Multidrug-Resistant Tuberculosis

CHEST

Global Medicine

Multidrug-Resistant Tuberculosis* A Menace That Threatens To Destabilize Tuberculosis Control Surendra K. Sharma, MD, PhD, FCCP; and Alladi Mohan, MD

Multidrug-resistant tuberculosis (MDR-TB), caused by Mycobacterium tuberculosis that is resistant to both isoniazid and rifampicin with or without resistance to other drugs, is a phenomenon that is threatening to destabilize global tuberculosis (TB) control. MDR-TB is a worldwide problem, being present virtually in all countries that were surveyed. According to current World Health Organization and the International Union Against Tuberculosis and Lung Disease estimates, the median prevalence of MDR-TB has been 1.1% in newly diagnosed patients. The proportion, however, is considerably higher (median prevalence, 7%) in patients who have previously received anti-TB treatment. While host genetic factors may contribute to the development of MDR-TB, incomplete and inadequate treatment is the most important factor leading to its development, suggesting that it is often a man made tragedy. Efficiently run TB control programs based on a policy of directly observed treatment, short course (DOTS), are essential for preventing the emergence of MDR-TB. The management of MDR-TB is a challenge that should be undertaken by experienced clinicians at centers equipped with reliable laboratory services for mycobacterial cultures and in vitro sensitivity testing as it the requires prolonged use of costly second-line drugs with a significant potential for toxicity. The judicious use of drugs; supervised standardized treatment; focused clinical, radiologic, and bacteriologic follow-up; and surgery at the appropriate juncture are key factors in the successful management of these patients. With newer effective anti-TB drugs still a distant dream, innovative approaches such as DOTS-Plus are showing promise for the management of patients with MDR-TB under program conditions and appear to be a hope for future. (CHEST 2006; 130:261–272) Key words: diagnosis; epidemiology; multidrug-resistant tuberculosis; predictors for development; prognostic factors; treatment; tuberculosis Abbreviations: ADR ⫽ adverse drug reaction; CDC ⫽ Centers for Disease Control and Prevention; DOTS ⫽ directly observed treatment, short-course; MDR-TB ⫽ multidrug-resistant tuberculosis; PCR ⫽ polymerase chain reaction; RFLP ⫽ restriction fragment length polymorphism; TB ⫽ tuberculosis; WHO ⫽ World Health Organization

(TB) is a medical, social, and ecoT uberculosis nomic disaster of immense magnitude that is

occurring the world over.1 Strains of Mycobacterium tuberculosis that are resistant to both isoniazid and rifampicin with or without resistance to other drugs have been termed multidrug-resistant strains. Isoniazid and rifampicin are keystone drugs in the man*From the Division of Pulmonary and Critical Care Medicine (Dr. Sharma), Department of Medicine, All India Institute of Medical Sciences, New Delhi, India; and the Division of Pulmonary and Critical Care Medicine (Dr. Mohan), Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, India. Drs. Sharma and Mohan have no financial interests in the subject of this article and no conflicts of interest to report. www.chestjournal.org

agement of TB. While resistance to either isoniazid or rifampicin may be managed with other first-line drugs, multidrug-resistant TB (MDR-TB) demands treatment with second-line drugs that have limited Manuscript received January 31, 2006; revision accepted March 31, 2006. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Surendra K. Sharma, MD, PhD, FCCP, Chief, Division of Pulmonary and Critical Care Medicine, Professor and Chairman, Department of Medicine, All India Institute of Medical Sciences, New Delhi 110 029, India; e-mail: [email protected] DOI: 10.1378/chest.130.1.261 CHEST / 130 / 1 / JULY, 2006

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sterilizing capacity, and are less effective and more toxic. MDR-TB is one of the most worrisome elements of the pandemic of antibiotic resistance.2,3 Resistance to anti-TB drugs is usually described in terms of “resistance among new cases” and “resistance among previously treated patients.”4 The term susceptible strains refers to those strains that have not been exposed to the first-line anti-TB drugs and respond to these drugs in a uniform manner. The term resistant strains refers to those strains that differ from the sensitive strains in their capacity to grow in the presence of a higher concentration of a drug.3

