tre
atm
ent)
mo
dif
icati
ons
base
d o
n
rifa
mycin
s,
flu
oro
qu
ino
lon
e
s, c
lofa
zim
ine,
bed
aqu
ilin
e,
del
am
an
id,
pre
tom
an
id,
and
ox
azo
lid
ino
nes
The
stu
dy
ou
tco
mes
sub
stanti
ate
th
e
requ
irem
ent
of
evalu
ati
ng t
he
tub
ercu
losi
s
resi
stance
patt
ern
again
st t
he
new
ly
reco
mm
end
ed
ther
ap
euti
c
ap
pro
ach
es t
o
min
imiz
e th
e ri
sk
of
MD
R-T
B
trea
tmen
t fa
ilu
re
The
pro
spec
tiv
e cl
inic
al
tria
ls r
equ
ire
evalu
ati
ng
the
pro
pose
d M
DR
-TB
ther
ap
euti
c re
gim
ens
to
effe
ctiv
ely c
ontr
ol
the
pre
vale
nce/
ou
tbre
aks
of
TB
/MD
R-T
B/X
DR
-TB
and r
elate
d
com
orb
idit
ies/
morb
idit
ie
s
Seu
ng,
Kes
havje
e,
and R
ich
(2015)
Narr
ati
ve
Rev
iew
The
au
thors
evalu
ate
d t
he
cau
sati
ve
fact
ors
,
epid
emio
logy,
and
manag
emen
t
ap
pro
ach
es f
or
MD
R-T
B
The
auth
ors
per
form
ed
exte
nsi
ve
rese
arc
h o
f
clin
ical
lite
ratu
re i
n t
he
conte
xt
of
acq
uir
ing
MD
R-T
B’s
pre
dis
posi
ng
fact
ors
, th
erapeu
tic
stra
tegie
s, a
nd s
ide-
NA
T
he
rese
arc
her
s
exp
lore
d
evid
ence-
base
d
clin
ical
lite
ratu
re t
o
evalu
ate
ther
ap
euti
c
mo
dali
ties
, ri
sk
The
pre
lim
inary
cau
ses
of
MD
R-
TB
inclu
de
com
mu
nit
y-
base
d/f
acil
ity-
base
d
transm
issi
on,
inap
pro
pri
ate
- T
he
ad
min
istr
ati
on o
f
com
mu
nit
y-b
ase
d
pro
gra
ms/
rob
ust
trea
tmen
t re
gim
en a
nd
earl
y d
rug r
esis
tance
iden
tifi
cati
on i
ncl
ud
e
som
e of
the
sig
nif
icant
evid
ence-
base
d
7
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rt0
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N:
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96
effe
cts’
managem
ent
inte
rven
tions
fact
ors
, ca
use
s,
trea
tmen
t
ap
pro
ach
es,
adv
erse
eff
ects
,
and
epid
emio
log
y o
f
MD
R-T
B/X
DR
-
TB
trea
tmen
t, d
rug-
resi
stant
patt
ern
am
pli
fica
tio
n
base
d o
n
inad
equ
ate
pharm
acoth
erap
y,
and f
ragil
e
med
ical
syst
ems
stra
teg
ies
warr
ante
d t
o
min
imiz
e th
e p
revale
nce
of
MD
R-T
B/X
DR
/TB
- C
linic
ians
mu
st
ov
erco
me
the
pre
ven
tab
le M
DR
-TB
risk
fact
ors
inclu
din
g,
chaoti
c tr
eatm
ent,
short
-
term
pharm
aco
ther
ap
y’s
am
pli
fier
eff
ect,
com
mu
nit
y
transm
issi
on,
and
faci
lity
-base
d
transm
issi
on t
o
effe
ctiv
ely i
mp
rov
e th
e
manag
emen
t o
f M
DR
-
TB
and X
DR
-TB
case
s
Sharm
a,
Sharm
a,
Kadhir
avan,
and T
hary
an
(2013)
Syst
emati
c
revie
w
The
co
mpara
tive
ass
essm
ent
of
iso
nia
zid
ver
sus
rifa
mp
icin
regim
ens
was
un
der
tak
en i
n t
he
conte
xt
of
min
imiz
ing H
IV-
neg
ati
ve
pati
ents
’
pre
dis
posi
tion
tow
ard
s act
ivel
y
indu
ced
tub
ercu
losi
