Totally drug-resistant tuberculosis and adjunct therapies

doi: 10.1111/joim.12264

Totally drug-resistant tuberculosis and adjunct therapiesS. K. Parida1,*, R. Axelsson-Robertson2,3,*, M. V. Rao1, N. Singh4, I. Master4, A. Lutckii5, S. Keshavjee6,

J. Andersson7, A. Zumla8 & M. Maeurer1,3

From the 1Therapeutic Immunology Division, Department of Laboratory Medicine; 2Department of Microbiology, Tumor and Cell Biology,Karolinska Institutet; 3Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden; 4King DinuzuluHospital, Durban, South Africa; 5Research Institute of Children’s Infections, St Petersburg, Russia; 6Department of Global Health and SocialMedicine, Harvard Medical School, Boston, MA, USA; 7Department of Medicine, Karolinska Institutet, Stockholm, Sweden; and 8UniversityCollege London, London, UK

Abstract. Parida SK, Axelsson-Robertson R, Rao MV,Singh N, Master I, Lutckii A, Keshavjee S,Andersson J, Zumla A, Maeurer M (KarolinskaInstitutet; Karolinska University Hospital,Stockholm, Sweden; King Dinuzulu Hospital,Durban, South Africa; Research Institute ofChildren’s Infections, St Petersburg, Russia;Harvard Medical School, Boston, MA, USA;Karolinska Institutet, Stockholm, Sweden; andUniversity College London, London, UK). Totallydrug-resistant tuberculosis and adjunct therapies(Review). J Intern Med 2014; doi: 10.1111/joim.12264.

The first cases of totally drug-resistant (TDR)tuberculosis (TB) were reported in Italy 10 yearsago; more recently, cases have also been reportedin Iran, India and South Africa. Although there isno consensus on terminology, it is most commonlydescribed as ‘resistance to all first- and second-linedrugs used to treat TB’. Mycobacterium tuberculo-sis (M.tb) acquires drug resistance mutations in asequential fashion under suboptimal drug pres-sure due to monotherapy, inadequate dosing,treatment interruptions and drug interactions.

The treatment of TDR-TB includes antibiotics withdisputed or minimal effectiveness against M.tb,and the fatality rate is high. Comorbidities such asdiabetes and infection with human immunodefi-ciency virus further impact on TB treatmentoptions and survival rates. Several new drugcandidates with novel modes of action are underlate-stage clinical evaluation (e.g. delamanid, be-daquiline, SQ109 and sutezolid). ‘Repurposed’antibiotics have also recently been included in thetreatment of extensively drug resistant TB. How-ever, because of mutations in M.tb, drugs will notprovide a cure for TB in the long term. Adjunct TBtherapies, including therapeutic vaccines, vitaminsupplementation and/or repurposing of drugs tar-geting biologically and clinically relevant molecularpathways, may achieve better clinical outcomes incombination with standard chemotherapy. Here,we review broader perspectives of drug resistancein TB and potential adjunct treatment options.

Keywords: adjunct therapies, drug resistance, exten-sively drug resistant, genotype, multidrug resis-tant, Mycobacterium tuberculosis.

Introduction

‘Drug resistance’ is a microbiological diagnosisreflecting the resistance pattern of the clinicalisolate of a given pathogen to a defined set ofantibiotics. Streptomycin (SM), introduced in 1946for the treatment of tuberculosis (TB), and SM-resistant M.tb, was first reported in 1947 from theclinical studies with non-responsive patients tothis antibiotic [1, 2]. The recognition of this phe-nomenon, i.e. nonresponsiveness to monotherapy,led to the principle of multiagent chemotherapy forTB, which was proved to be effective in a combi-nation with SM & para-aminosalicylic acid (PAS)[3]. Isoniazid (INH), introduced in 1952, was used

alone or in combination with SM or PAS by theBritish Medical Research Council (BMRC). Thefirst national survey of drug resistance in the UK,organized by the BMRC and led by WallaceFox, identified Mycobacterium tuberculosis (M.tb)strains resistant to only one of the three availabledrugs, even prior to treatment, in patients withpulmonary TB [4, 5]. This resulted in the evalua-tion by John Crofton of a three-drug regimen withSM, PAS and INH, with the notion that two of threedrugs would be available for almost any resistantstrain [6]. Multi-drug-resistant (MDR) TB was firstreported in the 1990s with resistance to INH andrifampicin (RIF), notably with the New York epi-demic in human immunodeficiency virus (HIV)-infected individuals [7]. This led to the declarationby the World Health Organization (WHO) of a*These authors contributed equally.

ª 2014 The Association for the Publication of the Journal of Internal Medicine 1

Review

global TB emergency in 1994. Extensively, drug-resistant TB (XDR-TB) was reported in March 2006in a joint publication from the Centres for DiseaseControl and Prevention (CDC) and WHO describingstrains of M.tb resistant not only to INH and RIF(i.e. MDR-TB), but also to at least three of the sixclasses of second-line anti-TB drugs (aminoglyco-sides, polypeptides, fluoroquinolones, thioamides,cycloserine and PAS) [8, 9]. The determination ofdrug resistance is dependent on difficult-to-per-form drug-susceptibility testing (DST), and someforms of drug resistance are more challenging fordiagnosis treatment. Therefore, the definition ofXDR-TB was eventually modified at a meeting ofthe WHO XDR-TB Task Force in October 2006 inGeneva, Switzerland, and is now defined as ‘resis-tance to at least rifampicin and isoniazid (i.e. thedefinition of MDR-TB), in addition to any fluoroqu-inolone, and to at least one of the three followinginjectable drugs used in anti-TB treatment: cap-reomycin, kanamycin and amikacin’ [10]. Up tothe end of 2012, XDR-TB had been reported in92 countries (Fig. 1) with an estimated 45 000new cases per year, that is, 9.6% of all reportedcases of MDR-TB [11]. Overall, more than 10cases of XDR-TB were reported in 13/92countries in the most recent year for which data

are available. The proportion of MDR-TB casesthat were classified as XDR-TB was highest inAzerbaijan (Baku: 12.8%), Belarus (11.9%), Latvia(16%), Lithuania (24.8%) and Tajikistan (Dush-anbe and Rudaki district: 21%). The proportion ofMDR-TB cases resistant to fluoroquinolones andsecond-line injectable agents was 16.5% and22.7%, respectively. A total of 32% of patientswith MDR-TB exhibited resistance to a fluoroqu-inolone, to a second-line injectable agent, or toboth. Treatment success with second-line therapyis only achieved in 12–28% of XDR-TB cases, asreported in the latest WHO Global TB Report,with mortality as high as 44–49%. Globally,only 1557 patients with XDR-TB received ade-quate second-line therapy in 2012. Thus, urgentaction is required to close the XDR-TB treatmentaccess gap, and to consider new treatmentoptions.