Epidemiology Though published studies from the developing world have suggested that drug resistance was a potential problem,3 it was the emergence of MDR-TB in the United States in the 1990s that attracted the attention.5,6 The global extent of the problem of drug-resistant TB is evident from the three rounds of surveys coordinated by World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease between 1996 and 2002. The third round of surveys7 included new data from 77 settings or countries that were collected between 1999 and 2002. Among new cases (Fig 1, top, A), the prevalence of MDR-TB (median,1.1%) ranged from 0% in eight countries to 14.2% in Kazakhstan (51 of 359 patients) and Israel (36 of 253 patients). Among previously treated cases (Fig 1, bottom, B), the median prevalence of MDR-TB was 7.0%. In the latest survey,7 as in the two previous surveys, MDR-TB was found in all regions of the world. The prevalence of MDR-TB was exceptionally high in almost all countries from the former Soviet Union that were surveyed, including Estonia, Kazakhstan, Latvia, Lithuania, the Russian Federation, and Uzbekistan. High prevalences of MDR-TB were also found among new cases in China (Henan and Liaoning provinces), Ecuador, and Israel. Central Europe and Africa, in contrast, reported the lowest median levels of drug resistance. Recent estimates8 from 184 countries suggest that an estimated 458,000 new cases of MDR-TB occurred worldwide in 2003, with 276,000 of those cases (60%) reported from high-burden countries China and India constituting 3.2% of all new TB cases. However, it should be remembered that increases in the prevalence of resistance can be caused by poor or worsening TB control, the immigration of patients from areas of higher resistance, outbreaks of drugresistant disease, and variations in surveillance methodologies.3 262

Molecular Basis of Drug Resistance Spontaneous chromosomally borne mutations occurring in M tuberculosis at a predictable rate are thought to confer resistance to anti-TB drugs.3,9 A characteristic feature of these mutations is that they are unlinked. A TB cavity usually contains 107 to 109 bacilli. If mutations causing resistance to isoniazid occur in about 1 in 106 replications of bacteria, and the mutations causing resistance to rifampicin occur in about 1 in 108 replications, the probability of spontaneous mutations causing resistance to both isoniazid and rifampicin would be 106 ⫻ 108 ⫽ 1 in 1014 replications.3 Given that this number of bacilli cannot be found even in patients with extensive cavitary pulmonary TB, the chance of the development of spontaneous dual resistance to rifampicin and isoniazid is practically remote.3,9 Table 1 lists the perturbations in the individual drug target genes that are responsible for the genesis of anti-TB drug resistance.3,9 Rifampicin resistance has been shown to be caused by an alteration of the ␤-subunit of RNA polymerase, which is encoded by the rpo␤ gene. More than 95% of rifampicin-resistant strains are associated with mutations within an 81-base pair region of the rpo␤ gene, which is termed the rifampicin resistance determinant region.10 On the contrary, resistance to isoniazid is more complicated, as mutations in several genes10,11 can lead to drug resistance (Table 1). While certain mutations are widely present, pointing to the magnitude of the polymorphisms at these loci, others are not common, suggesting diversity in the multidrug-resistant M tuberculosis strains that are prevalent in the given region. Furthermore, rifampicin resistance has been considered to be a surrogate marker for checking multidrug resistance in clinical isolates of M tuberculosis since rifampicin resistance is often accompanied by resistance to isoniazid.12 Potential Causes of Drug Resistance Following factors have been implicated in the causation of MDR-TB.3,13 Factors Related to Previous Treatment In most of the published studies, a history of TB and anti-TB treatment have been implicated in the causation of MDR-TB.3,14 –17 Incomplete and Inadequate Treatment: A review of the published literature strongly suggests that the most powerful predictor of the presence of MDR-TB is a history of treatment of TB (Table 2). Global Medicine

Figure 1. Top, A: prevalence of MDR-TB in new cases from 1994 to 2002. Bottom, B: prevalence of MDR-TB in previously treated cases from 1994 to 2002. Reproduced with permission from World Health Organization, International Union Against Tuberculosis and Lung Disease.7

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Table 1—Antituberculosis Drugs and the Genes Involved in Their Resistance Drug

Genes Involved in Drug Resistance

Isoniazid

Enoyl acyl carrier protein (acp) reductase (inhA) Catalase-peroxidase (katG) Alkyl hydroperoxide reductase (ahpC) Oxidative stress regulator (oxyR) ␤-Ketocyl acyl carrier protein synthase (kasA) Rifampicin RNA polymerase subunit B (rpoB) Pyrazinamide Pyrazinamidase (pncA) Streptomycin Ribosomal protein subunit 12 (rpsL) 16s ribosomal RNA (rrs) Aminoglycoside phosphotransferase gene (strA) Capreomycin Haemolysin (tlyA)* Ethambutol Arabinosyl transferase (emb A, emb B, and emb C) Fluoroquinolones DNA gyrase (gyr A and gyr B) *The tlyA gene in M tuberculosis encodes a 268-amino acid polypeptide, which shows striking similarity to a haemolysin/cytotoxin, tlyA, from the spirochete Serpulina hyodysenteriae.

