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Multidrug-Resistant TuberculosisNews From the FrontMary D. Nettleman, MD, MS

DURING THE PAST DECADE, MULTIDRUG-RESISTANT TU-berculosis (MDR-TB), defined as resistance to atleast isoniazid and rifampin, has declined in theUnited States.1 The number of reported MDR-TB

cases has decreased from 486 in 1993 to 114 in 2003, andthe proportion of resistant strains of Mycobacterium tuber-culosis has decreased by half.1 The decline is heartening butthis issue of JAMA includes 2 reports from California andRussia showing why celebration would be premature.2,3

In this issue of JAMA, Granich and colleagues2 show thatCalifornia has not shared in the proportionate decline of re-sistant strains. From 1994 to 2003, the authors analyzed thesensitivity of 28 712 culture-positive cases of TB and iden-tified 407 MDR-TB cases. Although the absolute number ofMDR-TB cases per year decreased during the 10-year pe-riod, the number of sensitive cases also declined, leadingto stable proportions of resistance. Matching several data-bases, they identified key risk factors for resistance, includ-ing a previous diagnosis of TB, a positive smear, Asian/Pacific Islander ethnicity, and being a US resident for lessthan 5 years. In fact, 84% of cases were in foreign-born per-sons residing in the United States. The authors conclude thatmuch of the MDR-TB problem in California was imported,underscoring the global nature of TB.

Unfortunately, global rates are increasing.4 Measures thathave improved health in the United States have done littleto stem the tide of TB in other countries where famine, war,and especially human immunodeficiency virus (HIV) havecreated new opportunities for TB to spread. Lack of fund-ing and poor public health infrastructure have led to pa-tients with TB being treated incorrectly or incompletely, giv-ing rise to resistance. Multidrug-resistant strains ofM tuberculosis are particularly problematic in developingcountries because alternative agents, such as pyrazin-amide, ethambutol, and the quinolones, are less effective,more expensive, and less well-tolerated than their more stan-dard counterparts (ie, isoniazid and rifampin).5-7

In 2005, the World Health Organization (WHO) reportedthat 1.1% of new (ie, previously untreated) TB cases in theworld were multidrug-resistant.8 This was based on the larg-est survey available to date and included 55 779 TB cases, al-though half of these were from Western Europe, North

America, New Zealand, and Australia. More countries par-ticipated in the survey than ever before, but some potentiallyhigh-prevalence areas did not. The survey showed that the pro-portion of multidrug resistance in new cases was signifi-cantly increased in 10 areas: Kazakhstan (14.2%), Israel(14.2%), the Tomsk Oblast in Russia (13.7%), Karakalpak-stan region of Uzbekistan (13.3%), Estonia (12.2%), Liaon-ing Province in China (10.4%), Latvia (8.3%), Henan Prov-ince in China (7.8%), and Ecuador (4.9%).8 Thus, some of thehighest proportions of drug resistance in the world occur inthe former Soviet Union and China. Indeed, the highest pro-portion of multidrug resistance in the study by Granich et al2

was found in individuals who emigrated from the Ukraine.Also in this issue of JAMA, Drobniewski and colleagues3 de-

scribe the significant and complicated interrelationships amongHIV, MDR-TB, and imprisonment in Russia. In this study, epi-demics of MDR-TB coincided with increasing rates of HIV, acatastrophic combination. Human immunodeficiency virus ismade worse by TB, and TB is most lethal in the presence ofHIV. Dual treatment of both infections is critical but oftenmeans an extraordinarily complex medical regimen that is dif-ficult to follow. Although HIV is not itself a risk factor for mul-tidrug resistance,9 it is associated with increased rates of TBand increased contagion.10 The breakup of the former SovietUnion resulted in dwindling public health resources, drugshortages, and incomplete and inadequate treatment courses.The study by Drobniewski et al3 shows how overcrowded pris-ons have become incubators for new cases. In 2003, the WorldBank approved a multimillion dollar loan for TB and HIV con-trol in Russia.11 The government has committed matching dol-lars, but the task is formidable.

Epidemiologic studies have made it clear that multidrugresistance is a man-made phenomenon. Exposure to anti-tuberculous therapy selectively allows for multiplication ofresistant bacilli, and resistant strains become dominant andtherapy fails. Once created, resistant strains may also be trans-mitted from person to person. In this way, resistant strainsmay present in patients who have never received treat-ment. However, resistance is largely preventable if primarycases are treated correctly.

