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R E V I E W A R T I C L E

Introduction

Te burgeoning drug-resisan uberculosis (DR-B) epidemic is a

public healh problem o global imporance. Alhough B incidence

and moraliy has decreased in several pars o he world, he

overall prevalence o mulidrug-resisan uberculosis (MDR-B)

is increasing in many high-burden counries, paricularly in

Arica (1). According o he laes WHO saisics, approximaely

hal a million new cases o MDR-B are diagnosed every year (2).

O hese, i is esimaed ha approximaely 40,000 have exensively

drug-resisan uberculosis (XDR-B). Despie his, limied

laboraory capaciy and lack o widespread drug suscepibiliy

esing in resource-poor setings means ha less han 6% o casesare hough o have been correcly diagnosed (2). In 2011, only

one in five o he esimaed DR-B cases among paiens noified

in he world were enrolled on reamen (3). A large reservoir o

paiens wih undiagnosed DR-B hus exiss ha coninues o

drives person-o-person ransmission, and hreaens o desabilise

global B conrol (4,5).

he reamen o paiens wih DR-B is complex, and

characerised by a longer duraion o reamen, he use o less

poen bu more oxic medicaions, higher relapse raes, and a lower

likelihood o reamen success when compared o drug-suscepible

B (6). reamen or DR-B reamen is also considerably moreexpensive: a recen sudy by Pooran et al.esimaed ha despie

only comprising 2.2% o he case burden o B in Souh Arica,

DR-B consumed 44% o he oal naional coss o diagnosing and

managing all orms o B (~$158 million) in 2011 (7).

In his review, we ouline he diagnosis, medical managemen

and reamen oucomes, and indicaions and oucomes o

adjuvan resecional surgery in he managemen o DR-B.

The medical and surgical treatment of drug-resistant tuberculosis

Gregory L. Calligaro1,2

, Loven Moodley3, Greg Symons

1,2,4, Keertan Dheda

1,2

1Lung Infection and Immunity Unit, University of Cape Town Lung Institute, Cape Town, South Africa; 2Division of Pulmonology, Groote

Schuur Hospital, Cape Town, South Africa; 3Division of Cardiothoracic Surgery, Groote Schuur Hospital, Cape Town, South Africa; 4Centre

for TB Drug Research and Innovation, University of Cape Town Lung Institute, Cape Town, South Africa

ABSTRACT Muli drug-resisan uberculosis (MDR-B) and exensively drug-resisan B (XDR-B) are burgeoning global problems

wih high moraliy which hreaen o desabilise B conrol programs in several pars o he world. O alarming concern

is he emergence, in large numbers, o paiens wih resisance beyond XDR-B (oally drug-resisan B; DR-B or

exremely drug resisan B; XXDR-B). Given he burgeoning global phenomenon o MDR-B, XDR-B and DR-B,

and increasing inernaional migraion and ravel, healhcare workers, researchers, and policy makers in B endemic

and non-endemic counries should amiliarise hemselves wih issues relevan o he managemen o hese paiens.

Given he lack o novel B drugs and limied access o exising drugs such as linezolid and bedaquiline in B endemic

counries, significan numbers o herapeuic ailures are emerging rom he ranks o hose wih XDR-B. Given he lack o

appropriae aciliies in resource-limied setings, such paiens are being discharged back ino he communiy where here

is likely ongoing disease spread. In he absence o effecive drug regimens, in appropriae paiens, surgery is a cri ical par o

managemen. Here we review he diagnosis, medical and surgical managemen o MDR-B and XDR-B.

KEYWORDS Exensively drug-resisan uberculosis (XDR-B); surgery; drug resisance

J Thorac Dis 2014;6(3):186-195. doi: 10.3978/j.issn.2072-1439.2013.11.11

Corresponding to: Keertan Dheda, Head. Division of Pulmonology, H46.41 Old Main

Building, Groote Schuur Hospital, Observatory, Cape Town, 7925, South Africa.

Email: [email protected].

Submitted Sep 17, 2013. Accepted for publication Nov 20, 2013.

Available at www.jthoracdis.com

ISSN: 2072-1439

Pioneer Bioscience Publishing Company. All rights reserved.