The prevalence of MDR-TB in a country correlateswith the duration of availability of second-linetreatment. In countries in which second-line TBtreatment has been available for more than20 years, higher rates of resistance have beenobserved compared with those with a shorterperiod of treatment availability [12].

Fig. 1 Global map of drug-resistant tuberculosis (TB). Countries with at least one reported case of extensively drug-resistant TB are shown in pink; four countries with reported cases of totally drug-resistant TB (Italy, Iran, India and SouthAfrica) are also shown (in dark pink). Adapted from [11].

S. K. Parida et al. Review: Totally drug-resistant tuberculosis

2 ª 2014 The Association for the Publication of the Journal of Internal Medicine

Journal of Internal Medicine

Totally drug-resistant tuberculosis

Totally drug-resistant tuberculosis (TDR-TB) refersto M.tb clinical strains that show in vitro resistanceto all first- and second-line drugs tested (INH, RIF,SM, ethambutol, pyrazinamide, ethionamide, PAS,cycloserine, ofloxacin, amikacin, ciprofloxacin,capreomycin and kanamycin). The presence ofTDR-TB was first observed in two patients in Italyin 2003 and subsequently reported by Miglioriet al. in 2007 [13]. These M.tb strains were alsoresistant to rifabutin, clofazimine, dapsone, clari-thromycin and thiacetazone. The authors sug-gested the new term ‘XXDR-TB’ to define this(TDR-TB) strain. The second report of TDR-TBcame from Iran: 10.3% of clinicalM.tb isolates from146 patients with MDR-TB were in fact found to beTDR-TB [14]. According to the WHO TB Report2013 quoting results from 2010, treatment successrate was 48% for MDR-TB and 22–28% for XDR-TB, with a mortality rate of 44–49% in patients withXDR-TB [11].

In January 2012, there was a report of four cases ofTDR-TB in India (one of the countries with thehighest burden of drug-resistant TB) with resis-tance against INH, RIF, SM, ethambutol, pyrazina-mide, ethionamide, PAS, ofloxacin, amikacin,ciprofloxacin, capreomycin and kanamycin (cyclo-serine was not tested). The situation caused wide-spread media attention leading to a consultativeexpert group meeting at WHO [15]. The WHOconsultative meeting on TDR-TB did not officiallyendorse the ‘TDR-TB’ terminology, which stillremains to be fully defined (e.g. resistance to theentire spectrum of anti-TB drugs, including drugsthat may be under development). Recently, threenew drugs, bedaquiline, delamanid and linezolidhave been approved by the US Food and DrugAdministration (FDA) and the European MedicinesAgency that may offer therapeutic solutions forTDR-TB. With more new anti-TB agents in thepipeline, there is hope of identifying drugs thatmay be bactericidal or bacteriostatic in TB treat-ment and thereby challenging the TDR-TBterminology.

Three of the four patients from India with TDR-TBdied as a result of their disease, despite treatmentwith double-dose INH, linezolid, clofazimine, thio-ridazine, meropenem and clavulanate. In a recentupdate on TDR-TB, 15 cases with resistance to alldrugs tested (as above) have been reported, andfive patients died due to their disease; salvage

regimens included surgical resection of pulmonarylesions [16].

Using transmission and atomic force microscopy,morphological variation in TDR-TB M.tb isolateswas identified, with round, oval and multiplebranching bacillary forms with thicker cell wallsand various types of symmetrical/asymmetricalbudding formations during the exponential growthphase [17–19]. However, the impact of structuraldifferences in M.tb on transmissibility and/or thequality and strength of immune responses remainsunclear.

Overall, 92% of 236 MDR M.tb strains collected inSouth Africa (Stellenbosch University) belonged toan atypical Beijing genotype resistant to 10 anti-TBdrugs (four first line: INH, RIF, pyrazinamide,ethambutol and six second line: SM, amikacin,kanamycin, capreomycin, ethionamide and oflox-acin). Some of these M.tb strains were also resis-tant to PAS, indicating emergence of TDR-TB inSouth Africa [20]. In total, TDR-TB has only beenreported from four countries (Fig. 1). This mayunder-represent the real extent of drug resistancein M.tb isolates because of many factors, and inparticular, constrained laboratory access inresource-limited settings with a high prevalenceof TB.

Clinical Mycobacterium tuberculosis spread and diagnosis

To date, more than 30 cases of TDR-TB havebeen reported; a majority of these cases suc-cumbed to the disease. This is likely to be a verysmall number of the total cases, as drug-resistantTB may be undetected due to the lack of diag-nostic capacity. Ninety-two countries reportedcases of XDR-TB. However, in Africa (the conti-nent with the highest TB rates per capita andincluding the country – South Africa – with themost reported cases of XDR-TB), only 17 out of54 countries reported cases of XDR-TB [11]. Itwas reported that two of the 27 countriesworldwide with the highest burden of MDR-TBroutinely tested for second-line drug resistance[21]. Lack of capacity and inconsistent methodsfor drug resistance testing remain some of thebiggest challenges to understanding the preva-lence of TDR-TB.

Lack of sufficient capability and capacity to testfor drug resistance in M.tb isolates are not theonly challenges in diagnostics; the lack of ability




to test new therapeutic options is also a concern.It is possible that antibiotic combination therapymay be effective in vivo even though there isresistance to individual drugs in vitro. Clinicalresponse to antibiotic combinations may also beinfluenced by inter-individual differences in phar-macodynamics as well as by the genetic make-upof the individual patient. Therapeutic drug mon-itoring has been proposed to evaluate desireddrug concentrations and the dynamics of resis-tance patterns in patients with XDR-TB or TDR-TB [22].

Standard methods for DST employ M.tb culture onsolid media (8–12 weeks) and in liquid media (2–4 weeks), both of which take a long time beforeresults are obtained during which inappropriatedrugs might be administered with increased resis-tance profiles as a result. Faster liquid mediasystems including the Mycobacteria Growth Indi-cator Tube (MGIT) system provide faster results,yet costs and infrastructure requirements limittheir clinical use in many parts of the world.Genotype-based tools provide the fastest way todiagnose resistance mutations in M.tb, yet geneticanalysis requires further characterization of M.tbwith DST (phenotypical). The Xpert MTB/RIF isapproved by the WHO to provide a relatively fastdiagnosis of TB as well as a test of RIF resistance[23]. Genotype MTBDRplus is a second-generationline-probe assay (LPA) for rapid diagnosis ofresistance to RIF and INH in culture medium[24]. Genotype MTBDRsl is the advanced versionof LPA to detect XDR-TB (resistance to fluoroqu-inolones, aminoglycosides/cyclic peptides andethambutol) in already characterized MDR M.tbisolates [25].

