multidrug-resistanttuberculosisandextensively drug...

Multidrug-Resistant Tuberculosis and ExtensivelyDrug-Resistant Tuberculosis

Kwonjune J. Seung1,2,3, Salmaan Keshavjee1,2,3, and Michael L. Rich1,2,3

1Division of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts 021152Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts 021153Partners In Health, Boston, Massachusetts 02215

Correspondence: [email protected]

The continuing spread of drug-resistant tuberculosis (TB) is one of the most urgent and difficultchallenges facing global TB control. Patients who are infected with strains resistant to isoni-azid and rifampicin, called multidrug-resistant (MDR) TB, are practically incurable by stan-dard first-line treatment. In 2012, there were approximately 450,000 new cases and 170,000deaths because of MDR-TB. Extensively drug-resistant (XDR) TB refers to MDR-TB strains thatare resistant to fluoroquinolones and second-line injectable drugs. The main causes of thespread of resistant TB are weak medical systems, amplification of resistance patterns throughincorrect treatment, and transmission in communities and facilities. Although patients har-boring MDR and XDR strains present a formidable challenge for treatment, cure is oftenpossible with early identification of resistance and use of a properly designed regimen.Community-based programs can improve treatment outcomes by allowing patients to betreated in their homes and addressing socioeconomic barriers to adherence.

EPIDEMIOLOGY

Even though tuberculosis (TB) is a treatableinfectious disease, an estimated 1.3 million

people died from TB in 2012 (WHO 2013a).One of the major reasons is that TB continuesto evolve resistance to drugs. For patients withdrug-susceptible TB, standard treatment basedon isoniazid and rifampicin, the two most pow-erful drugs, results in excellent cure rates. Pa-tients who are infected with strains resistantto isoniazid and rifampicin, called multidrug-resistant (MDR) TB, are practically incurable bystandard first-line treatment (Fig. 1).

Today, the continuing spread of MDR-TB isone of the most urgent and difficult challengesfacing global TB control. In 2012, there wereapproximately 450,000 new cases of MDR-TBand 170,000 deaths. Globally, MDR-TB is pre-sent in 3.8% of new TB patients and 20% ofpatients who have a history of previous treat-ment. The highest MDR rates are found incountries of Eastern Europe and central Asia,where MDR strains threaten to become as com-mon as pan-susceptible strains. In some coun-tries, MDR strains account for up to 20% ofnew TB cases and well over 50% of patientswith a history of previous TB treatment. In

Editors: Stefan H.E. Kaufmann, Eric J. Rubin, and Alimuddin Zumla

Additional Perspectives on Tuberculosis available at www.perspectivesinmedicine.org

Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a017863

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2011, Minsk, Belarus reported that 35% of newpatients had MDR-TB, as did 75% of those whohad been treated previously for TB (Skrahinaet al. 2012).

Equally worrisome rates have emerged fromChina and India, which have the highest andsecond-highest number of MDR-TB patientsin the world. In 2012, the China Centers forDisease Control and Prevention reported that10% of China’s 1.4 million TB patients hadMDR-TB, and the great majority of MDR-TBpatients had never been treated for TB—evidence of unfettered human-to-human trans-mission (Zhao et al. 2012). MDR-TB is also a

growing problem in South Africa, where highrates of HIV (human immunodeficiency virus)have exacerbated both the spread and deadlinessof MDR-TB, raising the specter of a “perfectstorm” of MDR-TB/HIV coinfection (Wellset al. 2007). In clinical practice today, the pos-sibility of unsuspected drug resistance must al-ways be considered when evaluating a TB pa-tient in any country (Box 1).

In 2006, the term extensively drug-resistantTB (XDR-TB) was coined to describe strains ofMDR-TB resistant to fluoroquinolones and sec-ond-line injectable drugs. It is estimated that9.6% of MDR-TB cases worldwide have XDR-

Percentageof cases

0–2.93–5.96–11.912–17.9

No dataSubnational data onlyNot applicable

≥18

Figure 1. Percentage of new TB cases with MDR-TB (WHO 2013a).

BOX 1. TYPES OF DRUG-RESISTANT TB (WHO 2013b) (TYPES ARE NOT MUTUALLY EXCLUSIVE)

Monoresistance: Resistance to one first-line anti-TB drug only.Polydrug resistance: Resistance to more than one first-line anti-TB drug, other than both isoniazidand rifampicin.Multidrug resistance (MDR): Resistance to at least both isoniazid and rifampicin.Rifampicin resistance (RR): Resistance to rifampicin detected using phenotypic or genotypicmethods, with or without resistance to other anti-TB drugs. It includes any resistance to rifampicin,whether monoresistance, multidrug resistance, polydrug resistance, or extensive drug resistance.Extensive drug resistance (XDR): Resistance to any fluoroquinolone, and at least one of threesecond-line injectable drugs (capreomycin, kanamycin, and amikacin), in addition to multidrugresistance.

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TB (WHO 2013a). Because access to second-line drug susceptibility testing (DST) is poorin many areas of the world, XDR-TB oftengoes unrecognized. Although patients harbor-ing MDR and XDR strains present a formidablechallenge for treatment, cure is often possiblewith early identification of resistance and use ofa properly designed regimen.

CAUSES OF DRUG RESISTANCE

Drug resistance is a biological phenomenonthat has been observed in Mycobacterium tuber-culosis since the discovery of the first anti-TBdrug, streptomycin. Many patients who wereinjected with streptomycin were brought fromthe brink of death and their sputum becametemporarily clear of M. tuberculosis. But despitecontinuing to receive treatment, they soon be-gan to excrete bacilli that were resistant to strep-tomycin in the laboratory (Pyle 1947).

With the advent of new drugs—thioaceta-zone and para-aminosalicylic acid in 1948 andisoniazid in 1952—it became clear that combi-nation chemotherapy was the key to preventingthe development of resistance. Initial combina-tion regimens required 18 mo of treatment, butthe invention of rifampicin in 1957, the mostpowerfully sterilizing anti-TB drug, paved theway for development of the shorter and moreeffective isoniazid- and rifampicin-containingregimens known as short-course chemotherapy.As part of the global TB control strategy cal-led DOTS (directly observed treatment, short-course), these regimens became the standard ofcare even in resource-limited settings starting in1993.

