Editorial

[Indian J Chest Dis Allied Sci 2008; 50: 183-185]

Preventing Extremely Drug Resistant Tuberculosis: DirectlyObserved Treatment Is The Only Answer

The term XDR (“extreme” drug resistant) tuberculosiswas first developed at the Centers for Disease Control(CDC)

in March 2005 based on data on second-linedrug resistance from a global survey

and the results of multi-drug resistant (MDR) TB treatment outcomesunder directly observed treatment, short-course(DOTS)-Plus in Latvia.

In March 2006, CDC incollaboration with the World Health Organization(WHO) and participating supranational referencelaboratories, agreed to define XDR TB (the word“extreme” was replaced by “extensive”) as cases of TBdisease whose

Mycobacterium tuberculosis

isolates wereresistant to isoniazid and rifampicin,

i.e.

MDR TB, and atleast three of the six main classes of second-line drugs,

i.e.

aminoglycosides, polypeptides, fluoroquinolones,thioamides, cycloserine, and para-aminosalicyclic acid.

Subsequently, in October 2006, WHO organised the firstmeeting of the Global XDR TB Task Force in Geneva,Switzerland,

and the case definition of XDR TB wasrevised as, MDR TB plus resistance to

(i)

anyfluoroquinolone, and

(ii)

one of three injectable second-line drugs,

i.e.

capreomycin, kanamycin, amikacin. Thereasons for this revision was

(a)

drug-susceptibilitytesting to fluoroquinolones and second-line injectabledrugs (

i.e.

, amikacin [aminoglycoside], kanamycin[aminoglycoside], or capreomycin [polypeptide]) yieldsreproducible and reliable results, whereas drug-susceptibility testing to other second-line drugs is lessreliable, and

(b)

implication of resistance tofluoroquinolones and second-line injectable drugs hasbeen poor treatment outcomes. The term “extremely”drug resistant (XXDR) TB has now been proposed forcases resistant to all available first-and second-linedrugs.

The exact prevalence of XDR TB in India is notknown. However, one recent study (“High Prevalenceof XDR TB from a Tertiary Care Hospital in India”, ATSMeeting 2007; Abstract 1398) has found 8% of theisolates from sputum in MDR pulmonary TB cases in areferral laboratory to be XDR. India’s rate is relativelyhigh, lower than only Eastern Europe and Russia (14%)and South Korea (15%).

In an earlier WHO/ International Union Against TB and Lung Diseases(IUATLD) Global Surveillance Project,

the prevalenceof MDR TB in New Delhi was found to be 14%, andhence India was declared a “hot zone” of MDR TB. Theprevalence of primary multidrug-resistance was only1.4%, indicating that most MDR TB was acquiredresistance. It has been acknowledged that goodtreatment is a pre-requisite to the prevention of emergence of resistance. One of the recommendations of the XDR Task Force

is that the WHO Guidelines for theprogrammatic management of drug-resistanttuberculosis DOTS-plus must be implemented asswiftly as possible. The DOTS-plus is an additionalintervention in the existing DOTS programme. TheDOTS-Plus includes a Supranational TB ReferenceLaboratory Network (SRL) for global surveillance of MDR-TB, guidelines on MDR-TB management and theGreen Light Committee (GLC) to promote access tohigh-quality second-line drugs (SLDs) at low prices. Theprogramme is based on compelling evidence onfeasibility, effectiveness and cost-effectiveness of MDR-TB management under programmatic conditions and inresource-limited settings. However, previous experiencehas shown that use of second-line drugs by physiciansand control programmes result in increased cases XDRTB

and perhaps “extremely drug resistant” (XXDR)cases.

The problem of drug resistance in TB is not new andvirtually a man made problem. Drug resistance in

Mycobacterium tuberculosis

occurs by randomspontaneous mutations. The probability (P) of incidenceof drug-resistant cases is calculated by the formula:

P =1 – (1-r) n

, where, r is the probability of incidence of drug-resistant mutants, and n is the number of bacilli inthe lesion.

The value of r for rifampicin is 10

-8

, that forisoniazid, ethambutol, streptomycin, kanamycin andpara aminosalicylic acid is 10

-6

, and that forethionamide, cycloserine and capreomycin is 10

-3

8,9

Thevalue of r for two drugs becomes the product of the twoindividual resistance,

e.g.

-12

or 10

-14

and for three drugsas low as 10

-18

or 10

-20

. The number of bacilli (n) in thelesion also influences the probability of drug-resistance,as per the formula. Cavitary lesions usually containfrom 10

to 10

organisms. Hence, the probability of acquiring drug resistance is practically nil when threedrugs are utilised together for the treatment of TB.