Other methods include, for example, use of TKmedium [26], the microscopic observation drug-susceptibility assay (MODS) [27] and the FASTPl-aque-Response bacteriophage assay [28]; molecu-lar methods are based either on nucleic acidamplification combined with electrophoresis,hybridization and sequencing, direct sequencing,reverse hybridization [29] or a TB Biochip platform[30].

Causes of TB resistance

Factors affecting the mutation rate of bacteria canbe divided into two groups: (i) cellular mecha-nisms, such as lack of mismatch repair, micro-satellites, existence of drug resistance-conferring

mutations, mistranslations and error-prone DNApolymerases and (ii) external factors, such asantibiotics, anti-retroviral drugs, host environ-ment and smoking (reviewed in detail in [31]).There are two types of drug resistances: primary(transmitted) and acquired. The development ofacquired MDR-/XDR-/TDR-TB is a multifactorialprocess. Treatment of TB disease depends on thehealth care system (e.g. DST, antibiotic medi-cines, control programmes, access to medicalfacilities and quality of drugs), the treating doctor(e.g. type of drug, dose of drug, drug interactionsand duration of treatment) and the patient (e.g.adherence to therapy, individual pharmacokinet-ics [32] and co-infections). Also the use of anti-TBdrugs to treat other bacterial infections inpatients who are positive for M.tb might contrib-ute to the emerging resistance [33]. Primary drug-resistant TB occurs due to direct transmission ofthe drug-resistant strains of M.tb resulting inprimary TB disease. This has been well estab-lished through molecular epidemiology and con-tact tracing, confirming transmission of M.tbstrains.

It seems that most patients who acquire XDR-/TDR-TB have been previously treated with anti-TB drug. Despite successful completion of theprevious treatment, a small fraction of the bacillimight survive as ‘persisters’ and acquire drugresistance following withdrawal of the drug-induced pressure, before ‘growing out’ and caus-ing more resistant forms of the disease. This oftenoccurs in a sequential way in which increasinglymore resistance is acquired over time whentreatment with second-line drugs is initiated.Indeed, previous treatment with second-lineanti-TB agents, if not properly managed, is oneof the strongest risk factors for acquiring XDR-TB[12].

Examples of acquired antibiotic resistance mech-anisms include passive resistance, modification ofdrug targets, chemical drugs modification, enzy-matic drug degradation, molecular mimicry of drugtargets, drug deportation by efflux pumps andepigenetic drug tolerance [34]. Acquired antibioticresistance mechanisms often result in reduction infitness of the resistant M.tb mutants, which in turndetermine the stability and further propagation ofthe resistance phenotype. However, there can becompensatory mutations that restore the fitness ofthe resistant strains, stabilizing the emergingresistance phenotype and thereafter enhanc-




ing transmission amongst common populations[35, 36].

The microenvironment at the site of TB disease isinfluenced by many factors, such as the immuneresponse profile, severity of inflammation andcellular necrosis, and oxygen availability. Thesefactors play a crucial role in M.tb mutation ratesand selection of resistant M.tb strains. Jenkinset al. showed an increased M.tb mutation rate atlow pH as a result of M.tb adaptation to stresscausing upregulation of error-prone polymerases[37]. M.tb isolates from the cavity wall, pericavitytissue or apparently healthy tissue demonstrateddifferent transcriptional profiles. Other environ-ment-related, non-genetic mechanism of drugresistance are transcriptional changes, such astranscriptional activity of drug efflux pumps inM.tb (reviewed in [38]).

Mycobacterium tuberculosis genotype and drug resistance

Virulence, immunogenicity and drug resistance allvary between different M.tb strains. Bacterial chro-mosomal mutations result in drug resistanceagainst anti-TB drugs. These mutations are rareand random events. The average M.tb mutationrates for INH, SM, ethambutol and RIF are2.56 9 10�8, 2.95 9 10�8, 1.0 9 10�7 and2.25 9 10�10 mutations per bacterium per gener-ation, respectively [39]. The highest proportion ofmutants that can be expected in an unselectedbacterial population was found to be 3.5 9 10�6

for INH and 3.1 9 10�8 for RIF. A double-resistantM.tb mutant is therefore estimated in a populationof 1015 bacilli. A recent mathematical modeladdressed the issue of spontaneous emergence ofMDR-TB taking into account the dynamic interplaybetween innate and acquired immune responses ofthe host leading to death of certain M.tb popula-tions. The probability of the development of drugresistance during clonal expansion of an initiallysensitive TB infection is the orders of magnitudehigher than previously estimated [35]; the proba-bility of MDR, at the time of diagnosis, may be1000–10 000 times higher than previously consid-ered. Caution may be required as dual-resistantM.tb strains are expected in a small minority ofpatients even prior to treatment; standard drugregimens administered properly are likely to resultin the selection of the preexisting dual resistance.M.tb mutations and TB drug resistance data can beretrieved from the TB drug resistance mutationdatabase (http://www.tbdreamdb.com/) [40].

Whole-genome sequencing to define the genetic determinants ofdrug resistance

There have been a number of internationalattempts across many institutions in differentgeographical regions to identify the entire reper-toire of naturally-occurring mutations in M.tbresponsible for drug-resistant TB to create acatalogue of resistance-conferring mutations bysequencing large numbers of geographically andphenotypically diverse M.tb strains. These M.tbstrains have been characterized according to theirresistance to a broad spectrum of first- andsecond-line antibiotics. The aim of these effortshas been to: (i) guide development of rapidtests for accurate diagnosis of drug resistancein TB, (ii) guide TB treatment and (iii) discovernew targets for developing improved anti-TBtherapeutics.

Leading institutions involved in this endeavourinclude the Broad Institute (http://www.broadinstitute.org/annotation/genome/mycobacterium_tuberculosis_diversity/MultiHome.html, http://www.broadinstitute.org/science/projects/gscid/genomic-sequencing-center-infectious-diseases); the SangerCentre, UK (http://www.sanger.ac.uk/resources/downloads/bacteria/mycobacterium.html); theSwissTropical and Public Health Institute (http://www.swisstph.ch/about-us/departments/medical-parasitology-infection-biology/tuberculosis-research.html);the University of California, San Francisco [41]; theGerman Research Centre, the Leibniz Centre ofMedicine and the Biomedical Research, Borstel,Germany [42, 43] and the Institute of Biophysics,the Chinese Academy of Sciences, Beijing, China[44]. This list is not comprehensive, but reflects theinternational effort to better map and understandM.tb diversity.