Multidrug-resistant strains acquire resistance through mu-tation; in nature, mutation is a spontaneous, although rare,

See also pp 2726 and 2732.

Author Affiliation: Department of Medicine, Michigan State University, EastLansing.Corresponding Author: Mary D. Nettleman, MD, MS, Department of Medicine,Michigan State University, B427 Clinical Center, East Lansing, MI 48823 (mary.nettleman@ht.msu.edu).

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event. Because of the high number of organisms, it is likelythat almost all untreated patients harbor a small subpopu-lation resistant to at least 1 drug. Therefore, it has long beenrecognized that effective therapy requires more than 1 agent.

As might be expected, acquiring resistance to multipledrugs means acquiring multiple mutations.12 Multidrug-resistant strains have a series of single-locus mutations; how-ever, mutation is a double-edged sword. Although confer-ring a survival advantage on the organism in terms of drugresistance, it is possible that some mutations may ad-versely affect other vital functions and ultimately impair thefitness of the organism to reproduce.13 In some multidrug-resistant strains, this appears to be the case. Unfortunately,the effect is not uniform and many strains appear to retainfull reproductive capacity. Simulation modeling has shownthat even if the proportion of relatively fit strains is small,the fit strains will eventually increase and replace the lessfit strains.13 Thus, MDR-TB is likely to remain a significantproblem in the future.

The corollary of unfitness is that strains could mutate tobecome unusually fit to survive. This may be the case with asingle genotype, known as the W-Beijing family that arosein Asia and has become the dominant strain there.14 The W-Beijing family has since spread throughout the world. Epi-demics of W-Beijing have been widely reported, includingmany from the United States.15 Drobniewski et al3 found thatthe W-Beijing strain comprised two thirds of the isolates ofTB in prisoners and civilians from the Samara Region of Rus-sia. The rapidity of spread and the tenacity of the strain hasled many to believe that the W-Beijing family has a survivaladvantage over other strains. In fact, some strains of the W-Beijing genotype have been shown to have alterations in thegenes that repair mutations, potentially allowing increasedmutation frequency.16 Drobniewski et al discuss other pos-sible reasons for the success of this strain, including inhibi-tion of proinflammatory cytokines. Notably, the W-Beijingfamily is strongly associated with multidrug resistance. In manyareas with high rates of multidrug-resistant strains, W-Beijing is the dominant genotype, including the study by Drob-niewski et al3 in which W-Beijing strains were more than twiceas likely to be multidrug-resistant than non–W-Beijing strains.It is not clear if this association is due to an increased ten-dency toward mutations that cause drug resistance or if it ismerely because the strain arose first in areas in which incom-plete treatment regimens were prevalent.

In a WHO survey,8 a surprising number of developingcountries reported low proportions of multidrug resis-tance. These included Gambia at 0.5% and Botswana at 0.8%,both of which were lower than US rates of MDR-TB. Fromthe 2005 WHO report,8 most of the few African areas sur-veyed were modestly afflicted with multidrug-resistantstrains. At first glance, this is curious given the high ratesof HIV in Africa. The unfortunate truth is that resistancearises from inappropriate therapy and many African pa-tients with TB do not receive therapy of any kind. Thus, there

is often little opportunity for selection of resistant strainsthrough treatment.

Although rates of resistance in Africa are still relativelylow, they are increasing.8 The articles in this issue of JAMAfrom California and Russia2,3 are cautionary tales: to pre-vent multidrug resistance from increasing dramatically, itis absolutely necessary that appropriate treatment for TB beprovided to individuals who are affected. Incomplete treat-ment is of no value because the patient is still infected andthe bacilli become resistant. The WHO efforts are focusingon a strategy of political commitment, case detection, di-rectly observed treatment, an uninterrupted drug supply,and standardized reporting.8 The United States has pledgedbillions of dollars to fight HIV and TB in Africa. Certainly,anti-tuberculous therapy represents a major opportunity toimprove the quality of life in Africa. Mishandling of treat-ment programs, however, will doom the continent to highrates of resistance that cannot be appropriately contained.