8,10

Poor chemotherapy, however, in the form of inadequatedrugs, inadequate drug doses or addition of a singledrug to a failing regimen (addition syndrome) results inselective growth of the drug resistant mutants andacquired drug-resistant tuberculosis. Contacts of theseresistant cases then develop primary drug resistanttuberculosis.

Therefore, a high level of acquiredresistance is a mark for a poorly functioningtuberculosis control programme in the current scenario,whilst primary resistance is an indicator for the efficacyof tuberculosis control efforts in the past.

The commondenominator, though is always poor control practices,“careless care” and weak health systems.

In 1972, Annik Pouillon, former Executive-Directorfor International Union Against TB and Lung Diseases(IUATLD) had observed “the person who swallows

184

drugs regularly in the absence of encouragement andhelp is an abnormal one”.

Self administered therapy(SAT) or directly observed treatment (DOT) are the twooptions for giving anti-tuberculosis chemotherapy. Self-administered therapy must always be prescribed usingfixed dose combinations (FDC) as they makemonotherapy impossible. However, SAT requiresconscientious effort and time on the part of thephysicians and health care workers to ensurecompliance, which they often seem to lack. Hence, since1993, WHO recommends DOT as an importantcomponent of their five-point programme; directlyobserved treatment, short-course (DOTS) to tackle theTB “global emergency”. The Revised National TBControl Programme (RNTCP) of India is based on theDOTS strategy. It will now be expanded to includeDOTS-Plus for the treatment of MDR TB using astandardised treatment regimen (STR), comprising of six drugs (kanamycin, ofloxacin, ethionamide,pyrazinamide, ethambutol and cycloserine) during 6-9months of the Intensive Phase and four drugs(ofloxacin, ethionamide, ethambutol and cycloserine)during 18 months of the Continuation Phase. Paraaminosalicylic acid (PAS) is included in the regimen asa substitute drug.

In our country, the infrastructure is often eitherpoorly utilised or even misutilised.

In the pre RNTCPera it was observed that although a peripheral healthcentre has a vast sanctioned strength of staff of all types,their main work appeared to be to sit in the healthcenter and wait for the people to attend there, when theneed was to go out and treat the patient at his/herdoorstep.

After implementation of RNTCP, studieshave shown that DOTS workers do not always ensureDOT,

when it becomes POTS (Partially ObservedTreatment, Short-course) or even KNOTS (Knowing butNot Observing Treatment, Short-course).

Directobservation of SLDs will be crucial for compliance of MDR TB therapy under DOTS-plus. A 24-monththerapy cannot be supervised using hard-pressed healthworkers at the DOTS centers and hence it is proposed touse DOT providers. Using family members to supervisetherapy has been shown to be as effective and may bean alternative option.

Reinforcing adherence throughtreatment literacy is important for the successfulcompletion of therapy and cannot be substituted by anyother intervention. The final option is to use legal actionin the form of compulsory detention when anindividual refuses treatment.

In practice this is seldomused, though some countries have employedcompulsory detention in as many as 1% of cases.

However, as the New York City Tuberculosis WorkingGroup

concludes: “It is unethical, illegal, and badpublic health policy to detain ‘noncompliant personsbefore making concerted efforts to address thenumerous systemic deficiencies that make adherence totreatment virtually impossible.”Failure to eliminate TB, the largest cause of death,infecting 1/3 of the world population, 100% preventableand 100% curable must rank as mankind’s worstongoing blunder.

New classes of anti-tuberculosisdrugs that could be used for treating XDR TB aredesperately needed; but are unlikely to becomeavailable for at least another few years. The potential of introducing drug resistance resulting from a failure toadhere to the principles of chemotherapy, however, cannever be overcome even by development of newdrugs.

Even if “third-line drugs” are available fortreatment of XDR/XXDR TB today, their improper usecan develop “ XXXDR TB”! In 1952, Dubos and Dubos

in their book

“The White Plague: Tuberculosis, Man and Society”

wrote, “However useful drugs, vaccines orother options in cases, (they) cannot solve the problemof TB.... It is through gross errors in organisation andindividual life that the problem (of TB) has reachedcatastrophic levels that it has in Europe......and willprevail in Asia....” Unfortunately, Rene and Duboisproved very accurate in their estimate of the magnitudeof the problem of TB control and the reasons for it. DOT,at present, therefore seems to be the only and DefiniteOpportunity To Stop TB, a “ticking time bomb”.

J.M. Joshi

Member, Editorial Board and Professor and Head Department of Respiratory Medicine BYL Nair Hospital Mumbai-400 008 E-mail: drjoshijm@gmail.com

REFERENCES

1.Holtz TH. XDR-TB in South Africa: revised definition.