Whole-genome sequencing (GWS) approach forrapid high-resolution M.tb genotyping is an attrac-tive emerging tool for the determination of thebroad range of genes involved in the generation ofXDR-/TDR-TB. A recent study using a GWSapproach confirmed all 11 drug resistance markersknown to date. In addition, 39 new genes associ-ated with resistance were described. It is interest-ing to note that most of the newly reportedmutations were found to be associated with M.tbcell wall permeability. This information is vitalbecause drug-resistant M.tb strains may containmutations not only in genes coding for keyenzymes, but also in those coding for cell wall




remodelling [45]. M.tb genes and related enzymestargeted by drugs and/or associated with drugresistance are listed in the Table 1 [128].

Clinical in vitro nonresponsiveness

Phenotype and drug resistance

In the clinical practice of drug-resistant TB man-agement, patients often demonstrate early cultureconversion to negativity during the first 3 monthsafter initiation of second-line therapy with rever-sion to culture positivity several months later. Also,in many instances, patients may not exhibit clin-ical improvement, despite appropriate second-linetherapy in conjunction with the in vitro DSTresults. The issues of re-infection or ‘super-infec-tion’ acquired in most cases in the hospital setting

and of diseases with multiple drug-resistant M.tbstrains versus microbiological testing complicatethe clinical reality of patient management.

Phenotype versus genotype

Phenotypic analysis of DST is essential to corrob-orate the genotypic detection of drug-resistant TBto determine the optimal therapeutic regimen foreach patient. This can be performed either byautomated liquid culture (MGIT system) or by solidculture methods. Other cost-effective optionsinclude MODS, slide DST, phage-based assays,colorimetric methods with MTT (3-(4,5-dim-ethylthiazol-2-yl)-2,5-diphenyltetrazolium Bro-mide) and resazurin as redox indicators and thenitrate reductase assay. It is also essential to

Table 1 Mutations associated with antibiotic resistance in Mycobacterium tuberculosis

Antibiotics Genes involved in drug resistance (and their proteins)

Amikacin, capreomycin, kanamycin,

streptomycin and viomycin

rpsL (Rv0682), tap (Rv1258c), rrs (MTB000019), rrl (MTB000020),

tlyA (Rv1694), eis (Rv2416c), whiB7 (Rv3197A) and gid (Rv3919c)

SQ109 mmpL3 (Rv0206c)

AZD5847, Linezolid and sutezolid rplC (Rv0701) and rrl (MTB000020)

Bedaquiline atpE (Rv1305)

Clarithromycin ermMT (Rv1988) and whiB7 (Rv3197A)

Clofazimine and thioridazine ndh (Rv1854c)

Cycloserine cycA (Rv1704c), ddlA (Rv2981c) and alr (Rv3423c)

Delamanid and PA-824 fgd1 (Rv0407), fbiC (Rv1173), fbiA (Rv3261), fbiB (Rv3262) and ddn

(Rv3547)

Ethambutol embR (Rv1267c), embC (Rv3793), embA (Rv3794) and embB

(Rv3795)

Gatifloxacin, levofloxacin, moxifloxacin and

ofloxacin

gyrB (Rv0005) and gyrA (Rv0006)

Imipenem, meropenem and co-amoxiclav pbpA (Rv0016c), blaC (Rv2068c), ldtA (Rv0116c), ldtB (Rv2518c) and

dacB2 (Rv2911)

Isoniazid, prothionamide and thiacetazone mshA (Rv0486), hadA (Rv0635), hadB (Rv0636), hadC (Rv0637),

mmaA4 (Rv0642c), mmaA3 (Rv0643c), mmaA2 (Rv0644c), mshB

(Rv1170), sigI (Rv1189), fabG1 (Rv1483), inhA (Rv1484), ndh

(Rv1854c), katG (Rv1908c), furA (Rv1909c), mshC (Rv2130), ahpC

(Rv2428), nudC (Rv3199c), nat (Rv3566c), ethA (Rv3854c) and ethR

(Rv3855)

Para-aminosalicylic acidand co-trimoxazole folC (Rv2447c), ribD (Rv2671), dfrA (Rv2763c), thyA (Rv2764c) and

folP1 (Rv3608c)

Pyrazinamide rpsA (Rv1630), pncA (Rv2043c) and panD (Rv3601c)

Rifampicin, rifapentine and rifabutin rpoB (Rv0667), rpoC (Rv0668) and rpoA (Rv3457c)

Adapted from K€oser et al. (Ref. 128) Whole-genome sequencing for rapid susceptibility testing of M. tuberculosis.




corroborate genotypic diagnosis with phenotypiccharacterization to follow up patients on therapy.In recent years, there have been several reports ofdeterioration of patients despite specific therapyfollowing DST, suggesting a drift in the drugresistance patterns with modification of phenotypiccharacteristics in terms of susceptibility and resis-tance [46]. Hence, a proportional concentrationmethod with multiple antibiotic concentrations isrecommended rather than using a single criticalconcentration. This is particularly important forpatients who deteriorate following therapy.

In a recent review, it was elegantly emphasized thatthe term ‘resistance’ with regard to M.tb is by nomeans a simple homogeneous category; insteadit represents several heterogeneous factorsfrequently composed of low-, moderate- andhigh-level drug resistance [47]. Low-level drugresistance may not necessarily correspond to clin-ical drug resistance; conversely, in the presence ofa high-level resistance phenotype, the drug may beof little, if any, clinical benefit. The clinical impli-cations of moderate levels of resistance are lessclear, and need to be addressed in prospectivestudies with standardized protocols for quantita-tive DST of both first- and second-line therapy forassessing the impact of resistance heterogeneity ontreatment results.

Host versus drug-resistant Mycobacterium tuberculosis

The biology and epidemiology of human TBdepends on a delicate balance between host (e.g.genetic variants of factors in the immune system)and pathogen-derived factors (e.g. virulence factorsand escape mutations) as well as co-infections (e.g.HIV, malaria and helminth infections), comorbid-ities (e.g. malnutrition and stress) and other asso-ciated host factors such as poverty. Different M.tbstrains display a geographically structured trans-mission pattern, suggesting adaptation betweendifferent human populations and M.tb strains [36,48]. Individuals infected with more ‘modern’ M.tblineages are more prone to develop active TB. Thisis also associated with decreased early inflamma-tory responses as compared with individualsinfected with more ‘ancient’ M.tb lineages [49].The more ancient M.tb lineages have probably beencirculating in the human population for a longertime and immune responses might have adapted tothese pathogenic variants. This ‘co-evolution’ of thepathogen–host relationship needs to be furtherexamined. The effect of chemotherapy in the

context of adaption to M.tb strains remains to beinvestigated, yet some strains have shown a ten-dency towards developing drug resistance muta-tions such as the Beijing W genotype [50]. Althoughgenetic differences, including insertions, deletionsand point-mutations, between different M.tbstrains are believed to be low [51], they may resultin phenotypic changes affecting the virulence andinfectiousness of the strains [52]. Most of thegenetic variation resides in nonessential genesand in parts of the M.tb genome that are notbelieved to be presented to the human immunesystem [53]. This has led to the hypothesis thatimmune recognition may be beneficial for thepathogen and not for the host; however, this notionrequires further testing.

