Cermin Dunia Kedokteran

TINJAUAN KEPUSTAKAAN

Management

of Multidrug Resistant Tuberculosis

Zul Dahlan

Department of Internal Medicine, Medical Faculty, Padjadjaran University, Bandung

INTRODUCTION

In the last decade, tuberculosis (TB) has reemerged as one

of the leading causes of death (nearly 3 million deaths annual-

ly). The estimated 8.8 million new cases every year correspond

to 52,000 deaths per week or more than 7,000 each day, which

translates into more than 1,000 new cases every hour, every

day. These death rates, however, only partially depict the

global TB threat; more than 80% of TB patients are in the

economically productive age of 15 to 49 years. The emergence

of AIDS and decline of socioeconomic standards contribute to

the disease's resurgence in industrialized countries. In most

developing countries, although the disease has always been

endemic, its severity has increased because of the global HIV

pandemic and extensive social restructuring due to rapid

industrialization and conflicts. A major public health problem

worldwide, TB is now a global emergency.

Figure 1. Global incidence of tuberculosis. Of the estimated 8.8 million

cases worldwide, more than 40% of the cases are in Southeast

Asia; India has approximately 53.3% of those cases. A, meri-

cas; Afr, Africa; WP, Westem Pacific; E, Europe; M, Eastem

Mediterranean; and SEA, Southeast Asia; Ind, Indonesia; B,

Bangladesh; Thai, Thailand; My, Myanmar. *Others include

Bhutan, 0.05%; Nepal, 1.2%; Maldives, 0.001%; Sri Lanka,

1%; DPR Korea, 1.2%. (Data from reference 1).

A major cause of drug-resistant TB and treatment failure

is patient nonadherence to prescribed treatment. Treatment

failure and drug-resistant TB can be life-threatening and pose

other serious public health risks because they can lead to

prolonged infectiousness and increased transmission of TB in

the community.

The World Health Organization (WHO) has for the first

time assembled hard evidence that the emergence of drug

resistant tuberculosis can be held back by properly controlled

treatment programmes

(2)

. Directly observed therapy (DOT) has

been endorsed by infectious disease experts to contain the

international epidemic of tuberculosis and the burgeoning

number of drug-resistant cases.

DOT is one method of ensuring adherence; it requires that

a health-care provider or other designated person observe

while the patient ingests anti-TB medications. DOT should be

considered for all patients because of the difficulty in predict-

ing which patients will adhere to a prescribed treatment

regimen.

PROBLEM OF DRUG RESISTANCE

Multidrug- resistance tuberculosis (MDRTB) is not a new

but "natural phenomenon", an iatrogenic disease arising under

the selective pressure of inadequate therapy. Clinically drug

resistant is divided into two types, secondary and primary drug

resistant tuberculosis (fig. 1). Secondary (or acquired) drug-

resistant tuberculosis develops when drug resistant tubercle

bacilli outgrow susceptible bacilli due to selection and multi-

plication of resistant mutants by inappropriate therapy.

Primary drug-resistant tuberculosis occurs in patients who

have never been treated with antituberculosis before, but have

become infected with resistant organisms. The term "initial

resistance" is used if resistance is observed in the first isolate

of a patient who claims never to have had chemotherapy.

The ratio secondary/primary resistance is important since

it provides information about the relative contribution of: 1).

Inadequate treatment delivery; 2). Transmission to the resistan-

ce problem. In some low prevalence countries, drug resistance

Presented at 3

Asia Pacific Conference on Travel Health, 6

National

Congress of Tropical Health and Infectious Diseases, Bali, July 21- 23, 2000.