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Journal of Thoracic Disease, Vol 6, No 3 March 2014 187

Defnitions

MDR-B is deined as resisance o a leas isoniazid and

riampicin, he wo mos eecive irs-line aniuberculous

drugs, while XDR-B is deined as MDR-B plus resisance

o any luoroquinolone and any second-line injecable (eiher

kanamycin, amikacin or capreomycin) (3). Pre-XDR-B reers

o MDR-B resisan o eiher a second-line injecable drug or a

fluoroquinolone.

Oher erms such as exremely drug-resisan B (XXDR-B) (8)

or oally drug-resisan B (DR-B) (9,10) have been used by

various auhors o described srains wih more exensive paterns

o resisance (o all irs-line and second-line drugs). hese

repors have given rise o he specre o so-called unreaable

B, which has been sensaionalized in he media. However, due

o problems wih he reliabiliy and reproducibiliy o in viro

drug suscepibiliy esing or second-line drugs, no inernaionalconsensus has been reached abou he deiniion o more

exensive resisance paerns, and he erm resisance beyond

XDR is preerred. Te relevance o hese resisance paterns on

oucomes is also an acive area o sudy.

Diagnosis of drug-resistant tuberculosis

Culture-based tests for DR-TB

For many years, he laboraory diagnosis o DR-B has

depended on he demonsraion o he presence o M.tbgrowhin he presence o speciic aniuberculous drugsso-called

convenional drug-suscepibiliy esing (DS). Solid agar

mehods are he diagnosic gold sandard (11), while liquid

culure mehods such as he Bacec MGI 960 sysem (Becon-

Dickinson, Sparks, MD, USA) have equivalen perormance,

and are WHO-endorsed (12). However, a lack o laboraory

inrasrucure in developing counries means ha very ew

counries have access o any DS a all: he WHO repors ha

globally less han 4% o baceriologically-posiive cases and only

6% o rereamen cases were esed or DR-B in 2011 (13).

Anoher major disadvanage o hese culure-based mehods is

he long delay (usually several weeks) in obaining DS resuls.During hese delays, regimens may be used which are no only

ineecive, bu which encourage he developmen o urher

drug resisance, and crucially, allow or resisan disease o be

spread. A sraegy ha aims o conrol DR-B mus hereore

aim no only o increase access o DS, bu also o reduce he

lead-ime or accurae diagnosis (14). New advances in rapid

growh- and microscopy-based DS, such as he microscopy

observed drug suscepibiliy (MODS) mehod and hin layer

agar (LA) echnique have shorened he delay o less han wo

weeks, bu are limied by he need or labour-inensive laboraory

inrasrucure (15). More recenly, he direc nirae reducase

assay (NRA), a rapid, low-cos, phenoypic mehod based on he

meabolic aciviy o M.tb which is usually perormed on solid

media, has been shown o accuraely diagnose DR-B afer ~21 days

when perormed direcly on smear-posiive specimens (16).

Molecular DST

New nucleic acid amplificaion ess (NAAs) promise o reduce

he inerval beween sample acquisiion and suscepibiliy

resul rom weeks o hours, and are also becoming increasingly

auomaed and easy o perorm. hey have he poenial o

ransorm he drug-sensiive and drug resisan B epidemic

in high burden counries by providing rapid DS resuls a he

ime o B diagnosis, increasing he number o cases ha arediagnosed wih DR-B and sared immediaely on he correc

reamen, and impacing on ransmission raes (17).

Xper MB/RI F (Cep heid, Sun nyvale, CA , USA) is a

semi-nesed quaniaive real-ime polymerase chain reacion

(PCR) assay ha can deliver simulaneous diagnosis o B and

riampicin resisance in less han wo hours. I is an auomaed,

carridge-based sysem ha can be perormed in decenralized

locaions, ouside o reerence laboraories and poenially a

poin-o-care, by sa wih minimal laboraory raining. I has

been widely validaed on spuum samples, alhough repors are

also emerging on is accuracy in oher respiraory specimensand exrapulmonary samples (18-21). A recen mea-analysis

has repored he sensiiviy and speciiciy o he assay or he

deecion o riampicin resisance in spuum o be 94.1% and

97.0%, respecively (22). Based on his evidence, he WHO has

srongly recommended ha Xper MB/RIF, where available,

should be he firs invesigaion in all paiens suspeced o having

DR-B or HIV-associaed B (23). A disadvanage is ha Xper

MB/RIF does no assay or isoniazid resisance and hereore

isoniazid mono-resisance, which has a requency o abou

10-15% in high burden setings, will be missed (24,25). Anoher

concern wih Xper MB/RIF is subopimal posiive predicive

value in seings where he prevalence o drug-resisan B isless han 20%. In relaively high-burden setings, even in Souh