A high degree of phenotypic variation between M.tbclinical isolates has been found to affect both thespread of the specific strain and the clinicaloutcome of infection. M.tb strains derived fromthe East-Asian lineage are able to acquire resis-tance more rapidly as compared with the Euro-American lineage. However, in the East-Asianlineage, Ford et al. found no association betweenthe increased ability to generate drug resistanceand the enhanced ability to survive and mutate inthe presence of drug(s), and no evidence of a‘fitness cost’ of such mutations [54]. Notably, in aprevious study [using the genome-wide associationstudy (GWAS) approach], the same authors foundthat M.tb could acquire mutations even in thelatent state [55].

The M.tb Beijing genotype is associated with‘hypervirulence’ as well as with an MDR phenotype[50]. A different, commonly circulating M.tb geno-type, Haarlem, has been shown to be over-repre-sented in patients with drug-resistant TB [56]. Thefact that certain strains are more prone to acquiringdrug resistance is of course of particular interest inthe context of TDR-TB: 10 out of 16 patients withTDR-TB (in Iran) were infected with either Haarlemor Beijing superfamily of strains [14]. The Beijinggenotype seems to be able to retain fitness despitethe acquisition of drug resistance [57]; this is a verydangerous quality in the context of the drug-resis-tant TB epidemic. Another phenotypic differencebetween certain susceptible and MDR-TB strains isthe capacity to stimulate immune cells to produceIL-17. This is thought to be due to differences in thebacterial cell wall of the strain, affecting theirrecognition by pattern recognition receptors of theinnate immune system [58].




In the context of mutations in the TDR-TB genome,the problem is not exclusively the mutations thatinduce resistance, but also those acquired by astrain that is situated in a part of the TB genomepresented to the immune system. Mutations maycause immune escape mechanisms, and suchmutations in T cell epitopes might affect theefficacy of therapeutic TB vaccines (Fig. 2).

TDR-TB, co-infection and comorbidity

Many factors have been associated with increasedrisk of acquiring active TB or worsening theoutcome of TB infection, including HIV infection[59], diabetes mellitus [60, 61], renal disease [62],solid organ transplantation [63], tumour necrosis

factor alpha (TNFalpha) antagonist treatment[64], cancer [65], alcohol abuse [66] and tobaccouse [67]. Only a few of these factors, for example,diabetes mellitus [68], have also been associatedwith higher risk of developing MDR-TB whereasothers, such as HIV infection and alcohol abuse[69], have been associated with a worse outcomeof MDR- or XDR-TB. Despite diabetes mellitusbeing a risk factor for developing MDR-TB, TBdisease outcome does not seem to be worseamongst diabetic patients [70]. However, theopposite appears to be true for HIV infection. Todate, it has not been conclusively proven thatHIV infection leads to a higher probability ofdeveloping MDR-TB disease [71] (only anincreased risk of acquired RIF resistance), but

Fig. 2 Factors that affect totally drug-resistant tuberculosis (TDR-TB). Interaction and adaptation between the host and themycobacterium are well documented. The host immune system drives Mycobacterium tuberculosis (M.tb) towards geneticand phenotypic changes, often increasing virulence. Factors (inflammation, necrosis and oxygen availability) within themicroenvironment (e.g. the lung) affect the mutation rate of M.tb as well as the transcriptional profile and thereby genotypeand phenotype. The bacterial phenotype might influence the host response by exhausting immune responses andintroducing anergy in immune cells targeting the pathogen. Bacterial escape mutations might also disarm the immuneresponse. External factors, such as anti-TB drugs, might influence both the genotype and phenotype by introducing drugresistance mutations in the bacterial genome which will give rise to a multidrug-resistant phenotype. The host environmentaffects the absorption and pharmacokinetics of the drugs; other medications might also influence the effect of anti-TB drugs.Drug resistance mutations might also arise in M.tb epitopes leading to immune escape mutations. Other ways of targetingthe TDR bacteria might be through the use of therapeutic vaccines with the aim of an improved and more focused immuneresponse through change from a nonproductive Th2 to a Th1 response; this may also involve the reduction in nonproductiveinflammation in TB. MSC, mesenchymal stromal cells; VitD, vitamin D.




HIV has been associated with numerous out-breaks of MDR-TB. Co-infection with MDR- orXDR-TB is life-threatening to individuals infectedwith HIV [9, 72]. In a study conducted in SouthAfrica, the mortality rate was as high as 98% inpatients co-infected with XDR-TB and HIV [9],and a mortality rate of 80% in co-infected indi-viduals in New York (compared with 47% inindividuals only infected with MDR-TB) was alsoreported [7]. Another complication of HIV–TB co-infection is that HIV is associated with gastroin-testinal malabsorption of anti-TB drugs whichmight lead to acquired resistance [73]. Further-more, interactions between anti-retroviral andanti-TB drugs lead to limited treatment optionsand thereby complicate the treatment of drug-resistant TB further in co-infected patients.

Because only a limited number of cases of TDR-TBhave been reported, it is currently too early todetermine the influence of comorbidities. The Ira-nian TDR-TB patients were all HIV negative [14],and information regarding comorbidities was lack-ing for the Italian and Indian TDR-TB cases [15,16]. Clinical information was not available in theSouth African study, thus the HIV status of thesepatients was uncertain; however, as the generalHIV prevalence in South Africa amongst TBpatients is high, it is likely that at least some wereinfected with HIV.

Novel anti-TB drugs

The desired attributes of a novel anti-TB drug are:(i) a new mode of action; (ii) good tolerability; (iii)good pharmacokinetic profile and bioavailability;and (iv) no interactions with other TB or HIVdrugs. By implication, a drug with these attributescould be used against MDR-/XDR-/TDR-TB inadults (as well as in children) together with anti-viral therapy against HIV. There are different typesof novel anti-TB drugs undergoing clinical trials,both ‘repurposed’ drugs and novel chemical com-pounds that belong to already existing drug clas-ses or classes with a completely new mode ofaction.