Errors in TB management such as the use of single drug to treat TB, the addition of a single drug to a failing regimen, the failure to identify preexisting resistance, the initiation of an inadequate primary regimen, the failure to identify and address nonadherence to treatment, inappropriate isoniazid preventive therapy, and variations in the bioavailability

Table 2—Causes of Inadequate Treatment* Causes

Description

Lack of political commitment Providers/programs: Inappropriate guidelines inadequate regimens Noncompliance with available guidelines Absence of guidelines Poor training No monitoring of treatment Poorly organized or funded TB control programs Drugs: inadequate Poor quality supply/quality Unavailability of certain drugs (stockouts or delivery disruptions) Poor storage conditions Wrong dose or combination Patients: inadequate Poor adherence (or poor direct drug intake observation of treatment) Lack of information Lack of money (No free treatment available) Lack of transportation Side effects Social barriers Malabsorption Substance abuse disorders *Adapted and reproduced with permission from Central TB Division, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India.17 264

of anti-TB drugs predispose the patient to the development of MDR-TB.18 Inadequate Treatment Adherence: Nonadherence to prescribed treatment is often underestimated by the physician and is difficult to predict. In the West, demographic factors such as age, sex, marital status, education level, and socioeconomic status have not been found to correlate with the degree of treatment adherence. On the other hand, certain factors such as psychiatric illness, alcoholism, drug addiction, and homelessness do predict nonadherence to treatment.3 The directly observed treatment, shortcourse (DOTS) strategy, which has been endorsed by the WHO as the only effective way to control TB, has to some extent addressed these problems.4,18 In India, innovative measures such as public-private mix and the use of Anganwadi workers have been tried out under program conditions to improve treatment adherence in patients with TB in general, and these measures would help patients with MDR-TB also. The reader can find more details on this topic at the Web site http://www.tbcindia.org. Logistic Issues Good, reliable laboratory support is seldom available in developing nations. When facilities for growing cultures and sensitivity testing are not available, therapeutic decisions are most often made by algorithms or inferences from previous treatment.19 While DOTS has been shown to reduce the transmission and incidence of both drug-susceptible and drug-resistant TB even in settings with moderate rates of MDR-TB,20 it has been observed that the “programmatic approach” to the management of patients who do not respond to treatment may fail in certain settings.21,22 First-line therapy may not be sufficient in settings with a high degree of resistance to anti-TB drugs.21 Although the DOTS strategy is the basis of good TB control, the strategy should be modified in some settings to identify drug-resistant cases sooner and to make use of second-line drugs in appropriate treatment regimens.5,23 Virulence of the Organism Substantial progress has been made in the understanding of the molecular epidemiology of tubercle bacilli with the availability of genome sequence data in the public domain (available at http:www.cdfd.org.in/ amplibase; http://www.cdc.gov/ncidod/EID/vol7no3/ sola_data.htm; and https://hypocrates.rivm.nl/bnwww/ IS6110-RFLP-bands.htm). Phylogenomic analysis suggests that the “ancient strains” of M tuberculosis may have undergone adaptive evolution as a result of selection at many loci.23 Global Medicine

Extrapolating data on the virulence and survival capability of isoniazid-resistant strains to multidrugresistant strains of M tuberculosis, it has been assumed that multidrug-resistant isolates have lower virulence and survival capability.3 It has been observed that emergence of multidrug resistance may result in the organism becoming unusually fit to survive. This is exemplified by a genotype, which was first described in 1995, known as the W-Beijing family. Published reports24,25 have suggested that W-Beijing genotype is highly prevalent in some regions of Asia and Eastern Europe such as Estonia, Azerbaijan, and Russia. The strains belonging to the W-Beijing family have been shown to exhibit a constant spoligotype and high degrees of similarity among IS6110 restriction fragment length polymorphism (RFLP), polymorphic GC-rich sequence RFLP, and variable numbers of tandem repeats profiles. W-Beijing genotype is well-known for its rapidity of spread and tenacity, and notably for its strong association with multidrug resistance.24,25 Given that the Beijing strain has already made its appearance in India where 20% of the TB patients in the world are located, the consequences can be disastrous.26 However, caution must be exercised while interpreting these data as these observations need to be validated in multiple settings before definitely linking the clone to the given host population.23