Arica where MDR-B prevalence raes are ~5% o 6% (14), he

posiive predicive value is only likely o be approximaely 70%

o 80%, hough he precise igure remains unclear. his means

ha approximaely one in hree or our riampicin-resisan

resuls will possibly be alsely posiive, creaing uncerainy

around he decision o sar MDR-B reamen. In Souh Arica,

he policy is o iniiae MDR-B reamen on an Xper MB/


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Calligaro et al. Medical and surgical management of drug-resistant tuberculosis188

RIF showing riampicin resisance, paricularly i he paien is

unwell, unil urher conirmaory es resuls on wo samples

(eiher phenoypic DS or alernaive PCR-based es like Hain

MBDRplus) become available.

A line probe assay is laboraory-based ype o nucleic acid

ampliicaion assay in which producs are hybridized ono

a niro-cellulose srip. An example is he MBDRplus assay

(Hain Liesciences), which offers similar perormance o Xper

MB/RIF or B deecion, and has excellen perormance

or he deecion o MDR-B (26,27). I has he advanage

o inerrogaing or boh riampicin and isoniazid resisance.

More recenly, he MBDRsl assay (second line) assay has

Table 1. Firs- and second-line drugs based on he World Healh

Organizaion classificaion (32).

Group 1: first-line oral TB drugs

Isoniazid (H)

Pyrazinamide (Z) or PZAEthambutol (E) or (EMB)

Rifampicin/rifampin (R) or (RIF)

Rifabutin (RFB)

Group 2: second-line injectable TB drugs

Kanamycin (KAN)

Amikacin (AMK)

Capreomycin (CAP)

Streptomycin (STR)

Group 3: fluoroquinolones

Levofloxacin (LFX)

Moxifloxacin (MFX)

Ofloxacin (OFX)

Gatifloxacin (GFX)

Group 4: oral bacteriostatic second-line TB drugs

Para-aminosalicylic acid (PAS)

Cycloserine (DCS)

Terizidone (TRD)

Ethionamide (ETH)

Prothionamide (PTO)

Group 5: TB drugs with unclear efficacy or unclear role in

treating drug resistant-TB

Clofazimine (CFZ)

Linezolid (LZD)

Amoxicillin/clavulanate (AMX/CLV)

Thiacetazone (THZ)

Clarithromycin (CLR)

Imipenem/cilastatin (IPM/CLN)

High-dose isoniazid (high-dose H)

been inroduced which ess or drug-resisance o second line

injecable drugs (muaions on he rrs gene), luoroquinolones

and ehambuol (28). However, his assay has diminished

accuracy in smear-negaive specimens (29), meaning ha culure

isolaes sill need o be awaied o rule-in resisance.

he diagnosis o exrapulmonary DR-B is even more

challenging as obaining samples or diagnosis oen requires

specialized skills (e.g., lumbar puncure or biopsy), and he

radiional mehods o smear microscopy and culure perorm

poorly on paucibacillary non-spuum samples. Perorming an

Xper MB/ RIF on concenraed urine can ideni y 40% o

HIV-B cases who are spuum-scarce (30), and sensiiviy is

approximaely 23%, 53%, and 78% in he pleural, pericardial

and CSF comparmens, respecively [R. Meldau and K. Dheda,

submied; S. Pandie and K. Dheda, submied; (31)]. In he

CSF and urine comparmens, cenriuging he fluid significanly

improved accuracy. In BAL luid obained by bronchoscopy,Xper yield was ~75% and was unaffeced by HIV saus (18).

Medical management of DR-TB

MDR-TB treatment

he reamen regimen or MDR-B consiss o a backbone o

a laer generaion luoroquinolone (moxiloxacin, gailoxacin

or levoloxacin) and an injecable aminoglycoside (eiher

amikacin or kanamycin), any irs line drug o which he

isolae is suscepible, and he addiion o group 4 drugs such ascycloserine/erizidone, and ehionamide, such ha as leas our

drugs o which he isolae is likely o be suscepible are being used

(see ables 1,2). he inensive phase (wih injecable) is eigh

monhs, ollowed by a coninuaion phase o 12 o 18 monhs.

he recommended duraion o reamen is guided by culure

conversion and is usually deermined by adding 18 monhs o

he dae o he irs o consecuive negaive culures; he WHO

recommends a oal reamen duraion o a leas 20 monhs (33).