s
- T
he
auth
ors
eff
ecti
vel
y
exp
lore
d v
ari
ous
random
ized
contr
oll
ed
clin
ical
tria
ls a
nd
uti
lized
random
eff
ects
model
in t
he
conte
xt
of
pooli
ng t
he
confi
den
ce
inte
rvals
and r
elati
ve
risk
s fo
r th
e se
lect
ed
pati
ents
- T
he
auth
ors
use
d t
he
GR
AD
E s
trate
gy t
o
evalu
ate
the
quali
ty o
f
the
sele
cted
evid
ence
- T
he
sele
cted
clin
ical
tria
ls
wer
e base
d
on 9
8%
HIV
neg
ati
ve
chil
dre
n a
nd
adult
s
- S
am
ple
size:
10717
subje
cts
The
au
thors
evalu
ate
d
clin
ical
pra
ctic
e
imp
lica
tio
ns
of
ison
iazid
an
d
rifa
mp
icin
wh
ile
ass
essi
ng
vari
ou
s
att
rib
ute
s,
inclu
din
g a
ctiv
e
tuber
culo
sis,
trea
tmen
t
adh
eren
ce,
trea
tmen
t-
lim
itin
g a
dv
erse
epis
od
es,
and
- T
he
short
er
rifa
mp
icin
ther
ap
y (
as
com
pare
d t
o
iso
nia
zid
regim
en)
do
es n
ot
lead t
o t
he
elev
ate
d a
ctiv
e
tub
ercu
losi
s ra
tes
- R
ifam
pic
in
pro
ves
eff
ecti
ve
in i
mp
rov
ing t
he
tub
ercu
losi
s
trea
tmen
t
acc
om
pli
shm
ent
rate
wh
ile
The
pro
spec
tiv
e st
ud
ies
requ
ire
evalu
ati
ng t
he
freq
uen
cy o
f adv
erse
effe
cts
and t
reatm
ent
dis
co
nti
nu
ati
on r
ate
for
ass
essi
ng t
he
scop
e of
ad
min
iste
rin
g a
ther
ap
euti
c co
mb
inati
on
of
iso
nia
zid a
nd
rifa
pen
tin
e
8
Tex
ila I
nte
rnati
onal
Jou
rnal
of
Cli
nic
al
Res
earc
h
Vo
lum
e 6
, Is
sue
1,
Au
g 2
019
hep
ato
tox
icit
y
(i.e
. tr
eatm
ent
side-
effe
ct)
min
imiz
ing t
he
adv
erse
ther
ap
euti
c
ou
tco
mes
Sotg
iu,
Cen
tis,
D’a
mbro
sio,
and M
igli
ori
(2015)
Narr
ati
ve
revie
w
The
au
thors
exp
lore
d s
ever
al
MD
R-T
B t
reatm
ent
stra
teg
ies
in t
he
conte
xt
of
evalu
ati
ng t
hei
r
scop
e of
imp
rov
emen
t
The
auth
ors
evalu
ate
d
evid
ence-
base
d a
rtic
les
to e
ffec
tivel
y e
xplo
re
the
rati
onale
and h
isto
ry
of
tub
ercu
losi
s
managem
ent
inte
rven
tions/
pharm
acot
her
apy
NA
T
he
au
thors
evalu
ate
d
vari
ou
s M
DR
-
TB
pharm
acoth
erap
euti
c re
gim
ens
alo
ng w
ith t
hei
r
adv
erse
eff
ects
,
com
pli
cati
ons,
and t
her
ap
euti
c
barr
iers
- T
he
au
thors
cou
ld n
ot
fin
d a
ny
standard
reg
imen
for
the
sati
sfact
ory
trea
tmen
t o
f
MD
R-T
B
- T
he
MD
R-T
B
ther
ap
euti
c
succ
ess
rate
requ
ires
sub
stanti
al
imp
rov
emen
t
wh
ile
enhancin
g
the
aff
ord
ab
ilit
y
and e
ffic
acy
of
MD
R-T
B
trea
tmen
t dru
gs
in
reso
urc
e-li
mit
ed
faci
liti
es
The
lon
g-t
erm
eff
icacy
of
bed
aqu
ilin
e an
d
del
am
an
id w
arr
ants
pro
spec
tiv
e
inv
esti
gati
on i
n t
he
conte
xt
of
dev
elop
ing
rob
ust
and
com
pre
hen
siv
e
ther
ap
euti
c ap
pro
ach
es
for
TB
/MD
R-T
B
manag
emen
t in
med
ical
faci
liti
es
Yang,
et a
l.