Associations among HLA-DRB1*1, DRB1*14,29 and HLA-DRB1*0803 haplotypes,30 and the susceptibility to MDR-TB suggests that these loci or the alleles linked with them play a permissive role in conferring increasing susceptibility to the development of MDR-TB. These issues merit further study. HIV Infection A review of the published literature2,3 suggests that, in the early 1990s, several institutional outbreaks of MDR-TB among HIV-infected patients drew attention to the problem. Current evidence suggests that HIV infection per se does not appear to be a predisposing factor for the development of MDR-TB. Some studies31,32 have found that MDR-TB is not more common among people infected with HIV. However, increased susceptibility to TB, increased opportunity to acquire TB due to overcrowding, exposure to patients with MDR-TB due to increased hospital visits, and malabsorption of anti-TB drugs resulting in suboptimal therapeutic blood levels despite strict adherence to the treatment regimen potentially increase the chances of MDR-TB occurring in persons with HIV/AIDS, if not adequately addressed.3 Diagnosis of MDR-TB Conventional Methods

Multidrug Transporters Multidrug transporters mediate both intrinsic and acquired resistance to various drugs.27 P-glycoprotein is a human analog of these multidrug transporters and is expressed on immune effector cells. The infection of experimental cell lines by M tuberculosis results in the increased expression of P-glycoprotein and the decreased accumulation of isoniazid inside the cells. Apart from the up-regulation of host cell P-glycoprotein, M tuberculosis per se expresses at least three multidrug transporter proteins such as Tap, Lfr A, and Mmr.3,27 Evidence is available demonstrating a clear association between multidrug resistance and transcription levels of a Tap-like pump (Rv1258c) and the overexpression of an efflux protein.28 The potential contribution of these multidrug transporter proteins in the causation of MDR-TB merits further evaluation. They also appear to be novel targets for drug therapy in the future. Host Genetic Factors Though there is some evidence to postulate host genetic predisposition as the basis of the development of MDR-TB, it has not been conclusive.29,30 www.chestjournal.org

Traditionally, Lowenstein-Jensen culture has been used for drug sensitivity testing using (1) the absolute concentration method, (2) the resistance ratio method, and (3) the proportion method.3 With the conventional methods, a duration of 6 to 8 weeks is required before sensitivity results are known. Newer Methods Several newer methods have been developed to document anti-TB drug resistance faster. Most of these methods are expensive and are not available in the field setting. Radiometric methods (eg, BACTEC-460; Becton-Dickinson; Franklin Lakes, NJ) have been developed for rapid drug-susceptibility testing of M tuberculosis by which results are available within 10 days.3,33 The mycobacteria growth indicator tube system (Becton-Dickinson) is a rapid, nonradioactive method for the detection and susceptibility testing of M tuberculosis.3,33 Ligase chain reaction facilitates the detection of a mismatch of even one nucleotide.3,33 Luciferase reporter assay is a reporter gene assay system for the rapid determination of drug resistance that can identify most strains within 48 h.3,33 As rifampicin resistance is considered to be a surrogate marker for MDR-TB, CHEST / 130 / 1 / JULY, 2006

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techniques such as a rapid bacteriophage-based test (FASTPlaqueTB-RIF; Biotec Laboratories; Ipswich, UK) that is used to identify rifampicin susceptibility in clinical strains of M tuberculosis after growth in a semi-automated liquid culture system (BACTEC460; Becton-Dickinson) have also shown potential to diagnose MDR-TB.14,34 Polymerase chain reaction (PCR)-based sequencing has often been employed to understand the genetic mechanisms of drug resistance in patients with M tuberculosis.3,33–35 RFLP patterns have been used to categorize and compare isolates of M tuberculosis.35 As the DNA fingerprints of M tuberculosis have been observed not to change during the development of drug resistance, RFLP analysis has also been used to track the spread of drug-resistant strains.35 Molecular markers for epidemiologic and evolutionary studies such as mycobacterial interspersed repeat units-variable number tandem repeats, fluorescent amplified fragment length polymorphism have been used to study the molecular epidemiology of M tuberculosis.14,36,37 Spoligotyping,