Delamanid (OPC-67683) and PA-824 are com-pounds that belong to the nitroimidazole antibi-otics, which have been used since the 1950s totreat anaerobic bacterial and parasitic infections[74]. Delamanid and PA-824 are pro-drugs andare activated by M.tb enzymes. The effect of thesedrugs is thought to be different under aerobic

and anaerobic conditions. Under anaerobic con-ditions, the drugs generate nitric oxide (NO)leading to NO poisoning of the cytochrome Coxidase [75]. Under aerobic conditions, they blockthe synthesis of mycolic acid, leading to destabi-lization of the mycobacterial cell wall [76]. Bothdelamanid and PA-824 are active against repli-cating and nonreplicating bacteria and are cur-rently in late-stage clinical trials for the treatmentof MDR-TB. In a recent study published by Gleret al. in the New England Journal of Medicine, itwas shown that delamanid could increase spu-tum conversion in MDR-TB patients [77]. Anothernext generation nitroimidazole with more potentanti-mycobacterial properties is TBA-354. Thiscompound is currently undergoing preclinicaltoxicity testing.

Bedaquiline (TMC207), which belongs to the di-arylquinoline antibiotics, blocks ATP synthaseleading to lower intracellular ATP levels [78]. Thisdrug candidate exhibits a long half-life and ispotent against both replicating and dormant M.tb[79]. It has been tested in Phase II clinical trials incombination with standard treatment for MDR-TB,and demonstrated shorter culture conversion timeand an increased proportion of patients achievingculture conversion [80]. It has received fast-trackapproval from the FDA for use in patientswith MDR- and XDR-TB [81], however, it carriesa warning due to an association with fatalarrhythmia.

The ethylenediamine SQ109 was originally synthe-sized as an analogue of ethambutol but withcompletely different mode of action; it is thereforeactive against many ethambutol-resistant strains[82]. SQ109 inhibits mycobacterial growth byinhibiting the assembly of mycolic acid into themycobacterial cell wall [83]. It has the same highminimum inhibitory concentration for both drug-susceptible and drug-resistant M.tb and no antag-onistic drug interactions with first- and second-linedrugs have been detected [84]. On the other hand,it has been shown that SQ109 has synergisticeffects with bedaquiline because it weakens the cellwall of the mycobacterium, thereby allowing forbedaquiline to reach its target ATP synthase moreeasily [85]. In addition, synergistic effects of SQ109with INH and RIF have been reported [86]. Anotherinteresting characteristic of this drug is its very lowmutation rate (2.55 9 10�11 mutations per bacter-ium per generation), which gives it a desirableprofile for inclusion in treatment of patients with




relapsing/recurrent TB. SQ109 is currently inPhase II clinical trials for drug-sensitive TB [84].

A new class of antibiotics that was recently discov-ered is the oxazolidinones [e.g. linezolid, sutezolid(PNU-100480) and AZD5847]; the novel mecha-nism of action of this group is inhibition of proteinsynthesis by blocking parts of the ribosome [87].No cross-reactivity with other anti-TB drugs hasbeen reported. Linezolid was first used for treatingantibiotic-resistant Gram-positive bacteria due toits broad spectrum of activity, but it has recentlybeen evaluated for the treatment of MDR- andXDR-TB [88, 89]. The disadvantage of linezolid isits side effects, including neuropathy and myelo-suppression [88]. Sutezolid is an analogue oflinezolid with a superior ability to kill M.tb alongwith improved safety profile [90]. It is a novelcompound currently in Phase II clinical trials inpatients with MDR-/XDR-TB, and has demon-strated a lower minimum inhibitory concentrationthan linezolid towards clinical isolates of MDR-TB[91]. Furthermore, AZD5847 has been shown tohave superior efficacy and an improved safetyprofile [92] and is currently in Phase II clinicaltrials (Table 2).

Other medicines that have been repurposed asanti-TB drugs in the context of MDR-TB includethe recently developed fluoroquinolones moxiflox-acin and gatifloxacin, as well as the anti-leprosydrug clofazimine [93].

Traditionally, drug development progressesthrough target-based approaches, which unfortu-nately have not yielded many viable end products

in the case of anti-TB drugs. Hence, recentapproaches using phenotypic anti-bacterialwhole-cell assays have helped to drive the newercompounds (such as SQ109, PA-824 and bedaq-uiline) in the current drug development pipeline.

Multidrug regimens are essential for avoidingresistance. Each drug in a regimen can have asynergistic or antagonistic effect on the bioavail-ability of the others. This makes it difficult toextrapolate efficacy and safety data between differ-ent regimens and call for extended testing ofdifferent regimens and different dosing prolongingthe need for extensive and complicated clinicaltrials. New drugs such as sutezolid, delamanid,bedaquiline, PA-824 and linezolid may providehope for effective treatment of patients with TDR-TB. Susceptibility to these drugs in the so-calledTDR-TB strains needs to be determined. Noveldrugs can be used together with already estab-lished regimens or as a completely new treatment.Therefore, SQ109 and sutezolid combined [94] orindividually sutezolid, bedaquiline, PA-824, SQ109and pyrazinamide [95] hold promise as potentialtreatment options for XDR-TB.

The discovery of a new ATPase-inhibiting anti-TBdrug candidate, Q203, which acts on the QcrBsubunit of the M.tb cytochrome bc1 complex, hasrecently been reported [96]. Q203 demonstrateshigh potency in vitro and in vivo against intracel-lular drug-susceptible M.tb (H37Rv) as well asMDR-TB and XDR-TB clinical isolates. Addition-ally, Q203 has an impressive safety profile; itenhances bactericidal effects [~3.5-log reductionsin lung colony forming units (CFU)] with minimal

Table 2 Novel drugs for the treatment of tuberculosis

Novel drugs Clinical phase Drug class Mode of action

Delamanid III Nitroimidazole Generate NO, block synthesis of mycolic acid,

destabilize cell membrane

PA-824 II Nitroimidazole Generate NO, block synthesis of mycolic acid,

destabilize cell membrane

Bedaquiline II Diarylquinolines Inhibit ATP synthase, decreasing intracellular ATP level

Linezolid II Oxazolidinones Block the 23S rRNA, inhibiting protein synthesis

Sutezolid II Oxazolidinones Block the 23S rRNA, inhibiting protein synthesis

AZD5847 II Oxazolidinones Block the 23S rRNA, inhibiting protein synthesis

SQ109 II 1,2-diamine Inhibit the mycolic assay transporter MmpL3,

inhibiting assembly of the cell wall




pathology (dampened alveolar inflammation) in amouse model of TB. Q203 is currently underpreclinical evaluation. Because new anti-TB drugswill be used as part of combinatorial therapy, theissue of drug–drug interactions has beenaddressed by assessing the possible inhibition byQ203 of the human pregnane X receptor, cyto-chrome P450 and the P-glycoprotein efflux trans-porter. No drug–drug interactions have been found,which, in addition to the absence of cardiotoxicityand the high pulmonary bioavailability, add to thefavourable profile of Q203.