Outbreaks of MDR-TB were initiallythought to be driven by nosocomial transmis-sion, particularly among HIV-positive patients.One of the largest and best-documented out-breaks occurred in New York in the late 1980sand early 1990s (Frieden et al. 1993; Friedenet al. 1995). As DST laboratory capacity im-proved in resource-limited settings and globaldrug-resistant TB surveillance efforts grew, itbecame clear that MDR-TB was increasinglycommon throughout the world and a growingthreat to the general public health. The causes of

the global spread of MDR-TB include the fol-lowing:

† Chaotic treatment. Before the late 1980s,many countries were not using standard pro-tocols for the treatment of TB and did nothave systems in place to support patients.Furthermore, in many settings, TB treatmentwas not provided for free, contributing topoor adherence. Even today, drug-resistantTB can be created very quickly during timesof socioeconomic instability if there arestockouts of anti-TB drugs or other struc-tural weaknesses in the health care system.

† Amplifier effect of short-course chemother-apy. Once drug resistance has been created,the DOTS strategy can paradoxically exacer-bate the problem. In Figure 2, the initialstrain has polydrug resistance, but, as a resultof repeated use of short-course chemo-therapy, it becomes resistant to all first-lineanti-TB drugs (Seung et al. 2004). Amplifi-cation of drug resistance patterns throughrepeated courses of DOTS short-course che-motherapy continues to be a major drivingforce of the epidemic in many parts of theworld that do not have the resources to diag-nose or treat drug-resistant TB correctly(Keshavjee and Farmer 2012).

† Community transmission. In the early2000s, it was believed that resistance muta-tions conferred a loss of fitness, so the trans-mission of resistant strains would be self-limited (Dye et al. 2002; Cegielski 2010). Thishas not turned out to be the case. Currentmodels indicate that in most countries, themajority of MDR-TB patients were infectedinitially with an MDR-TB strain, rather thanslowly acquiring resistance caused by inade-quate or irregular treatment (Lin et al. 2011).

† Facility-based transmission. Nosocomialtransmission in busy, crowded hospitals andhealth centers is likely an important driver ofthe epidemic, especially in high HIV preva-lence settings. This can result in the spread ofdrug-resistant strains among patients receiv-ing therapy for drug-susceptible TB as well asto the health workers (Gelmanova et al. 2007).

MDR-TB and XDR-TB

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DIAGNOSIS OF MDR-TB AND XDR-TB

DST is required for the definitive diagnosis ofMDR-TB or XDR-TB. The traditional way to dothis is through phenotypic (or culture-based)methods. M. tuberculosis is isolated from patientsputum and then tested for growth in the pres-ence of anti-TB drugs. Culture-based methodscan take weeks to months. They are also expen-sive and difficult to master, making them mostlyunavailable in resource-limited settings.

Genotypic (or molecular) methods haverevolutionized the diagnosis of MDR-TB. Thesemethods generally use polymerase chain reac-tion techniques to detect the genetic muta-tions that are known to confer resistance todrugs. Commercially available systems includeGeneXpert System (Xpert MTB/RIF, Cepheid,USA), GenoType MTBDRplus and MTBDRslassays (Hain Lifescience GmbH, Germany),and INNO-LiPA Rif.TB line probe assay (Inno-genetics Inc., Belgium), but there are other sys-tems in development. Molecular methods ofDST give results much faster than culture-basedmethods. Some commercially available systemsare almost fully automated and require littletraining. For these reasons, these systems areincreasingly the method of choice for DST inresource-limited settings.

There is no “gold standard” for the diagno-sis of drug resistance. Molecular testing maydetect mutations that confer low levels of resis-tance that are not detected by culture-basedtesting but are still clinically significant. Molec-ular testing also cannot detect all of the muta-

tions that are known to confer resistance to adrug. Nevertheless, it is not necessary to rou-tinely confirm the results of molecular DSTwithculture-based DST, even though clinicians maychoose to do so if the clinical picture warrants it.Specifically, a positive molecular test for rifam-picin resistance can be considered diagnosticfor MDR-TB, because in most countries, grea-ter than 90% of rifampicin-resistant strains arealso resistant to isoniazid.

A public health strategy of “universal DST,”meaning testing all patients with active TB dis-ease for drug resistance at the start of therapy,is certainly feasible in the near future because ofthe increasing availability of molecular DST. AWHO analysis determined that this would be alifesaving and cost-effective strategy for anycountry with greater than 1% MDR-TB in newpatients (WHO 2011a).

At the current time, however, DST is notwidely available in many countries so patientswith risk factors for MDR-TB are prioritized fortesting. Empiric treatment for MDR-TB can beconsidered if there is clear bacteriological evi-dence of failure to respond to treatment, such aspersistently positive sputum smears after 4 moof regular treatment with a first-line DOTS reg-imen (Chavez Pachas et al. 2004; Satti et al.2013). Household contacts of MDR-TB patientsshould also be started empirically on treatmentif any delay in DST is anticipated (Box 2).

All patients diagnosed with MDR-TBshould be tested for XDR-TB. This includestesting for resistance to the three second-lineinjectable drugs (kanamycin, amikacin, and

2HREZ/4HR(Category I)

2SHREZ/1HREZ/5HRE(Category II)

HS

HRS

HREZS

Resistance patterns

2SHREZ/1HREZ/5HRE(Category II)

Figure 2. Amplifier effect of short-course chemotherapy. H, isoniazid; R, rifampicin; E, ethambutol; Z, pyr-azinamide; S, streptomycin.

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capreomycin) and at least one fluoroquinolone.Laboratories with a capacity for second-lineDST, however, are even less common than thosewith capacity for first-line DST. Patients whoshould be prioritized for second-line DST in-clude those who have failed to respond to anMDR-TB treatment regimen containing an in-jectable and fluoroquinolone, and close con-tacts with an individual with documentedXDR-TB or with an individual for whom treat-ment with a regimen including second-linedrugs is failing or has failed.

The GenoType MTBDRsl assays (Hain Life-science GmbH, Germany) test for mutations inthe gyrA gene, which confers resistance to fluo-roquinolones, and in the rrs gene, which confersresistance to injectable drugs. This assay can beconsidered a “rule-in” test for second-line drugresistance, although it cannot reliably rule outXDR-TB when no genetic mutations are de-tected. Because the sensitivity and specificityof this assay are not well characterized, cul-ture-based DST should be used as a confirma-tory test.