which is based on the variability in the direct-repeat locus of M tuberculosis, has been useful in detecting new outbreaks as well as in tracking TB epidemics.23 Molecular assays,14,38,39 such as heteroduplex and mismatch analyses, DNA sequencing, real-time PCR, molecular beacons, and line probe assays have all been used to screen for mutations that are responsible for the development of anti-TB drug resistance. Multiplex PCR, followed by hybridization on an oligonucleotide microarray,40 or low-density DNA oligonucleotide array (macroarray)10 have also been used to detect the DNA of M tuberculosis complex and to identify mutations associated with isoniazid and rifampicin resistance.

Management The treatment of MDR-TB is a challenge which should be undertaken by experienced clinicians at centers equipped with reliable laboratory service for mycobacterial culture and in vitro sensitivity test-

Table 3—Drugs Useful in the Treatment of MDR-TB* Drug

Daily Dosage

Aminoglycosides Streptomycin Kanamycin Amikacin Capreomycin†

15 15 15 15

Thioamides§ Ethionamide Prothionamide

10–20 mg/kg (500–750 mg) 10–20 mg/kg (500–750 mg)

mg/kg mg/kg mg/kg mg/kg

(750–1,000 (750–1,000 (750–1,000 (750–1,000

mg) mg) mg) mg)

Pyrazinamide Fluroquinolones

20–30 mg/kg (1,200–1,600 mg)

Ofloxacin Levofloxacin Ethambutol Cycloserine Terizodone㛳

7.5–15 mg/kg (600- 800 mg) 500–1000 mg 15–20 mg/kg (1,000–1,200 mg) 15–20 mg/kg (500–750 mg) 15–20 mg/kg (600 mg)

Para-aminosalicylic acid

150 mg/kg (10–12 g)

Adverse Drug Reactions Pain at injection site Ototoxicity (vertigo and deafness), nephrotoxicity, hemolytic anemia, aplastic anemia, agranulocytosis, thrombocytopenia, and lupoid reactions Hypokalemia, hypocalcemia and hypomagnesemia, cutaneous reactions, and occasionally hepatotoxicity‡; may potentiate the effect of neuromuscular blocking agents administered during anesthesia. Epigastric discomfort, anorexia, nausea, metallic taste and sulfurous belching, vomiting and excessive salivation; psychotic reactions including hallucinations and depression; hypoglycemia, hypothyroidism, and goiter; hepatotoxicity; gynecomastia, menstrual disturbance, impotence, acne, headache, and peripheral neuropathy; tolerance varies with ethnicity; usually well tolerated in Africa and Asia Hepatotoxicity, GI intolerance, hyperuricemia, and arthralgias Uncommon GI disturbance (eg, anorexia, nausea, and vomiting), CNS symptoms (eg, dizziness, headache, mood changes, and rarely convulsions)

Dose-dependent optic neuritis, and peripheral neuritis; Dizziness, slurred speech, and convulsions; Headache, tremor, insomnia, confusion, depression; and altered behavior; suicide risk; generalized hypersensitivity reaction or hepatitis. GI disturbance (eg, anorexia, nausea, vomiting, abdominal discomfort, and diarrhea); general skin or other hypersensitivity, and hepatic dysfunction; hypokalemia; hypothyroidism and goiter; best avoided in renal failure as it may exacerbate acidosis; sodium salt should not be given when a restricted sodium intake is indicated

*Adapted from Crofton et al19 and Blumberg et al.43 †No cross-resistance with other aminoglycosides such as kanamycin and streptomycin. ‡With capreomycin administration. §Chemical structure resembles thioacetazone, with which there is frequent and partial cross-resistance. However, strains that are resistant to thioacetazone are often sensitive to thioamides, but the reverse is seldom the case. Therapy is more acceptable if the drug is administered with orange juice or milk, after milk ingestion, or at bedtime to avoid nausea. 㛳Terizidone is a combination of two molecules of cycloserine. 266