Cermin Dunia Kedokteran No. 137, 2002 13

tuberculosis is observed predominantly in immigrants. If this is

the case, it is necessary to determine whether drugresistant

tuberculosis as imported, or resulted from poor treatment or

transmission after immigration. Control effort should focus on

the prevention of inadequate treatment

(4)

The World Health Organization (WHO) has assembled

hard evidence that-the emergence of drug resistant tuberculosis

can be held back by properly controlled treatment program-

mes. It warns, however, that the "window of opportunity" to

prevent the spread of drug resistant strains will be missed if

urgent action is not taken to persuade more health authorities

and doctors to use its recommended treatment strategy, which

still reaches only 1 in 5 patients with tuberculosis worldwide.

A global report shows a disturbingly high prevalence of drug

resistant strains of M. tuberculosis in parts of eastern Europe

and Asia.

By contrast, countries that have used the recommended

treatment strategy tend to have very low rates of resistance.

The report has data from 58 countries and other settings (such

as provinces of China) and enough data to detect trends in 28.

Its authors warn, however, that the picture is still incomplete.

The scale of drug resistance is not fully known in the five

countries with the highest incidence of tuberculosis world-

wide: India, China, Indonesia, Bangladesh, and Pakistan

(2)

THERAPY

Definition

Diagnosis of drug-resistant tuberculosis is made on the

clinical and microbiological data. Therapy is given based on

treatment principles, and specific regimens for certain resistan-

ce patterns, as proposed by Bureau of TB Control of New

York City

(3)

. In this protocol, MDRTB refers to a strain of M.

tuberculosis resistant to at least isoniazid and rifampin.

Treatment of Drug-Resistant Tuberculosis

Unlike protocols for the treatment of tuberculosis sus-

ceptible to all first-line anti-tuberculosis medications, it is not

possible to develop appropriate, standardized protocols for

treatment of known or suspected drug-resistant tuberculosis.

Several issues come into play:

Any treatment recommendation must take into account the

drug susceptibility results of an individual isolate;

Good data are lacking on the efficacy of non-standard

regimens; AND

Side effects to second-line medications, often serious and

intolerable, do not allow their use for the recommended period

of time in many cases.

Protocols for treatment of MDR-TB should be considered

guidelines only. Opinions vary on the best medications to use

for an individual patient.

The treatment of drug-resistant tuberculosis serves both an

individual (cure), and a public health benefit (breaking the

chain of transmission). It seems that treatment outcome of

patients with MDR depends to a high degree on the skills of

doctors and laboratories. Early diagnosis of tuberculosis, early

suspicion of resistance and early appropriate treatment are the

most important determinants for improved outcome in MDR

tuberculosis (Lambrebgts,1997)

(4)

Multidrug-Resistant TB Treatment Principles

(3)

1. MDRTB should never be treated without expert

consultation.

2. An individual must be treated with a regimen of at least

two (2), and preferably three (3) anti-tuberculosis medications

to which the organism is likely to be susceptible.

3. A single anti-tuberculosis medication should never be

added to a regimen that is failing. At least two (2), and pre-

ferably three (3) new anti-tuberculosis medications to which

the organism is likely to be susceptible, should be added.

4. Treatment for strains of TB resistant to at least isoniazid

and rifampin should be given for at least 18 months after

culture conversion to negative; and for up to 24 months after

culture conversion to negative in some HIV-seropositive

individuals or those with cavitary disease.

5. An individual with multidrug-resistant TB should be

treated under a program of directly observed therapy (DOT).

6. An individual with multidrug-resistant TB should not be

treated with intermittent therapy regimens.

7. For an individual with a positive M. tb culture after three

(3) months of anti-tuberculosis treatment, at least two (2)

treatment decision alternatives are available.

8. If an individual is not acutely ill, or clinically deterio-

rating, the current or last prior antituberculosis regimen is con-

tinued until the new drug susceptibility results are available.

This is often referred to as a "holding regimen".

9. If she/he is acutely ill, or clinically deteriorating, new

medications need to be started, based on an assessment of what

remaining medications the organism is likely to be susceptible

to. The original medications should be continued pending

repeat drug susceptibility testing results.