TREATMENT

MDR-TB treatment is difficult because the sec-ond-line TB drugs are mostly weak and toxic.Most of these drugs were developed decades agobut hardly ever used because of poor side effectprofiles. Because of the weak sterilizing activityof the second-line TB drugs, MDR-TB treat-ment generally takes 18–24 mo. In the besttreatment programs, which address socioeco-

nomic barriers and aggressively manage sideeffects, cure rates of 60%–80% have been re-ported (Mitnick et al. 2003; Shin et al. 2006).Globally, however, the cure rate for MDR-TB ismuch lower. In 2013, the WHO reported thatonly 48% of MDR-TB patients were cured. Theglobal cure rate for XDR-TB is even lower: Only20% are cured, and 44% die (WHO 2013a).

Anti-TB drugs have traditionally been di-vided into first- and second-line anti-TB drugswith isoniazid, rifampicin, pyrazinamide, eth-ambutol, and streptomycin being the primaryfirst-line anti-TB drugs. In this review, we usethe WHO system, which classifies the drugs intofive different groups based on efficacy, experi-ence of use, safety, and drug class. Drugs in thesame group do not always come from the samedrug class nor do they have the same safety pro-file or efficacy. Table 1 provides detailed infor-mation on each drug including the WHO group,dosage, side effects, and monitoring require-ments.

In recent years, there has been considerableresearch devoted to developing new anti-TBdrugs, with the goal of improving TB treatment.There are now two new purpose-built anti-TBdrugs, the first in over 40 yr. Bedaquiline wasconditionally approved by the U.S. FDA for thetreatment of MDR-TB in December 2012. De-lamanid was conditionally approved by the Eu-ropean Medicines Agency in November 2013.At least three additional new TB drugs are inlate-phase clinical testing. These new drugs arelikely to revolutionize the treatment of MDR-TB and XDR-TB.

BOX 2. RISK FACTORS FOR MDR-TB

† Failure to respond to a first-line DOTS regimen (WHO Category I or II)

† Relapse after a full course of treatment with a first-line regimen

† Treatment after defaulting from treatment with a first-line regimen

† Exposure to a known case of MDR-TB

† Exposure to TB in institutions with high prevalence of MDR-TB, such as a prison or hospital

† Living in areas or countries with high prevalence of MDR-TB

† HIV coinfection

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Table 1. Anti-TB drugs and their side effects

Drug name (abbreviation)

Description

and adult dose Side effects

Monitoring requirements

and comments

Group 1: First-line oral drugsIsoniazid (H) Description:

Bactericidal; inhibitsmycolic acidsynthesis mosteffectively individing cells;hepaticallymetabolized.

Dose: 300 mg daily or900 mg twice orthrice weekly.

Common: Hepatitis (10%–20% have elevatedtransaminases), peripheralneuropathy (dose-related;increased risk withmalnutrition, alcoholism,diabetes, concurrent use ofaminoglycosides, orethionamide).

Less common:Gynecomastia, rash,psychosis, seizure.

Monitoring: Considerbaseline and monthlyliver enzymes, especiallyif age .50 yr.

Comments: Give withpyridoxine 50 mg/d ifusing large dose or ifpatient is at risk forperipheral neuropathy(diabetes, alcoholism,HIV, etc.).

RifamycinsRifampicin (R)Rifabutin (Rfb)Rifapentine (Rpt)

Description:Bactericidal; inhibitsprotein synthesis byblocking mRNAtranscription andsynthesis; hepaticallymetabolized.

Dose: rifampicin600 mg/d; rifabutin300 mg/d.

Common: Orange-coloredbodily secretions, transienttransaminitis, hepatitis,gastrointestinal distress.

Less common: Cholestaticjaundice.

Monitoring: Considerbaseline liver enzymes,repeat if symptoms( jaundice, fatigue,anorexia, weakness, ornausea and vomiting)appear.

Pyrazinamide (Z) Description:Bactericidal;mechanism unclear;effective in acidicmilieu (e.g., cavitarydisease, intracellularorganisms);hepaticallymetabolized, renallyexcreted.

Dose: 15–40 mg/kgdaily.

Common: Arthritis/arthralgias, hepatotoxicity,hyperuricemia, abdominaldistress.

Less common: Impaireddiabetic control, rash.

Monitoring: Baseline liverenzymes; uric acid can bemeasured ifarthralgias, arthritis, orsymptoms of gout arepresent.

Comments: Usually givenonce daily, but can splitdose initially to improvetolerance.

Ethambutol (E) Description:Bacteriostatic atconventional dosing(15 mg/kg); inhibitslipid and cell wallmetabolism; renallyexcreted.

Dose: 15–25 mg/kg.

Common: Generally well-tolerated.

Less common: Opticneuritis, gastrointestinaldistress, arthritis/arthralgia.

Monitoring: Baseline andmonthly visual acuityand red/green colorvision test when dosedat greater than 15 mg/kgdaily (.10% loss isconsidered significant);regularly questionpatient about visualsymptoms.

Continued

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Table 1. Continued


Description



and comments

Group 2: Injectable drugsAminoglycosidesAmikacin (Amk)Kanamycin (Km)Streptomycin (S)PolypeptidesCapreomycin (Cm)

Description:Bactericidal;aminoglycosidesinhibit proteinsynthesis throughdisruption ofribosomal function;less effective inacidic, intracellularenvironments;polypeptides appearto inhibittranslocation of thepeptidyl-tRNA andthe initiation ofprotein synthesis;renally excreted.

Dose: 15–20 mg/kgdaily.

Common: Pain at injectionsite; proteinuria;electrolyte wasting (morecommon withcapreomycin); cochlearototoxicity (hearing loss,dose-related to cumulativeand peak concentrations,increased risk with renalinsufficiency, may beirreversible).

Less common:Nephrotoxicity (dose-related to cumulative andpeak concentrations,increased risk with renalinsufficiency, oftenirreversible); peripheralneuropathy; rash;vestibular toxicity(nausea, vomiting,vertigo, ataxia,nystagmus); eosinophilia;ototoxicity potentiatedby certain diuretics,especially loop diuretics.

Monitoring: Baseline andthen monthlycreatinine, urea, andserum potassium; morefrequently in high-riskpatients; if potassium islow, check magnesiumand calcium; baselineaudiometry andmonthly monitoring inhigh-risk patients (high-risk patients: elderly,diabetic, or HIV-positive patients, orpatients with renalinsufficiency).

Comments: Increasedosing interval orreduce dose andmonitor serum drugconcentrations asneeded to control sideeffects.

Group 3: FluoroquinolonesLevofloxacin (Lfx)Moxifloxacin (Mfx)

Description:Bactericidal; DNA-gyrase inhibitor;renally excreted.

Dose: levofloxacin750–1000 mg/d;moxifloxacin400 mg/d.

Common: Generally well-tolerated, well-absorbed.