Non-adherence, incorrec drug dosage, heero-resisance, and

malabsorpion should be considered in paiens who do no

show a clinical response and remain persisenly culure-posiive

despie exhibiing consisen suscepibiliy o second-line drugs.

Tese paiens may be considered or he addiion o alernaive

second line agens o heir regimens, and/or reerred or surgery

afer appropriae invesigaions are underaken.

XDR-TB treatment

Wih he loss o wo o he mos poen groups o second-line

drugs (namely luoroquinolones and aminoglycosides), he


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design o a reamen regimen or XDR-B is more complex (see

able 2). Exended regimens in B-endemic counries, given

he lack o availabiliy o linezolid, oen consis o a backbone

o capreomycin and para-aminosalicylic acid (PAS), wih oher

firs-line, second-line or hird-line ani-B drugs added o which

suscepibiliy has been demonsraed, or a he discreion o he

atending clinician. Te inensive phase wih capreomycin should

be a leas eigh monhs (15). Te exac number o drugs used o

rea XDR-B is no known, bu mos paiens will receive five

o six drugs. Unorunaely, high raes o capreomycin resisance

(~80%) in XDR paiens have been observed (E. Pieersen

and K. Dheda, unpublished work), presumably due o cross-resisance wih he oher aminoglycosides (34); similarly, as he

majoriy o paiens wih XDR-B have been previously reaed

or MDR-B (35,36), prior exposure o drugs like ehionamide

and erizidone usually excludes heir use. Despie documened

luoroquinolone resisance, moxiloxacin is usually added o

he regimen because i has increased aniuberculous aciviy

compared wih oloxacin, and because here is dierenial

srain-speciic suscepibiliy o he luoroquinolones (37).

Moxiloxacin has been shown o be eecive agains isolaes

phenoypically resisan o ofloxacin or ciprofloxacin (38), and

may be associaed wih improved oucomes or paiens wih

XDR-B (39). In isolaes where lack o isoniazid suscepibiliy

resuls rom muaions in he promoer region o he inhAgene

(40-42), low-level resisance can likely be overcome by increased

doses o he isoniazid (high-dose INH) (43). Tis patern o

resisance is oen accompanied wih cross-resisance o oher

second line ani-uberculosis agens, specifically ehionamide, as

i has a srucural similariy o isoniazid (44). Oher drugs like

cloazamine (45) and bea-lacam anibioics like meropenem

and co-amoxiclav (46) rom group 5 are also used, alhoughgood qualiy efficacy daa is lacking. Bedaquiline, he firs novel

aniuberculous drug o emerge in almos hal a cenury (47),

has been cauiously approved in an inerim recommendaion

by he WHO or paiens in whom a regimen conaining our

effecive second-line drugs canno be consruced, or in paiens

where h ere is MDR-B pl us documened res is a nce o a

fluoroquinolone (pre-XDR-B), provided ha bedaquiline can

be proeced by a leas hree eecive drugs (48). he laer

Table 2.Principles o managemen o drug-resisan B.

Principles of medical management of MDR-TB

A regimen is based, when possible, on proven or likely susceptibility to at least four drugs

A regimen is generally based on a backbone of a later generation fluoroquinolone (moxifloxacin or levofloxacin), and injectable

agent (usually an aminoglycoside, i.e., either amikacin or kanamycin), any first line drug to which the isolate is susceptible (seeTable 1), and addition of group 4 drugs such as cycloserine/terizidone and ethionamide, and others, such that at least four drugs

to which the isolate is likely to be susceptible are being used

The injectable drugs are used for 6-8 months, and longer in certain cases, and the total duration of treatment is suggested to be

24 months

If the patient has previously been on treatment with a specific drug for three or more months, then this drug is generally avoided

Addressing psychological factors to ensure compliance is critical

Patients should be monitored for adverse drug reactions, which are common

A single drug should not be added to a failing regimen

Principles of medical management of XDR-TB

Regimens should be constructed based on prevailing DST patterns

Given the high background rates of TB and MDR-TB in several countries, and lack of availability of newer agents like linezolidand bedaquiline, regimens are often constructed around a backbone of capreomycin and PAS