(2017)
Conse
cuti
v
e revie
w/r
etr
osp
ecti
ve
stu
dy
The
au
thors
evalu
ate
d t
he
side-
effe
cts
of
MD
R-T
B
med
icati
on t
o
faci
lita
te
ther
ap
euti
c
mo
dif
icati
ons
warr
ante
d t
o
imp
rov
e th
e quali
ty
- T
he
rese
arc
her
s
exp
lore
d m
edic
al
record
s of
the
sele
cted
subje
cts
for
extr
act
ing
thei
r M
DR
-TB
-rel
ate
d
data
incl
udin
g c
linic
al
outc
om
es,
trea
tmen
t
regim
en,
adver
se e
ffec
ts
of
the
recom
men
ded
ther
apy,
dru
g
The
rese
arc
her
s
inclu
ded
256
subje
cts
who
recei
ved
MD
R-T
B
ther
apy
insi
de
the
sele
cted
hosp
ital
for
a
The
rese
arc
her
s
record
ed t
he
side
effe
cts
of
vari
ou
s M
DR
-
TB
med
icati
ons
inclu
din
g
ison
iazid
,
rifa
mp
icin
,
etham
bu
tol,
pyra
zinam
ide,
The
co
mm
on
ly
rep
ort
ed s
ide
effe
cts
of
MD
R-
TB
ther
ap
y
inclu
ded
nep
hro
tox
icit
y,
oto
tox
icit
y,
der
mato
logic
al
com
pli
cati
ons,
epil
epti
c se
izu
res,
- T
he
rep
ort
ed M
DR
-TB
ther
ap
y’s
sid
e-ef
fect
s
pre
do
min
antl
y l
ead t
o
trea
tmen
t n
on-
com
pli
ance
or
wit
hdra
wal
that
even
tuall
y e
levate
s th
e
risk
of
morb
idit
y a
nd
mort
ali
ty o
f th
e tr
eate
d
pati
ents
9
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96
of
trea
tmen
t
inte
rven
tions
susc
epti
bil
ity t
esti
ng
outc
om
es,
com
orb
idit
ies,
and
dem
ogra
phic
s fo
r th
eir
stati
stic
al
analy
sis
- T
he
ass
essm
ent
of
majo
r and m
inor
side
effe
cts
of
MD
R-T
B
ther
apy w
as
under
taken
thro
ugh t
he
calc
ula
tion
of
thei
r st
andard
dev
iati
on a
nd m
ean
inte
rval
tenure
of
6
conse
cuti
ve
yea
rs
stre
pto
my
cin,
kanam
ycin
,
am
ikaci
n,
pro
thio
nam
ide,
para
-
am
inosa
licy
lic
aci
d,
cycl
ose
rin
e,
levofl
ox
aci
n,
ofl
ox
aci
n,
and
mox
iflo
xaci
n
hyp
oth
yro
idis
m,
per
iph
eral
neu
rop
ath
y,
hep
ati
tis,
art
hra
lgia
,
psy
ch
iatr
ic
dis
ord
er,
and
gast
roin
test
inal
(GI)
com
pli
cati
ons.