10. If a regimen is not failing, but it is too soon to discontinue

any medications (i.e., individual has clinical improvement and

M. tb cultures have converted from positive to negative) and

the individual is having severe-enough side effects from an

identifiable medication, precluding its further use, two (2)

therapeutic chokes are available, depending upon the duration

and success of treatment until the adverse reaction occurred.

11. The medication responsible for the side effect should be

omitted and the remainder of the anti-TB treatment regimen

continued;

12. Alternatively, a new, previously unused agent for the

offending drug should be substituted.

13. If the cause for the adverse reaction (e.g, hepatotoxicity,

skin rash) cannot be readily identified, all medications should

be discontinued and retested by reintroduction singly into a

regimen or trial.

14. Aminoglycosides or capreomycin, when indicated, should

be used for the recommended time period of four (4) to six (6)

months unless ototoxicity or nephrotoxicity develops. A course

of antibiotics which continues six months after culture conver-

sion may be appropriate, if there is extensive disease or slow

conversion of sputum cultures. With documented MDRTB,

overtreatment is far preferable to undertreatment, which may

have dire consequences for the individual and his/her family.

Regiment of anti tuberculosis drug

The goal of treatment is to cure the patient and to prevent

Cermin Dunia Kedokteran No. 137, 2002

the acquisition of (more) resistance. Decision regarding the

choice of regiment in the intensive phase of treatment based

on, the results of susceptibility testing, which is rarely

available before treatment is implemented. General guidelines

to select regiment is then based on Lambregsts- Weezenbeek

(1997)

(4)

I. If drug resistance is suspected, but not proven

The choice of the regimen depends on the reason for the

suspicion. In these circumstances the following guidelines

apply: 1) in a case with a history of previous treatment the

initial regimen should contain at least two, but preferably three

or four, drugs the patient has not taken before; 2) in a case

when the patient is known (or believed) to be infected by a

drug-resistant "index case", the initial phase of treatment

should be based on the susceptibility pattern found with the

index case; 3) in a case when the patient originates from a

region with high levels of drug resistance (mostly INH or

streptomycin), an intensive phase with at least four drugs

should be started (INH, rifampicin, pyrazinamide, ethambutol).

The continuation phase of treatment should not be started until

the susceptibility test has proved the strain concerned to be

susceptible for both INH and rifampicin; 4) if the suspicion is

based on clinical information (persistence of positive smears,

poor clinical response, reoccurrence of positive smears after

sputum conversion), at least two new drugs must be added. A

single drug should never be added to a failing regimen since

that may cause acquisition of new drug resistance.

II. General guidelines in cases when the susceptibility

pattern is available

a. INH or INHlstreptomycin resistance. A three drug

regimen with rifampicin, pyrazinamide and ethambutol given

for 6-9 months is highly effective. Some clinicians prefer

continuing isoniazid in the regimen.

b. Resistance to rifampicin only. A rational regimen would

consist of an initial phase of at least two months (until sputum

conversion) with INH, pyrazinamide, ethambutol and strepto-

mycin, followed by a prolonged (the sterilizing effect of

rifampicin is lacking) continuation phase with INH and

ethambutol.

c. Mul6dru4g resistance (resistance to at least INH and

rifampicin). Sometimes the most important move a physician

can make is to consult a more experienced colleague.

The treatment regimen depends on the susceptibility

pattern, the potency of the drugs for which the strain con-

cerned is still sensitive in vitro, and the clinical status of the

patient. The optimal duration of such a regimen has yet to be

identified. In the literature a duration of 24 months after

sputum culture conversion is advised, based on the impression

that discontinuation before this time increases the risk of

relapse.