Any drug that the isolate is susceptible to from category 1, and any remaining available drugs from category 3 or 4, are added to

the regimen

Patients should be carefully monitored for adverse drug reactions, particularly capreomycin (renal failure, hypokalemia and

hypomagnesaemia), which are common

Patients on capreomycin should have weekly urea and electrolytes monitored for the first eight weeks and then monthly

thereafter. Attention should be paid to correcting risk factors for renal failure (dehydration, nausea, vomiting and diarrhea,

avoidance of other nephrotoxic drugs (cotrimoxazole and nevirapine), and early identification of underlying renal disease (diabetes

and HIV-associated nephropathy)


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is oen no possible in B-endemic counries wih currenly

available drugs. Saey concerns have been raised abou he

ineracion beween bedaquiline and cloazamine and he

luoroquinolones, as all cause Q prolongaion. he addiion

o linezolid o he regimen o paiens ailing sandard XDR-B

reamen has been shown o improve culure-conversion, bu

longer-erm oucomes are unknown, and cos and oxiciy are

major concerns (49). Neiher bedaquiline nor linezolid are

currenly available o Naional reamen Programs in counries

where XDR-B is prevalen and endemic.

Monitoring during treatment

reamen or DR-B involves he use o oxic medicaions:

drug-associaed adverse effecs are common, and can requenly

inerrup reamen (50). In addiion o monioring spuum

culures, i is essenial o monior renal uncion and poassium a

leas monhly during he inensive phase o reamen involving

an injecable. Oooxic hearing loss is common in paiens wih

DR-B reaed wih aminoglycosides: a recen sudy rom SouhArica ound ha 57% o paiens had developed high-requency

hearing loss afer hree monhs o aminoglycoside reamen (51).

All pa i en s sh ou ld h er e or e be sc reen ed mo n hl y wi h

audiomery during he inensive phase o reamen. hyroid

uncion should be moniored beween six and nine monhs

o reamen wih ehionamide, prohionamide or PAS, and a

ull blood coun should be checked monhly in paiens aking

linezolid.

Treatment outcomes in DR-TB

Globally, survival and reamen oucomes o drug-resisan

B vary widely depending on geographical locaion, regimen

choice, duraion o reamen, and background prevalence o

B and HIV (6), bu in general, correlae wih he degree o

drug resisance. he overall reamen oucomes are ar rom

saisacory: he WHO repors ha o he esimaed hal a

million MDR-B paiens sared globally on reamen in 2009,

only 48% were reaed successully (2). reamen oucomes

in XDR-B are even worse; while he overall success rae or

XDR-B in a recen mea-analysis was repored o be 44% (39),

addiional resisance o second- and hird-line B medicaions

beyond he minimum definiion o XDR-B was associaed wih

urher reducions in he likelihood o success. Te cure rae in

high-burden counries may be even lower: in Souh Arica, less

han 20% o paiens wih XDR-B culure-convered wihin six

monhs o iniiaion o reamen, and his poor oucome was

independen o HIV saus (35). Tere is hus a desperae need

or new drugs and addiional inervenions o improve hese

oucomes, paricularly in XDR-B. A number o novel drugs are

undergoing clinical esing, bu are unlikely o be available or

several years ye (52).

Adjuvant surgical management of

drug-resistant TB

Rationale and indications for surgery

hick walled caviaory lesions and areas o desroyed lungconain up o 107 o 109M.tb organisms (53), harbouring

acively replicaing bacilli even in paiens who are spuum

culure-negaive (54,55). hese uberculous lesions have

reduced exposure o hos deenses, and are peneraed

poorly by aniuberculous drugs (56). Caviies ac no only

as huge reservoirs o M.tbinecion (wih he poenial or

inrapulmonary or conralaeral spread), bu also as he likely

sie o he developmen o drug resisance (57). he raionale

behind surgery or DR-B is ha excision o hese caviies (along

wih debulking o any necroic or non-viable lung issue) w ill

dramaically reduce he overall organism burden in he lungwhile simulaneously removing he sies o high concenraions

o drug resisan bacilli. he surgical removal o caviies is

hoped o enhance he serilizing properies o pos-surgical

chemoherapy and increasing he likelihood o reamen success

(58,59). Complicaions o B including massive haemopysis,

aspergilloma, bronchiecasis, pneumohorax, bronchopleural

fisula, racheal or bronchial senosis and empyema remain valid

indicaions or surgery in boh drug-sensiive and drug-resisan

Table 3.Crieria or selecion or candidaes or surgery in DR-B.