Tuberculosis does not respect political boundaries and can-not be eliminated in the United States unless it is eliminatedin other countries. More than half of US multidrug-resistantstrains occur in foreign-born individuals who reside in theUnited States.1 Control measures require intensive case find-ing, appropriate treatment programs, and the willingness offoreign-born residents to comply with treatment. The latteris a difficult task because cultural and language barriers alongwith fears about the US legal system hamper public healthefforts. As shown in the study by Granich et al,2 some foreign-born residents may just disappear into society without com-pleting therapy. On a positive note, the US reported rate ofcompletion (within 1 year) of drug therapy in foreign-bornindividuals is more than 80%, a rate that is almost identicalto that of US-born individuals.1 However, this is short of the90% completion rate targeted by Healthy People 2010.17 Inthe study by Granich et al,2 only 67% of patients with MDR-TBcompleted therapy but 14% died, and it is not clear how manytreatment courses were interrupted by death. Certainly, mor-tality rates with MDR-TB are very high.

Tuberculosis is increasing and multidrug resistance is sap-ping the strength of prevention efforts in Asia. As efforts turnto treating TB in Africa, there is a potential for a major pub-lic health victory or a stunning defeat heralded by an ex-plosion of resistant strains. In this fight, weapons that weredeveloped decades or even centuries ago (tuberculin skintesting, patient isolation, sputum analysis, surveillance, andolder drugs) are still being used. But there is hope on thehorizon. DNA fingerprinting has already revolutionized out-break investigation.18 Radiometric analysis has cut the wait-ing time for drug susceptibility testing and better genetictesting for resistance is in the wings.19 The genome of M tu-berculosis has been fully sequenced and important informa-tion may soon be revealed.20,21 Although decades have elapsedwithout the advent of new therapies, there are several can-didate agents, including a diarylquinoline compound, thatappear to be highly active, even against multidrug-

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resistant strains.22 These results do not guarantee that clini-cal trials will be successful, but they are encouraging.

The optimal approach to prevent TB is primary preven-tion through vaccination. For reasons that are not entirely clear,the BCG vaccine has shown inconsistent efficacy in clinicaltrials, especially in adults. Numerous vaccine candidates areunder study and at least 2 are currently in early human trials.23

With uncharacteristic optimism, the Centers for DiseaseControl and Prevention still has a Division of TuberculosisElimination. Using current tools, resistant TB is unlikely tobe eradicated. However, history has shown that resistancecan be reduced through more appropriate treatment pro-grams and the spread of resistant strains can be reducedthrough public health measures. Some of the articles in thisissue of JAMA clearly show that multidrug resistance in theUnited States is inextricably linked to resistance in the restof the world. Therefore, to control resistance in the UnitedStates, areas where resistance is epidemic must receive as-sistance and exquisite care must be taken not to create newproblems on continents like Africa. In the future, with newdrugs, tests, and vaccines, the elimination of multidrug re-sistance may be achievable but difficult.

Financial Disclosures: None reported.

REFERENCES

1. Centers for Disease Control and Prevention. Trends in tuberculosis—United States,2004. MMWR Morb Mortal Wkly Rep. 2005;54:245-249.2. Granich RM, Oh P, Lewis B, Porco TC, Flood J. Multidrug resistance amongpersons with tuberculosis in California, 1994-2003. JAMA. 2005;293:2732-2739.3. Drobniewski F, Balabanova Y, Nikolayevsky V, et al. Drug-resistant tubercu-losis, clinical virulence, and the dominance of the Beijing strain family in Russia.JAMA. 2005;293:2726-2731.4. Espinal MA, Laszlo A, Simonsen L, et al. Global trends in resistance to antitu-berculosis drugs. N Engl J Med. 2001;344:1294-1303.