Although the treatment of MDR tuberculosis requires an

individual analysis for each case, some general guidelines

were presented by Iseman (1993)

(5)

. 1) initiate the therapy in

hospital to permit observation of toxicity and intolerance and

to allow a change of regimen before strongly aversive con-

ditioning makes the patient psychologically and physically

intolerant of antituberculous medication, 2) initiate treatment

with small doses of each drug and increase to the planned dose

within 3-10 days; 3) drug dosages and optimal timing of

administration should be determined for each patient in order

to achieve maximal serum concentrations in the target range

with minimal side-effects; 4) absorption of antituberculous

drugs should be documented in AIDS patients who are at risk

for malabsorption.

In case of MDR tuberculosis the treatment regimen should

include at least four, but possibly as many as six or seven

drugs, to which the strain concerned is still susceptible. The

regimens proposed by Iseman (1993)

(5)

are summarized in

table 1.

The fluoroquinolones (ofloxacin, ciprofloxacin) are pre-

ferable to the other second-line drugs with regard to both

antimycobacterial activity and safety.

Table 1. Potential regimens for patients with tuberculosis with various

patterns of drug resistance

(4)

Resistance

Suggested

regimen

Duration

of therapy

months

Comments

Isoniazid,

streptomycin,

and pyrazinamide

Rifampin

Pyrazinamide

Ethambutol

Amikacin*

6-9

Anticipate 100%

response rate and less

than 5% relapse rate

Isoniazid and

ethambutol

(

± streptomycin)

Rifampin

Pyrazinamide

Ofloxacin or

ciprofloxacin

Amikacin

6-12

Efficacy should be

comparable

to above region

Isoniazid and

rifampin

(

± streptomycin)

Pyrazinamide

Ethambutol

Ofloxacin or

ciprofloxacin

Amikacin*

18-24 Consider

surgery

Isoniazid, rifampin,

and ethambutol

(

± streptomycin)

Pyrazinamide

Ofloxacin or

ciprofloxacin

Amikacin*

Plus 2+

24 after

conversion

Consider surgery

Isoniazid, rifampin,

and

pyrazinamide

(

± streptomycin)

Ethambutol

Ofloxacin or

ciproftoxacin

Amikacin

Plus 2+

24 after

conversion

Consider surgery

Isoniazid, rifampin,

pyrazinamide and

Ethambutol

(

± streptomycin)

Ofloxacin or

ciproftoxacin

Amikacin*

Plus 3+

24 after

conversion

Surgery, if possible

*; If there is resistance to amikacin, kanamycin and streptomycin,

capreomycin is a good alternative. Injectable agents are usually continued for

4-6 months if toxicity does not intervene. All the injectable drugs are given

daily (or twice or three weekly) and may be administered intravenously or

intramuscularly. t: Potential agents from which to choose : ethionamide,

cycloserine, or aminosalicylic acid. Others that are potentially useful but of

unproved ability include capreomycin and amoxycyline clavulanate.

Clarithromycin, azithromycin, and rifabutin are unlikely to be active.

The MIC of both drugs is low for strains not previously

exposed to the drug. However, resistance to fuoroquinolones

has been shown to develop if they are used in an inadequate

regimen. Fluoroquinolones are well tolerated with little

Cermin Dunia Kedokteran No. 137, 2002 15

toxicity despite long-term high dose administration (Iseman,

1993). Of all tuberculous drugs, ethionamide is the most

poorly tolerated (severe gastrointestinal distress). Because few

patients can tolerate therapeutic doses, its use should be

restricted to situations without other alternatives

(5)

Due to high levels of cross-resistance with rifampicin,

rifabutin does not play an important role in the treatment of

patients with MDR tuberculosis, except in those few patients

who have rifabutin-susceptible strains

(5)

. Pretet and co-workers

did report good results with rifabutin-containing regimens in

the treatment of MDR, but it is difficult to assess the respective

role of rifabutin and companion drugs in cases of successful

treatment.

Cycloserine is known for potential central nervous system

toxicity

(5)

. It is advised to monitor serum concentrations (peak

concentrations should be 25-35 ug.ml

. Pyridoxine 50-100

mg.day

is often added, although its value has not been proved.