Less common: Diarrhea,dizziness, gastrointestinaldistress, headache,insomnia,photosensitivity, rash,vaginitis, tendonitis,psychosis, seizure (CNSeffects seen almostexclusively in elderly).

Monitoring: No laboratorymonitoringrequirements.

Comments: Do notadminister withantacids, sucralfate,iron, zinc, calcium, ororal potassium andmagnesiumreplacements;levofloxacin,moxifloxacin have themost activity againstM. tuberculosis.

Group 4: Oral bacteriostatic drugsCycloserine (Cs) Description:

Bacteriostatic;alanine analog;interferes with cell-

Common: Neurologic andpsychiatric disturbances,including headaches,irritability, sleep

Monitoring: Considerserum drug monitoringto establish optimaldosing.

Continued

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Table 1. Continued


Description



and comments

wall proteoglycansynthesis; renallyexcreted.

Dose: 500–1000 mg/d.

disturbances, aggression,and tremors.

Less common: Psychosis,peripheral neuropathy,seizures (increased risk ofCNS effects withconcurrent use ofethanol, isoniazid,ethionamide, or othercentrally actingmedications),hypersensitivity.

Comments: Give 50 mg ofpyridoxine for every250 mg of cycloserine(to lessen neurologicadverse effects).

ThiamidesEthionamide (Eto)Prothionamide

(Pto)

Description: May bebactericidal orbacteriostaticdepending onsusceptibility andconcentrationsattained at theinfection site; thecarbothioamidegroup, also found onthiacetazone, and thepyridine ring, alsofound on isoniazid,appear essential foractivity; hepaticallymetabolized, renallyexcreted.

Dose: 500–1000 mg/d.

Common: Gastrointestinaldistress (nausea,vomiting, diarrhea,abdominal pain, loss ofappetite); dysgeusia(metallic taste);hypothyroidism(especially when takenwith PAS).

Less common: Arthralgias,dermatitis, gynecomastia,hepatitis, impotence,peripheral neuropathy,photosensitivity.

Monitoring: Considerbaseline liver enzymes.

Comments: May split doseor give at bedtime toimprove tolerability;ethionamide andprothionamideefficacies are consideredsimilar; prothionamidemay cause fewergastrointestinal adverseeffects.

Para-aminosalicylicacid (PAS)

Description:Bacteriostatic;disrupts folic acidmetabolism(thought to inhibitthe biosynthesis ofcoenzyme F in thefolic acid pathway);hepatic acetylation,renally excreted.

Dose: Depends onspecific formulation.

Common: Gastrointestinaldistress (nausea,vomiting, diarrhea);hypersensitivity;hypothyroidism(especially when takenwith ethionamide).

Less common: Hepatitis,electrolyte abnormalities.

Drug interactions:Decreased isoniazidacetylation; decreasedrifampicin absorption innongranular preparation;decreased vitamin B12

uptake.

Monitoring: No laboratorymonitoringrequirements.

Comments: PASERconsists of entericcoated granules thatneed to be administeredwith an acidic food orbeverage (e.g., yogurt oracidic juice); PASER isstable for up to 8 wk at40˚C and 75%humidity, and thereforecan be distributed to thepatient on a monthlybasis in mostenvironments with nocold chain; if storage of

Continued

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Table 1. Continued


Description



and comments

.8 wk is needed,refrigeration below 15˚Cis required.

Group 5: Drugs with limited data on efficacy or long-term safetyBedaquiline (Bdq) Description: A

diarylquinolineantimycobacterialdrug that inhibitsATP synthesis.

Dose: 400 mg oncedaily for 2 wk,followed by 200 mgthree times per weekfor 22 wk with food;the drug has a 5.5-mo half-life.

Common: Gastrointestinaldistress (nausea,vomiting, abdominalpain, loss of appetite);joint pain; headache.

Less common: QTprolongation,hyperuricemia,phospholipidosis (theaccumulation ofphospholipids in thebody’s tissues), elevatedaminotransferases, chestpain, hemoptysis(coughing up blood).Possibly an increased riskof pancreatitis.

Drug Interactions: AllCYP3A4 inhibitors orinducers. Rifampicin (aCYP3A4 inducer)reduces bedaquiline inblood by half; drugs thatprolong the QT interval(e.g., clofazimine,moxifloxacin,antifungals, and manyothers) may result inadditive cardiactoxicity—their use is onlyindicated when there areno other alternatives;more frequent ECGmonitoring is required.

Monitoring: Monitor QTinterval with ECG atbaseline, 2, 12, and 24 wk(more often if risk of QTprolongation is present);discontinue if significantventricular arrhythmiaor a QTcF interval.500 msec develops;monitor liver enzymesevery month.

Comments: A significantimbalance in fatalities wasnoted in Trial C208 Stage2, with a higher numberof deaths in thebedaquiline group (10 vs.2 in the placebo group;RR ¼ 5.1; P ¼ 0.017).There was no suddendeath reported in thestudy. There was nodiscernible pattern forcause of deaths, and thereason for theimbalance in deaths is notclear.

Linezolid (Lzd) Description:Oxazolidinone;inhibits proteinsynthesis;increasingly used fortreatment ofXDR-TB.

Dose: 600 mg/d(reduce to 300 mg/dif serious side effects

Common: Diarrhea andnausea.

Less common:Myelosuppression(decreased level of whiteblood cells, and/oranemia); lactic acidosis;optic and peripheralneuropathy (may beirreversible, and linezolid

Monitoring: Monitor forperipheral neuropathyand optic neuritis.Monitor with acomplete blood count(CBC) weekly duringthe initial period, thenmonthly. If symptoms oflactic acidosis develop, amedical evaluation

Continued

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Table 1. Continued


Description



and comments

or intolerancedevelops).

should be considered forsuspension weighedagainst the risk ofpermanent blindness ordisabling permanentneuropathy).

including a lactic acidblood test should beperformed.

Comments: All patientsshould receive pyridoxinewhile receiving linezolid(child: 5–10 mg/d; adult:50 mg/d); do not usewithpatients takingserotonergic drugs, suchas monoamine oxidaseinhibitors (MAOIs),selective serotoninreuptake inhibitors(SSRIs, e.g., fluoxetine,sertraline, paroxetine),lithium, etc., as it maycause serotoninsyndrome; avoid ormonitor closely withtricyclic antidepressants.

Clofazimine (Cfz) Description:Riminophenazine;has activity in vitrobut limited clinicalevidence of efficacy.

Dose: 100 to 200 mg/d(oral) has been used.A regimen of200 mg/d for 2 mo,followed by 100 mg/d has been used.