Global Medicine

ing.3,41 In the early reports of outbreaks of MDR-TB in HIV-coinfected patients in hospitals and prisons, the mortality rate was very high (range, 72 to 89%).3 However, subsequent studies3 have documented decreased mortality and improvement in clinical outcome for both HIV-seropositive and HIV-seronegative patients with MDR-TB. Principles of Management When MDR-TB is suspected on the basis of history or epidemiologic information, the patient’s sputum must be subjected to culture and anti-TB drug-sensitivity testing. These patients may be started on WHO category II treatment42 (under program conditions) or the regimens employing various drugs (Table 4), such as those suggested by the American Thoracic Society, the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America43 pending sputum culture report. Further therapy is guided by the culture and sensitivity report. These guidelines clearly mention that a single drug should never be added to a failing regimen. Furthermore, when initiating treatment, at least three previously unused drugs must be employed to which there is in vitro susceptibility.19,43 These guidelines43 suggest that among the fluoroquinolone levofloxacin is best suited for the treatment of MDR-TB, given its good safety profile with long-term use. The results of a study44 of communitybased outpatient treatment of MDR-TB reported from Peru suggest that community-based outpatient treatment of patients with MDR-TB is possible with high cure rates even in resource-poor settings. Need for Standard Definitions No randomized controlled trials exist addressing the issue of the optimal management strategy for MDR-TB. As in the case with the DOTS strategy, the systematic study of the efficacy of DOTS-Plus regimens requires the standardization of definitions for MDR-TB case registration and treatment out-

comes. Such definitions would permit the accumulation of evidence and would facilitate cross-program comparisons. The reader is referred to the study by Laserson et al45 for these definitions. DOTS-Plus Strategy DOTS is a key ingredient in the TB control strategy. In populations in which MDR-TB is endemic, the outcome of the standard short-course regimen remains uncertain.13 As a consequence, there have been calls for well-functioning DOTS programs to provide additional services in areas with high rates of MDR-TB. In order to promote the programmatic treatment of MDR-TB in low-income and middle-income countries that have adopted the DOTS strategy, the WHO and its international partners have been evolving the “DOTS-Plus for MDR-TB programs” (Table 4) since 1998.13,41 The WHO has also established a unique partnership known as the Green Light Committee to lower the prices of and to increase control over second-line anti-TB drugs, and to date 35 DOTS-Plus projects are underway across the globe.46 – 49 The DOTS-Plus strategy of identifying and treating patients with MDR-TB appears to have the potential to be effectively implemented on a nationwide scale even in a setting with limited resources.17 The results from the retrospective study50 designed to assess treatment outcomes for the first full cohort of MDR-TB patients (n ⫽ 204), who were treated under the Latvian DOTS-Plus strategy following WHO guidelines, have been encouraging; 66% patients were cured or completed therapy, 7% died, 13% defaulted, and 14% did not respond to treatment. Data on adverse drug reactions (ADRs) collected from five DOTS-Plus sites in Estonia, Latvia, Peru (Lima), the Philippines (Manila), and the Russian Federation (Tomsk Oblast)51 showed that, among 818 patients enrolled for MDR-TB treatment, only 2% of patients stopped treatment and 30% required removal of the suspected drugs from the regimen and use of alternative drugs due to

Table 4 —Comparison of the Principles Underlying DOTS and the DOTS-Plus Strategies* DOTS Strategy Political and administrative commitment Good-quality diagnosis by sputum microscopy Uninterrupted supply of good-quality first-line drugs for standardized treatment through outpatient therapy Directly observed treatment Systematic monitoring and accountability

DOTS-Plus Strategy Sustained political and administrative commitment Accurate, timely diagnosis through quality-assured culture and drug susceptibility testing Uninterrupted supply of quality assured first and second-line drugs; appropriate treatment strategies utilizing second-line drugs under strict supervision Directly observed treatment Standardized recording and reporting system that enable performance monitoring and evaluation of treatment outcome

*DOTS-Plus is an integral component of the existing National Tuberculosis Control Program to be implemented through program infrastructure. www.chestjournal.org