Ho
wev
er,
nep
hro
tox
icit
y
and G
I
dis
turb
ance
pro
ved
to b
e th
e
least
and m
ost
com
mo
nly
rep
ort
ed s
ide
effe
cts
of
MD
R-
TB
ther
ap
y
- T
he
clin
icia
ns
an
d
rese
arc
her
s m
ust
un
der
tak
e p
rosp
ecti
ve
stu
die
s in
th
e conte
xt
of
form
ula
tin
g
com
pre
hen
siv
e
ther
ap
euti
c ap
pro
ach
es
for
the
succ
essf
ul
trea
tmen
t o
f M
DR
-TB
pati
ents
wh
ile
min
imiz
ing t
he
sid
e
effe
cts
and o
ther
ther
ap
euti
c
com
pli
cati
ons
10
Texila International Journal of Clinical Research
Volume 6, Issue 1, Aug 2019
Discussion
Significant outcomes
The study findings effectively reveal various pharmacotherapeutic approaches and treatment
combinations for the systematic treatment of MDR-TB and XDR-TB. The findings also reveal the
absence of any standard approach to minimize the prevalence of MDR-TB and related comorbidities.
The timely tracking of the MDR-TB cases and their individualized causes is, therefore, highly necessary
for challenging the occurrence of preventable MDR-TB outbreaks.
MDR-TB Epidemiology
The clinicians require thoroughly evaluating the complete epidemiology of MDR-TB for developing
robust drug susceptibility interventions to facilitate the individualization of pharmacotherapy based on
the reported clinical manifestations [8]. Girum, Muktar, Lentiro, Wondiye, and Shewangizaw (2018)
describe HIV-seropositivity, TB medications’ side effects, and TB-related comorbidities as the
significant predisposing factors related to the increased prevalence of MDR-TB. The research findings
reveal a 65-80% therapeutic success rate for MDR-TB patients [8]. This rate does not effectively
comply with 75% MDR-TB therapy success requirement stipulated by WHO. The reduced success rate
of MDR-TB therapy against the elevated resistance of microbes leads to serious public health concerns
across developed or underdeveloped nations of the world. The clinicians require evaluating the baseline
weight, HIV seropositivity, mal-absorption, adverse treatment effects, and comorbidities level of the
MDR TB patients while recommending their comprehensive treatment approaches. The evidence-based
research literature effectively substantiates the MDR-TB epidemiology-related findings of the presented
study. The epidemiological findings of 2015 revealed 21% MDR-TB cases with a clinical history of
tuberculosis and 3.9% of the preliminary TB patients who reportedly developed MDR-TB and related
complications [5]. The literature findings also reveal rifampicin resistance as the greatest cause of
MDR-TB among predisposed patients. MDR-TB epidemiology impacts its prevalence and
complications in numerous ways. The elevated prevalence of tuberculosis reciprocally increases the
medication administration rate among the affected patients. This eventually elevates the risk of bacterial
resistance to many folds based on inappropriate drugs combination, treatment non-compliance, and
reduced health-related quality of life of the underprivileged patients in resource-limited settings [28].
Furthermore, consistent contact of the tuberculosis survivors with MDR-TB patients substantially
elevates their predisposition towards MDR-TB. The absence of ventilation and overcrowding also
elevates the prevalence of MDR-TB among high-risk patients. The individuals having known clinical
history of TB exhibit an elevated predisposition towards the development of rifampicin resistance that
eventually leads to the progression of MDR-Tb and associated comorbidities [10]. Therefore,
epidemiology-based findings of the presented study as well as evidence-based clinical literature
substantiate the requirement of MDR-TB drugs' susceptibility testing for the predisposed patients to
facilitate the timely administration of the appropriate pharmacotherapy [8]. Furthermore, the therapeutic
management of MDR-TB must focus on controlling the clinical manifestations while concomitantly
minimizing the adverse effects of the selected pharmacotherapy.