Common: Orange/reddiscoloration of skin,conjunctiva, cornea, andbody fluids; dry skin,pruritus, rash, ichthyosis,xerosis; gastrointestinalintolerance;photosensitivity.

Less common: Retinopathy,severe abdominalsymptoms, bleeding, andbowel obstruction; QTprolongation.

Monitoring: Symptomaticmonitoring only.

Comments: Discolors skinand body secretionsorange, red, or brownish-black; this should go awayafter stopping themedicine, but may take along time; avoid sun; usestrong sunscreens.

Amoxicillin/clavulanic acid(Amx/Clv)

Description:Penicillin/b-lactam inhibitor;very limitedclinical evidence ofefficacy.

Dose: 80 mg/kg dailyin two divided doses.

Common: Diarrhea andabdominal discomfortare most common;nausea and vomiting.

Less common:Hypersensitivity andrash; rare side effects havebeen reported in otherorgan systems.


Comments: Best toleratedand well absorbed whentaken at the start of astandard meal.

Imipenem/cilastatin (Imp/Cln)

Description:b-lactam/carbapenem(related to thepenicillin/

Common: Diarrhea, nausea,or vomiting.

Less common: Seizure(noted with CNSinfection), palpitations,


Comments: Meropenem ispreferred in children asfewer seizures have been

Continued

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Table 1. Continued


Description



and comments

cephalosporinfamilyof antibiotics butclassified asbelonging to thecarbapenem class);very limited clinicalexperience. Giventhat imipenem israpidly degraded byrenal proximaltubule dipeptidases,it is used incombination withthe dipeptidaseinhibitor cilastatin.Dose: 1000 mg IVevery 12 h.

pseudomembranouscolitis.

associated with it;consider addingclavulanate (available asAmx/Clv) 125 mg every8–12 h.

Meropenem (Mpm) Description: b-lactam/carbapenem (relatedto the penicillin/cephalosporinfamilyof antibiotics butclassified asbelonging to thecarbapenem class);very limited clinicalexperience.

Dose: 1000 mg IVevery8 h.

Common: Diarrhea,nausea, or vomiting.

Less common: Seizure (butless is seen than withimipenem), palpitations,pseudomembranouscolitis.


Comments: Consideradding clavulanate(available asamoxicillin/clavulanate) 500/125 mg every 8–12 h.

High-doseisoniazid(High-dose H)

Description: May bebactericidal orbacteriostaticdepending onsusceptibility andconcentrationsattained at theinfection site; thecarbothioamidegroup, also found onThz, and thepyridine ring, alsofound on H, appearessential for activity;hepaticallymetabolized, renallyexcreted.

Dose: 500–1000 mg/d.

Common: Gastrointestinaldistress (nausea,vomiting, diarrhea,abdominal pain, loss ofappetite); dysgeusia(metallic taste);hypothyroidism(especially when takenwith PAS).

Less common: Arthralgias,dermatitis, gynecomastia,hepatitis, impotence,peripheral neuropathy,photosensitivity.

Monitoring: Considerbaseline and monthlyliver enzymes, especiallyif age .50 yr.

Comments: Give withpyridoxine 50 mg/d.

Continued

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Table 1. Continued


Description



and comments

Clarithromycin(Clr)

Description: Moreactive againstnontuberculousmycobacteria,especially MAC, butsome isolates of TBare susceptible invitro; does not haveproven value for thetreatment of TB inhumans, and in vitrodata are notparticularlyencouraging(M. tuberculosis isintrinsically resistantto macrolides, acharacteristicassociated withexpression of theermB gene).

Dose: 500 mg twicedaily.

Common: Diarrhea,nausea, abnormal taste,dyspepsia, abdominalpain/discomfort,headache, rare allergicskin reactions, livertoxicity, QTprolongation,pseudomembranouscolitis, hearing loss.

Monitoring: No routinelaboratory monitoring isindicated.

Comments: Thismedication may be takenwith or without food;contraindicated inpatients taking cisapride,pimozide, astemizole,terfenadine, ergotamine,or dihydroergotamine.

Thioacetazone (T) Description: Known tobe active against TB(by inhibitingcyclopropanation ofcell wall mycolicacids inmycobacteria), butits role in MDR-TBtreatment is not well-established; cross-resistance with someof the other anti-TBdrugs (isoniazid,ethionamide, PAS)and overall is aweakly bacteriostaticdrug; prevents theemergence ofresistance when usedwith other first-linedrugs.

Dose: 150 mg oncedaily.

Common: Nausea,vomiting, diarrhea, lossof appetite, skin rashes,aching joints and muscles,neuropathy.

Rare: Severe cutaneoushypersensitivity (includingStevens–Johnsonsyndrome), seizures, moodchanges, hepatitis, bonemarrow suppression.

Monitoring: No routinelaboratory monitoringis indicated.

Comments:Contraindicated inHIV-infectedindividuals because of arisk of serious adversereactions (Stevens–Johnson syndrome anddeath); persons of Asiandescent also have a higherincidence of Stevens–Johnson syndrome; rarelyused in MDR-TBtreatment.

From Seung and Rich 2010; Curry International Tuberculosis Center & California Department of Public Health 2012;

Partners In Health 2013.

CNS, central nervous system; ECG, electrocardiogram; RR, relative risk; IV, intravenously; MAC, Mycobacterium avium

complex.

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REGIMEN DESIGN

One of the most important steps in designing anMDR-TB regimen is taking a detailed history ofpast TB treatment. This is particularly impor-tant in patients who have received multiple treat-ment courses with first- or second-line anti-TBdrugs, as there may be omissions or errors in thewritten medical record. As a general rule, anydrug that has been used in a regimen that didnot cure the patient should be considered un-likely to still be effective, even if a recent DSTindicates that the patient’s strain is still suscep-tible. For example, if the patient previously usedethambutol or pyrazinamide as part of a failedfirst-line regimen, neither of these drugs shouldbe considered likely to be effective.

All DSTresults should be compared careful-ly with the clinical history; DST can be incorrectlike any laboratory test. Only DST to first-lineanti-TB drugs, injectables, and fluoroquino-lones is considered reliable. Laboratory resis-tance to pyrazinamide, ethionamide, or PAS,combined with a history of use in a failing reg-imen, however, strongly suggests the drug is in-effective.