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ADRs. These findings indicate that ADRs are manageable in the treatment of MDR-TB even in resource-limited settings provided that standardized management strategies are followed. Monitoring Response to Treatment Patients receiving treatment for MDR-TB should be closely followed up. Clinical, radiologic, laboratory, and microbiological parameters should be frequently reviewed to assess the response to treatment. Additionally, considerable attention must be focused on monitoring the ADRs.3 Prognostic Markers Table 5 summarizes markers of poor prognosis in patients with MDR-TB. Recognition of these factors may help clinicians to monitor the patients more closely and to correct remediable factors such as malnutrition.3,44,50,52–55 Newer Anti-TB Drugs Patients are 4 to 10 times more likely to not respond to the currently available drugs used to treat MDR-TB (Table 3) than to the standard therapy for drug-susceptible TB.3 After the introduction of rifampicin, no worthwhile anti-TB drug with new mechanisms of action has been developed in ⬎ 30 years. Some of the older drugs that are being tested and the newer drugs with potential as anti-TB agents that are at various stages of development are listed in Table 6. A series of compounds containing a nitroimidazopyran nucleus that have shown anti-TB activity have been described.56 After activation by a mechanism that is dependent on M tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid, and exhibited bactericidal activity against both replicating and static M tuberculosis.

Table 6 —Some of the Older Drugs and Newer Drugs With Potential as Anti-TB Agents at Various Stages of Development* Drugs Older drugs Rifmaycin derivatives Rifapentine Rifabutin Fluoroquinolones Ofloxacin Sparfloxacin Levofloxacin Moxifloxacin Gatifloxacin Newer drugs Diarylquinoline R207910 Nitroimidazopyran PA-824 Nitro-dihydroimidazo-oxazole OPC 67683 Pyrrole LL3858, LL3522 Macrolides Clarithromycin Telithromycin Oxazolidinones Linezolid PNU-100480 Diamine SQ109 Ring-substituted imidazoles *Based on the studies of Sharma and Mohan,3 and O’Brien and Spigelman.56

Compound PA-824 showed potent bactericidal activity against MDR-TB and promising oral activity in animal infection models.57,58 Further, compounds belonging to the class pyrroles, such as LL3858 and LL3522, are also evoking interest.56 Recently, Andries et al59 reported a new class of inhibitors (diarylquinolines) that blocks the function of an

Table 5—Markers of Poor Prognosis in Patients With MDR-TB Study 52

Park et al Drobniewski et al53 Flament-Saillour et al54 Tahaoglu et al55 Mitnick et al44 Leimane et al50

Subjects, No. (% HIV-Positive) 173 (52) 90 (29)* 51 (16) 158 75 (1.5%)† 204 (0.5)‡

Markers of Poor Prognosis Extrapulmonary involvement Immunocompromised status, failure to culture the bacterium in 30 d or to apply appropriate treatment with three drugs to which the organism is susceptible, and age HIV coinfection, treatment with less than two active drugs, and knowledge regarding the multidrug-resistant status at the time of diagnosis Older age and history of previous treatment with a larger number of drugs Low hematocrit and a low body mass index Previous treatment for MDR-TB, the use of five or fewer drugs for ⱖ 3 mo, resistance to ofloxacin, and body mass index of ⬍ 18.5 at the start of treatment

*Twenty-three of the 79 patients tested had HIV infection. †One of the 65 patients tested had HIV infection. ‡One of the 197 patients tested had HIV infection. 268

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essential membrane-bound enzyme that makes adenosine triphosphate. Of the 20 interesting drug candidates, R207910 showed the best activity profile, is bactericidal, and is exceptionally specific against mycobacteria, with little or no activity against the other microorganisms tested. Furthermore, R207910 is active against both the drug-sensitive and drug-resistant forms of M tuberculosis. There have also been reports60 of novel ring-substituted-1Himidazole-4-carboxylic acid ethyl esters as a new class of anti-TB agents. Whether the initial enthusiasm with these newer compounds will eventually become established as practically useful newer first-line anti-TB drugs remains to be seen. Surgery Surgery is currently recommended for MDR-TB patients whose prognosis with medical treatment is poor and can be performed with a low mortality rate (⬍ 3%).3 The operative risks are acceptable, and the long-term survival is much improved over that with continued medical treatment alone. However, for this to be achieved, the chemotherapeutic regimen needs to continue for prolonged periods after surgery, probably for well ⬎ 1 year, otherwise recrudescence of the disease with poor survival is a real possibility.3 Nutritional Enhancement TB is a wasting disease. The degree of cachexia is most profound when MDR-TB occurs in patients with HIV infection/AIDS. Furthermore, several second-line drugs used to treat MDR-TB, such as para-aminosalicylic acid and fluoroquinolones, cause significant anorexia, nausea, vomiting, and diarrhea, which interfere with food intake, further compromising the cachectic state. Therefore, nutritional assessment and regular monitoring of the nutritional state by a dietician are essential for the successful management of MDR-TB patients and should be an essential part of such programs.3 Immunotherapy Since the early efforts by Robert Koch, several attempts have been made to modify the immune system of patients with TB to facilitate a cure. Some of the methods currently being tried are discussed below. Mycobacterium vaccae Vaccination Transiently favorable results were observed61 when immunoenhancement using M vaccae vaccination was used to treat drug-resistant TB patients who www.chestjournal.org