Causative Factors of MDR-TB
The narrative review by Seung, Keshavjee, and Rich (2015) describes various causative factors that
elevate the prevalence of MDR-TB among predisposed individuals [24]. These causative factors are
based on weak clinical approaches, inappropriate medication, drug resistance, community-based
transmission, and facility-based infection progression. However, evidence-based research literature also
describes various comorbidities that not only elevate the risk of MDR-TB but also decrease the life
expectancy of the affected patients. Accordingly, the literature findings reveal HIV as the greatest
comorbidity that elevates the risk of MDR-TB to many-fold [4]. The other comorbidities including
alcohol abuse, chronic kidney disease, and diabetes mellitus deteriorate the therapeutic outcomes of
MDR-TB patients in many clinical scenarios [22]. The clinical literature also reveals 14.1% TB patients
affected with single or multiple drug resistance [18]. Furthermore, 7.4% of TB patients tend to develop
11
DOI: 10.21522/TIJCR.2014.06.01.Art003
ISSN: 2520-3096
severe resistance against isoniazid. The metabolic remodeling of Mycobacterium tuberculosis reveals
its high tendency for developing antibiotic tolerance, and intrinsic drug resistance [9]. The reduced
growth rate, waxy cell wall, and thick structure of Mycobacterium tuberculosis are predominantly
responsible for its elevated tolerance against various antibiotics. Therefore, the outcomes of the
presented study along with the evidence-based findings warrant the thorough investigation of MDR-TB
causes to facilitate the customization of the appropriate pharmacotherapy [24]. The early identification
of drug resistance through community-based approaches will also improve the therapeutic outcomes
and recovery pace of the MDR-TB patients to an unprecedented level.
Pathophysiology/Pathogenesis of MDR-TB
The article by Koch, Cox, and Mizrahi (2018) discusses the pathogenesis of MDR-TB through the
utilization of evidence-based tools, including PhyResSE, TB Profiler, Poly TB, ReSeqTB, and
TBDreamDB [15]. The findings reveal genetic mutations in Mycobacterium tuberculosis as the
preliminary cause of MDR-TB development in high-risk patients. The study findings also substantiate
the requirement of evaluating Mycobacterium tuberculosis resistance pattern, strain type, and
heterogeneity level to facilitate the development of shortened pharmacotherapeutic measures for MDR-
TB patients. The complex virulence factors of Mycobacterium tuberculosis reduce the capacity of
alveolar macrophages in the context of ceasing its growth and development in the human host [1].
Furthermore, the ramification of caseous necrosis and development of multinucleated giant cells not
only elevates immunosuppression of the host cell lines but also reduces the antibiotic susceptibility of
Mycobacterium tuberculosis. Eventually, the immunosuppression of the human host along with
occupational and socioeconomic risk-factors (i.e. silicosis, malnutrition, and poverty) substantially
elevate the level of pathogen’s resistance against various antibiotics. Furthermore, the elevated toxicity
of MDR-TB/XDR-TB treatment therapies proves to be the greatest barrier against their long-term
administration to the MDR-TB/XDR-TB patients [20]. These evidence-based outcomes reveal the
requirement of evaluating the pathophysiology and complete treatment history of the MDR-TB patients
for effectively improving the overall quality of recommended antituberculosis pharmacotherapies.
Diagnostic approaches
Gilpin, Korobitsyn, and Weyer (2016) emphasize the requirement of following WHO-based
diagnostic interventions, including END TB approach and universal drug susceptibility testing to
effectively reduce the risk of comorbidities and treatment delay among MDR-TB patients [7]. However,
the evidence-based clinical literature also recommends various line probe assays based on GenoType
MTBDR and INNO-LiPA Rif. TB kit to effectively facilitate early identification and diagnostic
precision of MDR-TB cases. These assays exhibit 100% specificity and 95% sensitivity in the context
of tracking a range of MDR-TB/XDR-TB cases [17]. The clinicians recommend the complete
investigation of the drug-resistant source and its contact with suspected MDR-TB patients for their early
treatment through novel pharmacotherapeutic approaches [23]. The clinicians also require evaluating
pediatric patients through clinical examination and standardized diagnostic interventions, since they
experience a greater risk for MDR-TB as compared to the adult populations. The clinicians must
regularly utilize conventional diagnostic methods and clinically correlate their findings in the context
of improving the precision of MDR-TB assessment. Some of the significant diagnostic interventions
include radiologic study, AFB culture, nucleic acid amplification testing, line probe assay, and Xpert
MTB assay [21]. The findings of the presented study along with the evidence-based outcomes
recommend the systematic use of comprehensive diagnostic approaches to reduce the risk of unattended
MDR-TB cases in the clinical settings.