PLoS Med

2007; 4: e161. doi: 10.1371/journal.pmed.0040161.2.Shah NS, Wright A, Drobniewski F. Extreme drug resistancein tuberculosis (“XDR-TB”): global survey of supranationalreference laboratories for

Mycobacterium tuberculosis

withresistance to second-line drugs.

Int J Tuberc Lung Dis

2005; 9(Suppl. 1): S77.3.Holtz TH, Riektsina V, Zarovska E, Laserson KF, Wells CD,Leimane V. XDR-TB: extreme drug-resistance and treatmentoutcome under DOTS-Plus, Latvia, 2000-2002.

Int J Tuberc Lung Dis

2005; 9 (Suppl. 1): S258.4.Centers for Disease Control and Prevention (CDC).Emergence of

Mycobacterium tuberculosis

with extensiveresistance to second-line drugs-worldwide, 2000-2004.

MMWR Morb Mortal Wkly Rep

2006; 24: 55: 301-5.5.Report of the meeting of the Global WHO Task Force onXDR-TB.

Available at:

http://www.who.int/tb/xdr/ taskforcereport-oct06.pdf. Accessed on 14 June 2007.6.Migliori GB, Loddenkemper R, Blasi F, Raviglione MC. 125years after Robert Koch's discovery of the tubercle bacillus:the new XDR-TB threat: is “science” enough to tackle theepidemic?

Eur Respir J

2007; 29: 423-7.7.Cohn DL, Bustreo F, Raviglione MC. Drug resistanttuberculosis: review of the worldwide situation and theWHO/IUATLD Global Surveillance Project.

Clin Infect Dis

EditorialJ.M. Joshi

2008; Vol. 50The Indian Journal of Chest Diseases & Allied Sciences185

1997; 24 (Suppl. 1): S121-S130.8.Shimao T. Drug resistance in tuberculosis control.

Tubercle

1987; 68 (Suppl.): S5-S15.9.Rastogi N, David HL. Mode of action of anti-tuberculousdrugs and mechanisms of resistance in

Mycobacteriumtuberculosis

Res Microbial

1993; 144: 133-43.10.Vareldzis BP, Grossset J, de Kantor I, Crofton J, Laszlo A,Felten M,

et al.

Drug-resistant tuberculosis: laboratory issues.World Health Organization recommendations.

Tubercle Lung Dis

1994; 75: 1-7.11.Lambregts-van Weezenbeek CSB, Veen J. Control of drug-resistant tuberculosis.

Tubercle Lung Dis

1995; 76: 455-9.12.Kochi A, Vareldzis B, Styblo K. Multidrug resistanttuberculosis and its control.

Res Microbiol

1993; 144: 104-10.13.Raviglione M. XDR-TB: entering the post-antibiotic era?

Int J Tuberc Lung Dis

2006; 10: 1185-7.14.Rouillon A. “Defaulters” and “Motivation.”

Bull Int UnionTuberc

1972; 47: 58-63.15.Revised National TB Control Programme. DOTS-PlusGuidelines. Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare,Nirman Bhavan, New Delhi, March 2006.

Available at

:http://www.tbcindia.org/pdfs/dots-plus%20guidelines.pdf.Accessed on 14 June 2007.16.Editorial. Beyond, above and below.

Indian J Tub

1997; 44:105-6.17.Balasubramanium VN, Dommen K, Samuel R. DOT or not?:direct observation of anti-tuberculosis treatment and patientoutcomes, Kerala State, India.

Int J Tuberc Lung Dis

2000; 4:409-13.18.The Revised National TB Control Programme and the DOTSstrategy. Excerpts from an Observational Study in ThreeDistricts; 1998: www.ctrlaltesc.org/fighttb/02/02/11/ 102207.shtml.19.Wright J, Walley J, Philip A, Pushpananthan S, Dlamini E,Newell J,

et al.

Direct observation of treatment fortuberculosis: a randomized controlled trail of communityhealth workers

versus

family members.

Trop Med Int Health

2004; 9: 559-65.20.Gasner MR, Maw KL, Feldman GE, Fujiwara PI, Frieden TR.The use of legal action in New York City to ensure treatmentof tuberculosis.

N Engl J Med

1999; 340: 359-66.21.Coker RJ.

From Chaos to Coercion: Detention and the Control of Tuberculosis.

London: St Martins Press, 2000: p. 304.22.New York City Tuberculosis Working Group. Developing asystem for tuberculosis prevention and care in New York City. New York: United Hospital Fund; 1992.23.Reichman LB. Tuberculosis elimination-what’s to stop us?

Int J Tuberc Lung Dis

1997; 1: 3-11.24.Rieder HL. Drug-resistant tuberculosis: issues inepidemiology and challenges for public health.

Tuber Lung Dis

1993; 75: 321-3.25.Dubos RJ, Dubos J.

The White Plague: Tuberculosis, Man and Society.