At least four second-line anti-TB drugs likelyto be effective should be included in the MDRregimen. All regimens should include a later-generation fluoroquinolone such as levofloxacinor moxifloxacin (Johnson et al. 2006; Peloquinet al. 2008), a second-line injectable drug, andother oral second-line drugs as shown in Figure3 (Mukherjee et al. 2004). Pyrazinamide mayalso be included unless there is a contraindica-tion (such a historyof a drug allergy) orevidencethat it is not likely to be effective against thepatient’s strain (a clear history of failing to re-spond to a pyrazinamide-including regimenand DST indicating resistance) (Mitnick et al.2003). Pyrazinamide is often routinely includedin MDR regimens in resource-limited settingsbecause DST to pyrazinamide is often not avail-able. These recommendations are supported bya large meta-analysis of individual data frommore than 9000 patients (Ahuja et al. 2012).

Dosing of anti-TB drugs is based on theweight of the patient. For simplicity, commonlyused dosing tables use only a few weight bands.

When adults gain weight or move into a higherweight band, drug doses should be adjusted.Even though anti-TB drugs are generally ad-ministered once a day to improve peak-depen-dent killing, many of the second-line anti-TBdrugs have severe side effects that can be reducedby twice-daily divided dosing. For example, eth-ionamide and cycloserine are traditionally givenin two divided doses to reduce side effects, butonce-daily dosing is acceptable if tolerated.

In the case of XDR-TB, the same approachfor designing a regimen may be used, with someimportant caveats. In chronic patients with ahistory of multiple failed courses of treatment,a minimum of four likely effective second-lineanti-TB drugs may not be available. The XDRregimen may then include drugs that are resis-tant on DST but have never been used or drugsthat have been used but are still susceptible onDST. Many clinicians will use a later-generationfluoroquinolone such as moxifloxacin despitedocumented resistance to an early generationfluoroquinolone such as ofloxacin.

If there is an injectable drug that is still likelyto be effective, many clinicians will try to useit for a longer duration, such as 12 mo or eventhe entire duration of treatment. New drugswith demonstrated efficacy such as bedaquilineor delamanid should be strongly considered, aswell as resective surgery in patients with local-ized disease.

According to provisional guidance from theUnited States Centers for Disease Control andPrevention (CDC) and WHO, bedaquiline maybe used for MDR-TB patients in whom treat-ment options are limited (CDC 2013; WHO2013c). Bedaquiline should be added to a con-ventional MDR or XDR regimen designed asabove. There are still many uncertainties aboutthe risks and benefits of bedaquiline (Table 1).Bedaquiline may be used to treat strains withXDR or fluoroquinolone resistance. Bedaqui-line may also have a role when the injectabledrug is causing toxicity (such as ototoxicity ornephrotoxicity) that requires its suspension orwhen there is resistance to all second-line in-jectable drugs. Bedaquiline should be adminis-tered within a program that has the capacity toclosely monitor for side effects. Delamanid has

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no international recommendations or pub-lished drug insert at the time of this writing.

DURATION AND MONITORINGOF TREATMENT

The injectable should be continued for at least 8mo and at least 4 mo after the patient becomes

culture-negative, whichever is longer. Cliniciansmay use an individualized approach that reviewsthe cultures, smears, X-rays, and clinical statusto decide how long to continue the injectable.With respect to the duration of the injectable,however, the limiting factor is often toxicity. Oneoption is intermittent dosing of the injectable.Many patients have less nephrotoxicity or oto-

Choose a drug based on DSTand treatment history. Strepto-mycin is generally not used be-cause of high rates of resistancein patients with MDR-TB.

Add a later-generation fluoro-quinolone. If Ofx resistance issuspected or documented, useMfx.

Add Group 4 drugs until theregimen has at least foursecond-line drugs likely tobe effective (all three may beneeded). Choice is based ontreatment history and side effectprofile. DST is not fully reliablefor the drugs in this group.

Z is routinely added except ifthe patient is intolerant or ifresistance is highly likely basedon history and DST.

If the criteria of being a “likelyeffective drug” for E are met, itcan be added to the regimen(but not counted as a core drugin the regimen).

Group 2:Kanamycin (or amikacin)Capreomycin

Group 3:LevofloxacinMoxifloxacin

Group 4:Ethionamide (or prothionamide)CycloserinePara-aminosalicylic acid

Choose an injectable drug

Choose a fluoroquinolone

Step 1

Plus at least two Group 4 drugsStep 3

Add Group 1 drugsStep 4

Consider Group 5 drugsStep 5

Step 2

Group 1:PyrazinamideEthambutol

Group 5:BedaquilineLinezolidClofazimineAmoxicillin/clavulanic acidHigh-dose isoniazidlmipenem/cilastatin

If there are not four second-lineanti-TB drugs that are likely tobe effective from Groups 2–4,add at least two Group 5 drugs.

Figure 3. Designing an MDR-TB regimen. (Created from data in Varaine and Rich 2013.)

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toxicity if the injectable is given three times aweek (e.g., Monday, Wednesday, and Friday)compared with daily. For this reason, some cli-nicians routinely choose to switch to an inter-mittent schedule after the patient becomes cul-ture-negative even if there is no toxicity.

MDR-TB treatment should continue for aminimum of 20 mo and at least 18 mo after thepatient becomes culture-negative, whichever islonger. Chronic patients with extensive pulmo-nary disease may require MDR-TB treatmentfor 24 mo or longer, but there is limited evi-dence about the optimal length of treatmentfor patients with XDR-TB.

The previous recommendations about theduration of the injectable and of treatment aresupported by the meta-analysis of individualdata from more than 9000 patients, but thereis controversy about the optimal length of treat-ment. One study showed that a 9-mo treatmentregimen was sufficient to affect cure in a smallcohort of patients in Bangladesh (Van Deunet al. 2010). This particular regimen is currentlythe subject of a multisite clinical trial.

Sputum cultures should be performedmonthly during treatment. Other symptomsand signs are important, but they cannot be

relied on to determine treatment failure orcure. Programs with very limited culture capac-ity may consider doing smears monthly andcultures every other month after the injectablehas been discontinued, but this may delay iden-tification of treatment failure.

MANAGEMENT OF SIDE EFFECTS

Second-line anti-TB drugs have many more sideeffects than first-line anti-TB drugs. Side effectsare expected as part of the normal course oftreatment, and it is the responsibility of the cli-nician to diagnose and manage them. Mis-management of side effects is the major reasonwhy patients do not adhere or continue to takeMDR-TB treatment.

Even before starting treatment, the patientshould receive education regarding potentialside effects. During treatment, patients shouldbe evaluated regularly by a clinician. Commu-nity health workers can be trained to screen forside effects between clinical evaluations. Labo-ratory testing can be helpful in screening forsome side effects; a typical monitoring scheduleis shown in Table 2.