Preventive interventions
Podany and Swindells (2016) describe a range of novel treatment strategies and prophylactic
approaches to systematically prevent the occurrence of TB, MDR-TB, and XDR-TB outbreaks [19].
For example, they recommend the dosage enhancement of rifampicin beyond the conventional 600mg
requirement for improving the therapeutic outcomes for MDR-TB patients. The clinicians must attempt
to reduce the recovery time for the MDR-TB patients while configuring elevated-dose combinations of
12
Texila International Journal of Clinical Research
Volume 6, Issue 1, Aug 2019
potential drugs like bedaquiline, delamanid, clofazimine, linezolid, and rifampin [19]. However,
researchers require undertaking prospective clinical trials to evaluate the effectiveness of these drug
combinations for MDR-TB patients. The evidence-based research literature substantially emphasizes
the enhancement of risk assessment approaches to effectively reduce the prevalence of MDR-TB and
XDR-TB among predisposed patients. The drug susceptibility studies require radical improvement
through clinical trials and observational studies. The researchers also require modifying BCG (Bacillus
Calmette-Guerin) vaccine to facilitate its administration to HIV patients for reducing their risk of TB
and MDR-TB [11]. Furthermore, the development of molecular genetic approaches, rapid diagnostic
strategies, and laboratory information management systems is highly required to effectively improve
the quality of TB/MDR-TB/XDR-TB testing in various hospital settings [12]. The clinicians and nurses
should initiate various educational services in hospitals/community settings to elevate the tuberculosis
knowledge and awareness of the common masses. The outcomes of the presented study and evidence-
based clinical literature necessitate the requirement of improving the level of preventive/prophylactic
approaches through clinical studies for minimizing the onset and progression of MDR-TB among the
high-risk individuals.
Treatment modalities
Chang and Yew (2013) recommend various preventive and therapeutic strategies to reduce the
risk/prevalence of MDR-TB [3]. The preventive treatment for the suspected individuals is based on
twice-weekly administration of isoniazid and rifampicin for 12 weeks’ duration. The focused treatment
of HIV patients is highly needed through antiretroviral therapy to reduce their risk of tuberculosis or
MDR-TB. The administration of pharmacotherapy to MDR-TB patients reciprocates through clinical
correlation of their diagnostic findings and disease manifestations. MDR-TB treatment is based on first-
line oral medication, fluoroquinolones, injectable drugs, second-line (oral bacteriostatic) drugs, and
other miscellaneous medications. The first-line oral drugs include isoniazid, rifampicin, ethambutol,
and pyrazinamide. The orally administered fluoroquinolones include levofloxacin, moxifloxacin,
gatifloxacin, and ofloxacin. The injectable drugs for MDR-TB include capreomycin, kanamycin,
amikacin, and streptomycin. However, second-line MDR-TB therapy or oral bacteriostatic drugs
include ethionamide, prothionamide, para-aminosalicylic acid, cycloserine, and terizidone. However,
unconventional MDR-TB drugs include linezolid, amoxicillin-clavulanate, clofazimine, rifabutin,
clarithromycin, meropenem-clavulanate, and thioridazine. The clinicians require attempting various
combinations of these drugs based on the reported MDR-TB manifestations and therapeutic factors to
effectively improve the treatment outcomes. Sharma, Sharma, Kadhiravan, and Tharyan (2013)
consider rifampicin therapy as the treatment of choice to improve the MDR-TB treatment success rate
[26]. They consider rifampicin as the safest MDR-TB treatment drug based on its minimal side-effects.