5. Rajbhandary SS, Marks SM, Bock NN. Costs of patients hospitalized for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2004;8:1012-1016.6. Gupta R, Kim JY, Espinal MA, et al. Responding to market failures in tubercu-losis control. Science. 2001;293:1049-1050.7. Dye C, Espinal MA, Watt CJ, Mbiaga C, Williams BG. Worldwide incidence ofmultidrug-resistant tuberculosis. J Infect Dis. 2002;185:1197-1202.8. World Health Organization. Antituberculous Drug Resistance in the World, Re-port Number 3. Geneva, Switzerland: World Health Organization; 2005.9. Pablos-Méndez A, Raviglione MC, Laszlo A, et al. Global surveillance for an-tituberculosis-drug resistance, 1994–1997. N Engl J Med. 1998;338:1641-1649.10. Edlin BR, Tokars JL, Grieco MH, et al. An outbreak of multi-drug resistant tu-berculosis among hospitalized patients with the acquired immunodeficiencysyndrome. N Engl J Med. 1992;326:1514-1521.11. Webster P. World Bank approves loan to help Russia tackle HIV/AIDS andtuberculosis. Lancet. 2003;361:1355.12. Gillespie SH. Evolution of drug resistance in Mycobacterium tuberculosis: clini-cal and molecular perspective. Antimicrob Agents Chemother. 2002;46:267-274.13. Cohen T, Murray M. Modeling epidemics of multidrug-resistant M. tubercu-losis of heterogeneous fitness. Nat Med. 2004;10:1117-1121.14. Glynn JR, Whiteley J, Bifani PJ, Kremer K, van Soolingen D. Worldwide oc-currence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review.Emerg Infect Dis. 2002;8:843-849.15. Munsiff SS, Nivin B, Sacajiu G, Mathema B, Birani P, Kreiswirth BN. Persis-tence of a highly resistant strain of tuberculosis in New York City during 1990-1999.J Infect Dis. 2003;188:356-363.16. Rad ME, Bifani P, Martin C, et al. Mutations in putative mutator genes of My-cobacterium tuberculosis strains of the W-Beijing family. Emerg Infect Dis. 2003;9:838-845.17. US Department of Health and Human Services. Healthy People 2010: Un-derstanding and Improving Health. 2nd ed. Washington, DC: US Government Print-ing Office; 2000.18. Lambregts-van Weezenbeek CS, Sebek MM, van Gerven PJ, et al. Tubercu-losis contact investigation and DNA fingerprint surveillance in The Netherlands: 6years’ experience with nation-wide cluster feedback and cluster monitoring. Int JTuberc Lung Dis. 2003;7:S463-S470.19. Dubiley S, Mayorova A, Ignatova A, et al. New PCR-based assay for detec-tion of common mutations associated with rifampin and isoniazid resistance in My-cobacterium tuberculosis. Clin Chem. 2005;51:447-450.20. Pan H, Yan BS, Rojas M, et al. Ipr1 gene mediates innate immunity to tuberculosis.Nature. 2005;434:767-772.21. Rubin EJ. Toward a new therapy for tuberculosis. N Engl J Med. 2005;352:933-934.22. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug activeon the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307:223-227.23. Dye C. A booster for tuberculosis vaccines. JAMA. 2004;291:2127-2128.

Tuberculosis, Vulnerability,and Access to Quality CarePhilip C. Hopewell, MDMadhukar Pai, MD, PhD

AS WITH MOST INFECTIOUS DISEASES, TUBERCULOSIS

(TB) is not randomly distributed; it thrives in spe-cific groups and under specific conditions in as-sociation with identified and unidentified factors

that confer vulnerability to the disease. Available informa-tion on the association between TB and the many knownconditions and circumstances that influence vulnerabilityto the disease has been reviewed recently and is summa-

rized in the BOX.1,2 These conditions and circumstancesmainly include 3 broad categories of factors: individual bio-logical factors (eg, immunodeficiency states), social and eco-nomic circumstances (eg, crowding, poverty, poor nutri-tion), and environmental and institutional factors (eg, silicadust, poor ventilation).

See also pp 2719, 2726, 2762 and 2767.

Author Affiliations: Division of Pulmonary and Critical Care Medicine, Francis J.Curry National Tuberculosis Center, San Francisco General Hospital, University ofCalifornia, San Francisco (Drs Hopewell and Pai); and Division of Epidemiology,School of Public Health, University of California, Berkeley (Dr Pai).Corresponding Author: Philip C. Hopewell, MD, Division of Pulmonary and Criti-cal Care Medicine, San Francisco General Hospital, University of California, SanFrancisco, 1001 Potrero Ave, Room 5K1, San Francisco, CA 94110 (phopewell@medsfgh.ucsf.edu).

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