Table 2. Follow-up schedule for uncomplicated MDR-TB patients

Month

Clinical

consult Weight Smear Culture DST

Chest

X-ray LFT Cr, K TSH

0 (baseline)p p p p p p p p

1 Every 2 wkp p p p

2 Every 2 wkp p p p

3 Every 2 wkp p p p p

4p p p p

If culture posp

5p p p p p

6p p p p

If culture posp p

7p p p p p

8p p p p

If culture posp

9p p p p

If on inj.10

p p p pIf culture pos If on inj.

11p p p p

If on inj.12

p p p pIf culture pos If on inj.

p

Until completionp

Monthly Monthly Monthly If culture pos If on inj. Every 6mo

From Partners in Health 2013.

DST, drug susceptibility testing; pos, positive; LFT, liver function test; Cr, creatinine, K, potassium; TSH, thyroid-

stimulating hormone; inj., injectable.

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Mild side effects are common, and can bemanaged symptomatically with ancillary drugswithout altering the treatment regimen. Side ef-fects often diminish or disappear with time, al-lowing patients to finish their treatment withoutfurther problems. A numberof second-line anti-TB drugs have highly dose-dependent side ef-fects. With cycloserine and ethionamide, forexample, a patient may be completely intolerantat one dose and completely tolerant at a slight-ly lower dose. Unfortunately, given the narrowtherapeutic margins of these drugs, lowering thedose may also affect efficacy. Reducing the doseof these drugs should be performed only in casesin which the reduced dose is still expected toproduce adequate serum levels and not compro-mise the regimen.

A poorly tolerated drug may be temporarilysuspended. In patients with highly resistant TB,however, a satisfactory replacement drug maynot be available. In such cases, permanent dis-continuation of the drug should be avoidedif possible. The decision to suspend any drugshould be made by weighing the risk of contin-ued side effects against the chances of curing adeadly disease.

† Gastrointestinal distress is a common sideeffect of MDR-TB treatment, caused by PASand ethionamide. Nausea and vomiting arecommon in early weeks of therapy but usu-ally improve over time and with supportivetherapy.

† Nephrotoxicity is a known complication ofthe aminoglycosides and capreomycin. Be-cause symptoms of acute renal failure canbe nonspecific, serum creatinine monitoringis recommended. Patients with advancedage or a history of renal disease (includingcomorbidities such as HIV and diabetes)should be monitored more closely, particu-larly at the start of treatment.

† Electrolyte wasting with similar characteris-tics to Fanconi’s Syndrome can be inducedby all of the injectable drugs. It is reversibleonce the injectable is suspended, but it maytake weeks or months to be resolved com-pletely. Because electrolyte wasting is gener-

ally managed with electrolyte replacementtherapy, serum potassium should be checkedat least monthly in all patients during theinitial injectable phase.

† Hypothyroidism can be induced by pro-longed exposure to PAS or ethionamide/prothionamide. The exact incidence of hypo-thyroidism during MDR-TB treatment isunknown, but rates of up to 80% have beenreported in some patient populations. Be-cause symptoms are nonspecific, all patientsshould be screened for hypothyroidismstarting after the third month of MDR-TBtreatment.

† Neurotoxic effects such as psychosis or de-pression can be caused by cycloserine. Clini-cians should screen patients for abnormalbehavior and symptoms of depression, anx-iety, and agitation on a regular basis.

† Ototoxicity can be caused by the injectables,which can cause damage to cranial nerveVIII. This may result in hearing loss, tinni-tus (ringing in the ear), or other vestibularsymptoms such as nystagmus, ataxia, anddisequilibrium. Hearing loss is generallynot reversible on discontinuation of therapy.Hearing and balance should be assessed atleast monthly while the patient is receiv-ing the injectable. Where available, audiom-etry should be performed monthly and isan excellent way of detecting early hearingloss.

RESECTIVE SURGERY

Lung resection was once a mainstay of TB treat-ment but disappeared almost completely onceeffective chemotherapy was discovered. Therehas been a resurgence of interest in resectivesurgery as an adjunct to MDR-TB chemother-apy, which is much less effective. For patientswith localized disease, resection of a lobe or alung can significantly improve outcome (Pom-erantz et al. 2001; Somocurcio et al. 2007). Ex-perienced thoracic surgeons, stringent infectioncontrol measures, and excellent pre- and post-operative care are necessary; resective surgery

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for TB is often more complicated than for otherdiseases.

The most important indication for resec-tive surgery is lack of a sustained bacteriologicalresponse to chemotherapy. Computerized to-mography (CT) is the best way to assess if thereis a localized lesion that is amenable to resec-tion. Patients with bilateral cavitary disease, forexample, would not be good surgical candi-dates. Pulmonary function testing with predict-ed postoperative forced expiratory volume inone second (FEV1) can be helpful to evaluateif the patient has sufficient pulmonary reservepostresection.

Another type of surgical candidate isthose who have experienced culture conversionthrough chemotherapy, but who are thoughtto have a high probability of future failure orrelapse caused by a high level of resistance. Sur-gical resection can also be considered for com-plications of MDR-TB, such as massive hemop-tysis, empyema, or aspergilloma.

In patients who are smear- or culture-posi-tive at the time of surgery, treatment is contin-ued for minimum of 18 mo of negative sputumcultures, and generally includes an extended pe-riod of injectable. In patients who are smear-and culture-negative at the time of surgery,treatment should be continued for a minimumof 18 mo after culture conversion and no lessthan 6 mo after surgery.

SPECIAL SITUATIONS

Extrapulmonary MDR-TB

There is limited evidence about treatment ofextrapulmonary MDR-TB. In general, everyeffort should be made to obtain tissue or fluidsamples to confirm the diagnosis of MDR-TB,as the clinical or radiological picture may bedeceptive. The length of therapy has not beenclearly defined but should likely be at least aslong as treatment for pulmonary MDR-TB.

† MDR-TB lymphadenitis. Lymph node aspira-tion followed by culture-based or molecularDST is a simple way to confirm the diagnosisand can be useful in guiding therapy.

† MDR-TB osteomyelitis and spondylitis. Bonebiopsy or sampling of paravertebral fluid col-lections should be attempted to obtain ma-terial for DST. Persistent or increasing fluidcollections on CT despite treatment withfirst-line anti-TB drugs may be sufficient ev-idence for empiric MDR-TB treatment insome patients with other bacteriological ev-idence of TB. Operative intervention, eitherthrough open debridement or by percutane-ous drainage of fluid collections, is often re-quired in combination with drug therapy.