However, Sotgiu, Centis, D’ambrosio, and Migliori (2015) recommend the need for prospective clinical
trials in the context of testing the therapeutic potential of antituberculosis drugs, including bedaquiline
and delamanid [27]. Yang, et al (2017) consider the adverse effects of the standard MDR-TB treatment
therapies as the greatest barriers against their long-term utilization by the tuberculosis patients [30].
These findings substantiate the modification of existing antituberculosis therapies for improving the
treatment outcomes and overall recovery time of MDR-TB patients. WHO guidelines advocate the use
of surgical interventions and conventional treatment modification/reclassification to improve the
therapeutic outcomes in MDR-TB patients. For example, the guidelines emphasize the administration
of at least 5 medicines based on second-line drugs and pyrazinamide for treating the intensive phase of
MDR-TB. The shorter drug-resistant TB medication course is based on gatifloxacin (400-800mg),
moxifloxacin (400-800 mg), clofazimine (50-100mg), ethambutol (800-1200mg), pyrazinamide (1000-
2000mg), prothionamide (300-600mg), and kanamycin (<1g). The outcomes of the presented study and
evidence-based findings reveal various therapeutic approaches for MDR-TB management [13].
However, no therapeutic strategy has attained the status of the standardized MDR-TB treatment until
date. The researchers, therefore, require undertaking prospective clinical studies while considering
MDR-TB’s clinical presentation and causative factors in the context of designing comprehensive
treatment interventions for tuberculosis prevention and management in the hospital settings.
13
DOI: 10.21522/TIJCR.2014.06.01.Art003
ISSN: 2520-3096
Conclusion
The presented narrative review proves highly instrumental to the understanding of MDR-TB
etiology, causative factors, pathophysiology, diagnostic interventions, preventive approaches, treatment
options, and therapeutic barriers. The study outcomes provide substantial clinical evidence to improve
the overall decision-making process related to MDR-TB therapy. The MDR-TB relapse and treatment
resistance reciprocate with genetic mutations of Mycobacterium tuberculosis and inappropriate
therapeutic decisions. The physicians, therefore, require thoroughly examining each of the MDR-TB
cases or suspected patients for evaluating their therapeutic responses and drug susceptibility pattern.
They must utilize evidence-based research literature and correlate the respective outcomes with their
patients’ clinical manifestations to effectively improve the formulation of robust antituberculosis
therapies. Furthermore, shortening of the second-line therapeutic regimen through dosage modifications
is also recommended to reduce the risk of MDR-TB relapse and minimize the overall recovery time.
The physicians should effectively treat their HIV patients in the context of reducing their predisposition
towards MDR-TB and XDR-TB. The enhancement of health-related quality of life of the MDR-TB
suspected patients and their poverty eradication are highly warranted to effectively control the elevated
prevalence of tuberculosis across the resource-limited regions. The clinicians must stringently follow
the WHO-recommended diagnostic approaches to reduce the risk of treatment delays for MDR-TB
patients. The clinicians require modifying the presently implemented drug susceptibility testing
approaches and monitoring the pharmacotherapeutic adversities to improve the scope of MDR-TB
treatment quality. The appropriate determination of causative pathogen and its mutation status through
molecular imaging methods is highly needed for the development of targeted MDR-TB management
therapies. Furthermore, the clinicians must administer educational sessions at the population level for
increasing the awareness of common masses related to MDR-TB risk factors and preventive measures.
They must also proactively challenge facility-based and community-based Mycobacterium tuberculosis
transmissions while regularly monitoring the drug resistance level of MDR-TB patients against the
recommended pharmacotherapy. The regular monitoring of the adverse therapeutic outcomes and
clinical investigation of the recommended drugs are highly warranted to effectively improve the overall
healing process of MDR-TB patients. The findings of the presented study advocate the need for
customizing MDR-TB treatment therapy based on a range of diagnostic, therapeutic, clinical, and
individual factors. The study outcomes also substantiate the requirement of greater multidisciplinary
collaboration between physicians and researchers to facilitate the configuration of robust MDR-TB
management interventions across the clinical practice environment.
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