did not respond to chemotherapy. However, definite evidence confirming these observations is expected from randomized controlled trials.62 Mycobacterium w Results from controlled studies63,64 suggest that adjuvant therapy with Mycobacterium w vaccination along with anti-TB drugs is well-tolerated and facilitates early sputum conversion. A large-scale multicenter trial that is already underway is expected to provide definitive evidence regarding this treatment modality in category II TB patients (see http:// www.clinicaltrials.gov/ct/show/NCT00265226?order ⫽ 1). Cytokine Therapy Aerosolized IFN-␥, granulocyte-macrophage colony-stimulating factor-aerosolized IFN-␣, and lowdose recombinant human interleukin-2 may have all been used as adjunctive treatment for patients with MDR-TB.3 Evidence establishing their efficacy, optimal dosage, and schedule, however, needs to be generated in further studies. Other Agents Other agents used in the treatment of MDR-TB are listed in Table 7.3 Although there have been anecdotal reports of their usefulness, further studies are required to clarify their role. Prevention of Transmission of MDR-TB As TB poses a significant risk to health-care workers, doctors, and other patients, recommendations such as those issued by the WHO65 and the CDC in Atlanta, GA,66 regarding the prevention of the transmission of TB in hospitals, workplaces, and institutional settings should be implemented wherever it is feasible.

Table 7—Other Agents Used in the Treatment of MDR-TB* Thalidomide Pentoxifylline Levamisole Transfer factor Inhibitors of transforming growth factor-␤ Interleukin-12 Interferon-␣ Imiquimod (an oral agent that stimulates the production of interferon-␣ ) *Based on the studies of Sharma and Mohan,3 and O’Brien and Spigelman.56 CHEST / 130 / 1 / JULY, 2006

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Treatment of Latent MDR-TB Infection Newer IFN-␥-based assays show potential for the diagnosis of latent MDR-TB infection. For contacts thought to be infected with M tuberculosis that is resistant to both isoniazid and rifampicin, no satisfactory chemoprophylaxis is available.67 There is no consensus regarding the choice of the drugs and the duration of treatment. The CDC has put forth guidelines66 for the management of persons exposed to MDR-TB. The two suggested regimens for MDR-TB preventive therapy are as follows68: (1) pyrazinamide (25 to 30 mg/kg daily) plus ethambutol (15 to 25 mg/kg daily); or (2) pyrazinamide (25 to 30 mg/kg daily) plus a quinolone with anti-TB activity (eg, levofloxacin or ofloxacin). The recommended duration of therapy is 12 months for those patients with underlying immunosuppression and at least 6 months for all other patients. All patients should be closely observed for at least 2 years, and a low threshold for referral to a center with experience in managing MDR-TB should be maintained. Initial results indicate that the pyrazinamide and levofloxacin regimen was found to be poorly tolerated as severe ADRs developed in several patients. These issues merit further study in randomized controlled studies.

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Future Directions The efficacy of strategies such as DOTS-Plus in the management of MDR-TB patients under program conditions should be tested in well-designed operational field clinical trials strictly following standardized definitions and nomenclature. Ethnic variations in the pharmacokinetics of anti-TB drugs and the utility of therapeutic drug monitoring in the management of patients with MDR-TB need further study. The field testing of newer anti-TB drugs that is on the horizon and generating evidence regarding their efficacy deserves special mention as there is renewed hope of shortening the duration of treatment. ACKNOWLEDGMENTS: We sincerely thank Dr. L.S. Chauhan, Deputy Director General (TB), Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; and Dr. Fraser Wares, STP (TB), Office of the WHO Representative to India, New Delhi, for critically reading the manuscript and providing valuable suggestions.

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