Persistently positive smear or culture despite optimal antituberculous therapy

Extensive isolate drug resistance pattern with high probability of failure or relapse

Radiographically localized disease with high probability of near-total resection

Expectation of adequate cardiopulmonary reserve post-surgery

Presence of sufficient drug activity to facilitate healing of the bronchial stump


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B (60), bu hese opics are beyond he scope o his review.

he indicaions or surgery or DR-B have remained largely

unchanged since hey were firs described by Iseman et al.in 1990 (61),

(an adapaion o which is shown in able 3). Poenial surgical

candidaes include hose paiens wih localized disease and

adequae pulmonary reserve who have eiher: persisenly

posiive spuum smears and/or culures despie an adequae rial

o appropriae chemoherapy; or hose who have relapsed, or

are hough o be a high risk o relapse based on resuls o drug

resisance profiling or radiological findings. Te lack o effecive

serilizing chemoherapy or XDR-B means even cured

paiens remain a high risk or relapse, and may be considered

candidaes or resecion regardless o spuum culure saus. Te

prerequisie o he presence o sufficien suscepible drug aciviy

o aciliae healing o he bronchial sump is also less relevan in

he seting o XDR-B, where exended resisance paterns mean

ha surgery ofen remains he only opion or cure.

Timing of surgery

Ideally, surgery should be perormed once culure-conversion has

been achieved o minimize he risk o pos-surgical complicaions.

Perorming surgery laer in he course o reamen may also

allow or ime or nuriional supplemenaion and conrol o

coexising medical condiions. However, paricularly in he

case o XDR-B (as oulined above), his is unlikely o ever

be achieved. Delaying surger y and persising wih ine ecive

chemoherapy may only aciliae progression o disease, andurher promoe he developmen o drug resisance (62). he

iming o adjuvan surgery mus consider he likelihood o

poenial culure-conversion based on he resisance proile o

he M.tbisolae; however, a minimum o hree o six monhs o

pre-operaive chemoherapy is usually given (62-66).

An addi ional consideraion in he seing o HIV/DR-B

co-inecion is ha surgery may need o be posponed unil

immuniy has been resored wih anireroviral herapy (AR)

o he poin a which i is expeced ha major surgery can be

wihsood.

Preoperative workup, surgical approach and complications of

surgery

Te preoperaive workup is direced a assessing disease exen and

esimaing cardiopulmonary reserve (see able 4). A high-resoluion

C ches is a prerequisie o assess he presence o conralaeral

disease, and o plan he surgical approach. Spiromery is required o

esimae pulmonary reserve, while a 6-minue walk es (6MW)

is a good es o uncional capaciy. In borderline cases, quaniaive

perusion lung scanning can assis in esimaing he degree o

uncional loss ollowing surgery. Cu-o values or prediced

posoperaive lung uncion are no defined in his group o paiens,

bu can be adaped rom sudies o resecional surgery or lung cancer:

prediced pos-operaive orced expiraory volume in one second(FEV1) should likely be greaer han ~800 mL or pneumonecomy

candidaes (67). An ECG ollowed by an echocardiogram, where

indicaed, may be useul in excluding pulmonary hyperension,

whi ch wo ul d o he r wis e co n ra in di ca e su rger y. Posi r on

emission omography-compued omography (PE/C) has

been pro posed as a noninva sive imaging me hod ha may

give addiional inormaion abou uberculous disease saus,

paricularly abou he presence o conralaeral parenchymal as

well as nodal meabolic aciviy (68,69). Is role in guiding surgery

remains unclear. he preoperaive improvemen o nuriional

saus has been advocaed by many auhors (64,65,70,71) oimprove wound healing and pos-operaive recovery.

he exen o anaomical resecion (wedge resecion versus

segmenecomy, lobecomy or pneumonecomy) is deermined

by he disribuion o radiological disease, and is balanced by

he desire o remove as much pahological lung as possible

while preserv ing pos-operaive pulmonar y reserve. While he

procedures perormed in case series and cohor sudies were

predominanly lobecomies or pneumonecomies or unilaeral

Table 4. Pre-operaive workup o paiens or surgery or DR-B.