† MDR-TB meningitis. Diagnosis of MDR-TBmeningitis may be difficult because myco-bacterial concentration in cerebrospinal fluidcan be very low. Treatment of a patient withMDR-TB meningitis is complicated becausemany second-line drugs do not have goodpenetration into the cerebrospinal fluid.

Children

Most children with MDR-TB have been infectedby someone in the same household (Becerraet al. 2013). For this reason, careful investigationof family members is crucial. If it is difficult tocollect a specimen from the child for laboratoryanalysis for whatever reason, the regimens canbe designed based on the DSTof the index casein the same household. Otherwise, the basicprinciples of regimen design for children withMDR-TB are no different than those for adults.Children generally tolerate second-line anti-TBdrugs well. Pediatric formulations, however, donot exist for most drugs, and it is often neces-sary prepare adult formulations, for example, bysplitting tablets (The Sentinel Project 2012;Garcia-Prats et al. 2013; Varaine and Rich 2013).

Pregnant Women

Some second-line anti-TB drugs are known tocause birth defects. For this reason, all womenof childbearing age should be strongly advisedto use a reliable method of contraception dur-ing MDR-TB treatment. For pregnant womenwho are diagnosed with MDR-TB, the benefit oftreating MDR-TB in pregnancy in most cir-

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cumstances outweighs the risks. Most patientsshould start treatment as soon as the diagnosis ismade. Aminoglycosides can be particularly tox-ic to the developing fetal ear. Capreomycinmay also carry a risk of ototoxicity but may beused if an injectable is absolutely necessary. Eth-ionamide is also usually avoided as it can in-crease the risk of nausea and vomiting associat-ed with pregnancy, and teratogenic effects havebeen observed in animal studies. MDR regimensfor pregnant women may be designed with threeor four oral second-line anti-TB drugs plus pyr-azinamide. The regimen can then be reinforcedwith an injectable and other drugs immediatelypostpartum. The risk of birth defects in MDR-TB treatment is highest in the first trimester ofpregnancy, so the gestational age of the fetusshould be carefully confirmed, preferably bydating using ultrasound. In rare cases, in whichthe mother does not accept the risks of the treat-ment and is clinically stable, treatment can bedelayed until the second trimester.

HIV Coinfection

People living with HIV are vulnerable to MDR-TB infection and are at high risk of develop-ing active MDR-TB once infected. HIV-positivepatients often die while waiting for laboratoryconfirmation of MDR-TB and before startingeffective therapy. This was best illustrated bythe rapid and deadly spread of XDR-TB amongHIV-positive patients in South Africa (Gandhiet al. 2006). The WHO currently recommendsXpert MTB/RIF as the initial diagnostic test insettings with high prevalence of HIV-associatedTB or MDR-TB (WHO 2011b).

Early identification and prompt initiationof appropriate treatment can reduce mortalityamong HIV-infected patients infected withMDR-TB. ART improves survival in MDR-TBpatients infected with HIV and should be start-ed as soon as possible, as early as the first weekafter starting MDR-TB treatment. Stavudineand tenofovir are often avoided because of over-lapping toxicities (neuropathy and nephro-toxicity, respectively) with second-line anti-TBdrugs; nonetheless, cotreatment with ART isstill challenging in most patients because of

side effects and the high pill burden. HIV-pos-itive patients seem to experience a higher inci-dence of side effects with second-line anti-TBdrugs (Seung et al. 2009).

COMMUNITY-BASED CARE FOR MDR-TB

MDR-TB may be hospital-, clinic-, or commu-nity-based. These approaches may not be mu-tually exclusive, and in fact, they may all be usedwithin the same program. In some settings, pa-tients are hospitalized at the beginning of treat-ment to allow for more intensive monitoring ofside effects, especially for patients who are phys-ically debilitated. But in many countries, thelack of MDR-TB hospital beds becomes a bot-tleneck to scale-up. Mandatory hospitalizationmay also exacerbate nosocomial transmission ofMDR-TB because in many settings, infectioncontrol measures are not adequate.

Many countries have moved to decentralizeMDR-TB treatment to increase access. Onecommon method is to provide DOTat a prima-ry care clinic. This strategy can be quite physi-cally and economically burdensome to the pa-tient because it requires daily travel to the clinic,sometimes twice daily. This is especially true inrural areas where primary care systems are weak.

Community-based MDR-TB treatment al-lows patients to be treated in their homes. Byproviding a flexible and convenient solution, itpromotes patient adherence and reintegrationinto family, social, and work life. It can be fullysupervised by a nurse or community healthworker during daily home visits. Community-based care reduces cost in the health system andcan be more cost-effective than hospital care,but in many ways, it is more challenging to im-plement. Each dose is administered underDOT, often through a system of a compensated,trained, and well-supervised nurse or commu-nity health workers.

Another important aspect of MDR-TBtreatment is addressing socioeconomic determi-nants of health. Socioeconomic problems, in-cluding hunger, homelessness, and unemploy-ment, are common among MDR-TB patients.These problems have been successfully tackledthrough socioeconomic interventions that in-

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clude the use of provisions in the form of “in-centives” and “enablers.” Incentives are rewardsthat encourage patients to adhere to treatment,such as food packages, whereas enablers aregoods or services that make it easier for patientsto adhere to treatment, such as transportationvouchers. Addressing socioeconomic barriers toadherence is a crucial part of successful MDR-TB treatment (USAID 2011).

CONCLUSION

The continuing spread of MDR-TB is one ofthe most urgent and difficult challenges fac-ing global TB control. The main causes of theincreasing spread of resistant TB strains areweak medical systems, amplification of resis-tance through incorrect treatment, and ongo-ing transmission in communities and facilities.New molecular methods of DST have revolu-tionized the diagnosis of MDR-TB, but theyare still not widely available in resource-limitedsettings. Although patients harboring MDR andXDR strains present a formidable challenge fortreatment, cure is often possible with early iden-tification of resistance and use of a properly de-signed regimen. Community-based programscan improve treatment outcomes by allowingpatients to be treated in their homes and ad-dressing socioeconomic barriers to adherence.

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K.J. Seung et al.


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27, 20152015; doi: 10.1101/cshperspect.a017863 originally published online AprilCold Spring Harb Perspect Med

Kwonjune J. Seung, Salmaan Keshavjee and Michael L. Rich TuberculosisMultidrug-Resistant Tuberculosis and Extensively Drug-Resistant

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