Adjunct treatments

Therapeutic vaccines

The development of novel anti-TB drugs, drugregimens and other adjunct therapies will tempo-rally help in the fight against the totally resistantstrains of M.tb, but even if the new treatmentoptions are carefully implemented, sooner or laterM.tb will once again acquire resistance. Therefore,the only long-lasting solution to fight drug-resis-tant TB may be to develop improved vaccinesagainst the disease. Vaccines could be eitherprophylactic or therapeutic; the development ofpostexposure vaccines or cell-based immunother-apies might complement the currently used che-motherapy, including new anti-TB drugs. Thepurpose of adjunct immunotherapies is to engagethe immune system of the infected individual toprovide help in controlling the disease, either bydirecting the immune system to a productiveimmune protective response or by targeting per-sistent bacteria, that current chemotherapies arenot able to eradicate. This might lead to shortenedregimens of drug treatment, better compliancerates, higher cure rates, significant cost-savingsand, hopefully, lower transmission rates. Theseissues, especially increased compliance, are par-ticularly important in preventing the occurrence ofrelapses as well as MDR-, XDR- and TDR-TB.Adjunct immunotherapy might also provide a newoption for patients with, otherwise, limited treat-ment choices, such as those with extensive pulmo-nary damage. Even if adjunct therapies lead to onlya transient effect, they could still be of value byslowing down TB disease to provide time for DSTand alternative therapeutic interventions.

Several therapeutic TB vaccine candidates arecurrently under development. Unfortunately, noneis directed specifically at, or being tested in thecontext of, MDR-/XDR-/TDR-TB. TB vaccines that

have reached clinical trials comprise either inacti-vated forms of M.tb, that is, RUTI [97] or mycobac-teria other than TB, such asMycobacterium indicuspranii [98] orMycobacteria vaccae [99]. The vaccinebased on M. vaccae consists of heat-killed bacteriaand has been shown to promote an immune Th1response [100], whereas the RUTI vaccine consistsof detoxified fragments of antigens associated withM.tb latency. Immune responses elicited by RUTImight therefore target persistent mycobacteria. Ithas been proposed that combining these twotherapeutic vaccines may be effective due to theirdifferent modes of action [101]. ID93/GLA-SE andH56 are two other therapeutic vaccine candidates(both contain four M.tb antigens associated withvirulence or latency) in preclinical testing, which atleast in animal models resulted in an improvementin survival and reduced pathology and bacterialload in the lungs [102, 103]. In future, it might alsobe interesting to investigate the potential use ofother vaccine candidates that are currently under-going trials (e.g. VPM1002 [104] and HBHA), in thecontext of alternative use as therapeutic vaccinesfor treating drug-resistant forms of M.tb.

Cell-based immunotherapies

Cell-based immunotherapies might also be inter-esting as adjunct therapies in the context of TDRforms of M.tb. Following suggestions that they mayprovide an attractive immunotherapeutic optionfor immunocompromised individuals with MDR-TB [105], dendritic cell-based vaccines (either genemodified or subunit) are being tested at present ina mouse model. In addition, macrophages infectedwith M.tb have been tested in a mouse model of TB[106]. In a recent study using autologous mesen-chymal stromal cells in patients (n = 30) withMDR-/XDR-TB, with the aim of reducing nonpro-ductive pulmonary inflammation, restoring M.tb-directed cellular immune responses and restoringpulmonary function by tissue repair/regeneration,it was found that this treatment was safe and welltolerated [107]. Similar approaches may be effec-tive for adjunct treatment of patients with TDR-TB.

Vitamin supplementation

Nutritional status is known to affect the risk ofacquiring active TB. Vitamin D has been shownto influence TB-directed immune responses [108].In addition, vitamin D and its metabolites havebeen shown to have an effect on monocytes/macrophages. Because the infection of macro-




phages is a key step in M.tb pathogenesis,vitamin D supplementation has received attentionas an adjunct treatment for TB. It has beenreported that vitamin D supplementation accel-erates the resolution of adverse inflammatoryresponses [109] by suppressing proinflammatorycytokine responses [110] as well as by influencingepigenetics [111]. The metabolically active vita-min D metabolite 1,25-dihydroxyvitamin D3 (cal-citriol), which is formed by hydrolysis ofcirculating calcifediol, modulates adaptiveimmune responses by suppressing interferon-cand IL-2 production of Th1 cells as well as 1L-12production and major histocompatibility complexII expression of antigen-presenting cells [112].However, the vitamin D might also act directly onM.tb. Calcitriol has been shown to have an anti-mycobacterial effect by inducing: (i) reactive oxy-gen and nitrogen intermediates; (ii) the transcrip-tion of anti-microbial peptides such ascathelicidin and (iii) autophagy. Cathelicidin isinduced by the binding of vitamin D and thevitamin D receptor to its promoter [113]. Arelationship has been shown between the anti-microbial activity of macrophages and cathelici-din expression [114]. The peptide might havedual effects in cells by (i) inducing autophagy,that is, degradation of cytoplasmic componentsvia the lysosomal pathway, which may offerprotection against infection with M.tb [115, 116]and (ii) increasing the efficiency of macrophagesto kill mycobacteria [114].

Several studies of vitamin D supplementation in TBpatients have been conducted with mixed resultsbased on clinical outcomes [109, 117, 118]. Itmight be interesting to pursue this approach in thecontext of MDR-TB infections as it has been shownthat adjunct therapy with vitamin D is effective tosome degree in reducing immunopathologicalinflammation [109], which is associated with IL-17 production and cell wall composition of certainMDR strains of M.tb [58].

Another vitamin with potential bactericidal effecton M.tb is vitamin C. High doses of vitamin C killedMDR- and TDR-TB strains in vitro; the mycobacte-ria did not develop any resistance to this treatment[119].

Repurposing of drugs

Repurposing of drugs, such as the recentlyreported anti-tubercular activity of ibuprofen

[120] and verapamil [121, 122], highlights thepossibility of expanding the spectrum of currentlyavailable chemotherapeutic agents against TB.Peptide-conjugated phosphorodiamidate morpho-lino oligomers (PPMOs) potentially present a novelclass of antibiotics for future consideration.PPMOs are chemically stabilized nucleic acidsthat bind to bacterial mRNA, consequently silenc-ing gene expression, and they have been shownto exert gene-specific anti-bacterial effects againstboth enteropathogenic Escherichia coli and Sal-monella typhimurium [123]. Pathogen specificityand low toxicity prompted the evaluation ofPPMOs in the context of hospital-acquired bacte-rial infections. Potent in vitro and in vivo bacte-ricidal activity of PPMOs against MDR strains ofthe pulmonary pathogens Burkholderia multiv-orans [124] and Acinetobacter baumannii [125]was successfully shown. Encouraging resultshave also been reported with PPMOs againsttachyzoites of the apicomplexan parasite Toxo-plasma gondii, which, like M.tb, represents apersistent intracellular pathogen [126]. Assuch, the results of initial laboratory-basedstudies of PPMOs in clinically-relevant infec-tious diseases hold promise for treating drug-resistant TB. Newer treatment options mayalso include interference with mycobacterialmicro-RNAs [127].