HRCT to assess for bilateral disease and to plan surgical approach (PET/CT may be a useful adjunct to confirm contralateral

metabolically active nodal or parenchymal disease in borderline cases or those with radiological changes secondary to previous TB)

Spirometry

ECG ( echocardiogram) to exclude pulmonary hypertension

Six-minute walking test (6MWT), quantitative ventilation: perfusion scanning and arterial blood gas measurement in borderline

cases

CD4 count in patients with HIV co-infection

Nutritional assessment by dietician with supplementation if required


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disease, sequenial resecion o bilaeral caviies in paiens wih

adequae pulmonary reserve has also been described (70,72,73).

he surgical approach is almos always via a muscle-sparing

poserolaeral horacoomy; he median approach has also been

sudied, bu offers limied exposure or lef-sided resecions (74).

Video-assised horacoscopic surgery (VAS) is associaed wih

less wound pain, ewer pulmonary complicaions, and a shorer

hospial say han wih a horacoomy. his echnique has

recenly been shown o be a easible opion or smaller wedge

resecions and isolaed lobecomies in careully seleced paiens

wih less exensive disease (75). Te oblieraion o he pleural

space, he presence o ineced lymph nodes in he peribronchial

area, and exensive adhesions (beween he lung, vasculaure

and he ches wall) occurring as a resul o chronic uberculous

sepsis, ypically limi horacoscopic inervenion and are a

conraindicaion o VAS (63).

Bronchial sump closure is usually by sapling, alhoughinerruped suures wih absorbable or non-absorbable suures

(eiher on heir own or as addiional reinorcemen), are also

used (59,65). Muscle-lap buressing o he bronchial sump

has been advocaed o preven he pos-operaive complicaion

o bronchopleural isula especially in paiens wih posiive

spuum a he ime o operaion (65); however, his pracice has

no been universally adoped, and a series o 106 paiens rom

Souh Arica in which bronchial sump reinorcemen was only

perormed in wo cases repored no cases o bronchopleural

fisula ormaion (64).

Wih careul paien selecion, he operaive moraliy in lungresecion is less han 5% (62-66,76). Common complicaions

range in requency beween 12% and 30%, and include bleeding,

empyema, wound complicaions and bronchopleural fisula.

Outcomes of surgical treatment

here is a dearh o good qualiy o daa supporing he

use o adjuvan surgical reamen or DR-B, and curren

recommendaions are based on exper opinion. No randomized

conrolled rials have been perormed, and i is likely ha

he available daa rom case series and cohor sudies is

biased owards surgery in paiens wih less exensive disease.Neverheless, a recen sysemaic review and mea-analysis o

24 comparison sudies o MDR- and XDR-B (involving more

han 5,000 paiens) ound a signiican associaion beween

surgical inervenion and successul oucome when compared o

non-surgical reamen alone (OR 2.24, 95% CI: 1.68-2.97) (77).

Sub-group analyses o sudies involving XDR-B paiens

revealed an even more pronounced reamen eec (OR 4.55,

95% CI: 1.32-15.7), which would suppor he widely held

view ha surger y as a herapeuic opion becomes even more

atracive as effecive chemoherapeuic opions dwindle.

Conclusions

MDR-B, XDR-B, and now resisance beyond XDR-B (DR

or XXDR-B) are growing epidemics uelled by ailing naional

B programs, HIV co-inecion, and povery, and no only have

a high moraliy bu hreaen o desabilise many naional B

programs. For example, in Souh Arica, despie drug-resisan

B orming less han 3% o he oal case load, i consumes

over 40% o he ~US$160 million naional B program budge.

here is also he growing problem o herapeuic ailures who,

because o lack o appropriae alernaive aciliies, are now being

discharged back ino he communiy (78). Alhough surgery

remains a criical par o managemen, only a small number

o paiens are amenable o surgery. In B endemic counries,where i is needed mos, qualified horacic surgeons and surgical

aciliies are lacking. Even where horacic aciliies are available,

here may be hesiaion and relucance amongs some horacic

surgeons o operae on paiens wih a deadly disease. Even wih

surgery, oucomes in B endemic counries are poor. New B

drugs are urgenly needed, however, policy makers ace an ehical

dilemma o making hese available as par o drug-sensiive

regimens, hus preserving heir medium o long erm efficacy, or

risking shorening he effecive liespan o hese drugs by using

hem irs in hose wih DR-B. Newer and less cosly poin-

o-care diagnosics or drug-resisan B are also needed, as isan eecive B vaccine. Above all, however, exising naional

B programs need o be srenghened so ha drug-resisan B

is prevened. In parallel, he exising case burden needs o be

ackled and ongoing ransmission minimised.

Acknowledgements

Disclosure: Te auhors declare no conflic o ineres.

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