Conclusion

A number of cases of TDR-TB have beenreported; the causes are most probably multifac-torial including host-associated variables, phar-macokinetics, co-infections and comorbidities.Several factors associated with the M.tb strain,including genetic and phenotypic changes, alsocontribute to the phenomenon of TDR-TB. Noveldrugs are being developed, but will not eradicateresistance in M.tb. Thus, adjunct treatmentoptions should be considered for patients withdrug-resistant TB.

The clinical viewpoint from one of the most experi-enced TB hospitals in South Africa, reflecting thegap between clinical reality and academic ‘textbook’views, is summarized in Box 1. The clinical experi-ence in managing patients with drug-resistant TBhighlights a multifactorial approach taking intoconsideration the cultural factors. As shown in Box1, there are many challenges that need to beaddressed to pro-actively dealwith themanagementof drug-resistant TB.




Box 1. Clinical experience from King Dinuzulu Hospital (in Durban, province of KwaZulu–Natal), which isthe leading South African provincial hospital for the treatment of drug-resistant TB

Clinicians’ viewpoint from the frontline of MDR-/XDR-TB patient management: the real-life clinical situation

Clinicians experience many challenges in the management of patients with drug-resistant TB. Thesuccess of treatment is often dependent on the following:

• Quality of diagnosis and testing

• Medication, side effects and drug regimens

• The patient and the programme

Quality of diagnosis and testingThrough the decades of working in an MDR-/XDR-TB facility, clinicians face many confounding andconflicting results in day-to-day clinical practice. At times, they are confronted with radically differentlaboratory findings on drug sensitivity patterns obtained from sputum samples taken on consecutive oreven the same day, assessed by standard culture techniques. Often these will have been performed at thesame laboratory or at different laboratories having stringent quality controls. Recently, discordancebetween phenotypic and genotypic testing has been observed. A switch from a fully sensitive result, toisoniazid mono-resistance, to isoniazid and rifampicin resistance on genotypic testing, then reported asfully sensitive or total XDR patterns on full phenotypic sensitivity testing have also been observed onconsecutive sputum samples from the same patient. Sometimes, these conflicting results have beenencountered in totally asymptomatic patients. There have also been patients who have had intermittentfindings of nontuberculosis mycobacterium interspersed with results of MDR-/XDR-TB. Some patientsfail treatment, despite minimal resistance and good compliance. It is challenging to manage drug-resistant TB patients facing these conflicting results.

Many experts point out that this discordance is only observed in a small percentage of patients, but thereare greater numbers of these patients and more apparent dilemmas in a country with a high burden ofdisease. Any nonoptimal treatment may have a negative impact on the individual patient in terms ofincreased morbidity or mortality. Several plausible reasons have been proposed for the discordantresults, such as multiple anatomical sources causing multiple strains of M.tb within the same patient,selective mutations due to different degrees of bioavailability of anti-TB drugs in the different lesion sites,re-infection due to poor infection control in congregate settings, laboratory errors, poor quality of drugs,mixing of specimens at collection points or even fraudulent samples being presented to obtain a disabilitygrant.

The consequence is uncertainty, and therefore the basis of treatment decisions is challenged. Without adoubt the new genotypic tests such as GeneXpert have detected far more patients. In theory, genetictesting should save more lives and reduce the costs of unnecessary treatment and consequent morbidityin some patients. The term ‘acceptable collateral damage’ has been applied to this situation.

Medication, side effects and drug regimensExcellent treatment and drug regimens are the keys to achieve success in any MDR programme. The idealtreatment comprises a cheap, safe, high-quality medication, for a short duration, and with high efficacy.However, in reality, expensive medication is required for long periods with a large number of side effects.The consequence is often reluctance amongst patients to take toxic medications for the requiredduration. The essential component of the current intensive phase of chemotherapeutic regimen is long-term injectables. Many patients, who were productive members of society, have been reduced to deaf,




unemployed patients, who become a burden to their families and the state as a consequence of treatment.Other patients, especially in countries with a high HIV burden, have a particular high likelihood ofelectrolyte imbalances and renal issues, requiring either hospitalization or intensive monitoring (which isdifficult in a resource-poor setting). Other patients also suffer from neuropsychiatric side effects such asepilepsy, depression, suicidal ideation and peripheral neuropathy. These side effects are also morefrequent in HIV-positive patients. Many of the newer drugs require more intensive electrocardiographic,and particularly QT interval, monitoring that has not been implemented routinely in many programmes.At present, effective treatment is often associated with many side effects and a long treatment duration.To change this scenario and to improve outcomes, novel, cheaper, effective drugs and drug combinationsthat need to be taken for short durations and with minimal side effects are urgently required.

The patient and the programmeMost effective TBprogrammes require patients tounderstand their disease and treatment plans, alongwithsupport to assist them to effectively complete their regimens. Inmany resource-poor high-burden settings,there is a lackof adequate counselling forpatientsand their families. Thereare often insufficientnumbersofbeds for sick patients who require hospital care. The impact of GeneXpert in certain areas has resulted in adramatic increase in patient numbers, which has not been matched by an increase in the capacity formanagementbyhealth caresectors. Thishas resulted inwaiting lists for admissionor for the initiationofM/XDR-TB treatment in some regions. In many areas, DOT programmes have failed and patients thereforetake ‘self-supervisedmedication’. When patients fail treatment, there is never any certainty whether or notthey have actually been adherent to treatment. Some regular attendees of MDR-TB units have beenobserveddiscarding theirmedicationon theirwayoutof the facility. Themanagementof patientswithMDR-TB requires some capacity at the district and regional level for supervision of treatment in a way that isacceptable to the patient and in a culturally appropriate context. Proper adherence depends on propersupport of patients, monitoring of key outcomes and effective management of adverse effects.

Conflict of interest statement

All authors have no conflicts of interest to declare.None of the funding bodies had any role in thepreparation of the manuscript.

Funding

This work was funded by HLF, Vinnova, VR, SIDA,Sweden and EDCTP (TBNeat) (to MM), and the UKMedical Research Council, European UnionFramework7 Rid-RTI, European Developing Coun-tries Clinical Trials Partnership (EDCTP), UBSOptimus Foundation, Switzerland and the NIHRBiomedical Research Centre, University CollegeHospitals, London, UK (to AZ).

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Correspondence: Markus J. Maeurer, TIM, F79, H€alsov€agen,

Karolinska University Hospital Huddinge, SE 14186 Stockholm,

Sweden. (fax: +46 8 585 83074; email: [email protected]).




Totally drug-resistant tuberculosis and adjunct therapies

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