In case of resistance to amikacin, kanamycin cannot be

used (cross-resistance), but capreomycin can be used (no

cross-resistance with either of these two drugs).

Surgical intervention

(4)

Experience with large numbers of patients with MDR

tuberculosis indicates that a favourable bacteriological

response to chemotherapy usually occurs within 4 months. If

sputum conversion does not occur or the patient relapses, the

potential benefits of surgery should be as an adjunct to medical

treatment. In particular, patients with high levels of resistance

to INH, rifampicin and the otter first line drugs should be

considered for operation, provided their disease is sufficiently

localized and they have adequate cardiopulmonary reserve.

The goal of surgery is to excise all gross disease.

MANAGEMENT OF CONTACT OF MDR CASES

Therapy Strategy

Person contacted by MDR tuberculosis at the risk of

developing active MDR tuberculosis should be advised to take

an alternative preventive (AP) regiment , which-depending on

the susceptibility pattern is advised to use either a quinolone in

combination with ethambutol or pyrazinamide, or a combina-

tion of ethambutol and pyrazinamide.

Who should be treated with AP-regimens?

Infected contacts with a normal immune status, who have

never been infected with tubercle bacilli before, face a 5-10%

risk of developing active tuberculosis during their life. Eighty

per cent of those who do break down to active disease, do so

within 2 years of infection. The risk of break down to active

disease is much smaller if the contact case has been infected

with tubercle bacilli before (known to have a positive tuber-

culin skin test or previous disease).

On the other hand, the risk of developing active tuber-

culosis is much higher in immunocompromised contacts,

especially HIV-infected persons, iminunodeficiency being the

most important determinant of whether a person infected with

M. tuberculosis will break down to active disease. Given the

unknown effectiveness of these alternative preventive regi-

mens and the high rates of side-effects, the use of these AP

regimens should be limited to: 1) infected contacts who are at

high risk of developing active MDR tuberculosis; and 2)

infected contacts who, after proper information, decide that

they prefer preventive treatment. It must be stressed that the

likelihood of a recent infection with MDR tubercle bacilli must

be assessed according to the diagnostic guidelines, and the

presence of active tuberculosis should be ruled out before

preventive treatment is started. This advice implies that all

contacts of MDR tuberculosis cases should be informed about

the relative risk of developing active disease and the increased

risk in case of coexistence of HIV infection.

Contacts at high risk of developing active MDR tuber-

culosis

Immunocompromised persons believed to be recently

infected with MDR tubercle bacilli should be advised to take

an AP regimen. The choice of this regimen must be based on

the last susceptibility pattern found in the index case. Before

AP treatment is started, active tuberculosis must be ruled out.

Since extrapulmonary tuberculosis is common in HIV-infected

persons, these patients should be questioned about nonpulmo-

nary symptoms. Although extrapulmonary tuberculosis cannot

be excluded in all cases, the risk must be reduced as much as

possible. CDC advises to continue AP-treatment in HIV-

infected contacts for 12 months. However, the optimal

duration is yet to be clarified. All persons on treatment must be

advised to report immediately in case of symptoms and/or

side-effects.

Contacts at low (0-10%) risk of developing active MDR

tuberculosis

Some contacts, who realize that the chance of remaining

healthy is probably >90%, prefer clinical control visits to a 6

month AP regimen of unknown effectiveness, which is often

not well tolerated. This policy seems perfectly responsible

provided that these contacts are systematically controlled for at

least 2 years following infection. At the end of this period their

risk is reduced to 0-2%. These patients must be instructed to

report in case of (even minor) clinical symptoms. However,

some patients cannot endure the presence of, as one patient put

it "a time bomb in my body with a 10% risk of exploding".

In those cases an AP regimen can be of great physical and

mental support to the patient. Furthermore, the risk of side-

effects and poor compliance is probably much smaller in these

cases.

Prevention of the occurence of MDR

In response to the increasing prevalence of drug-resistant

TB in the United States, CDC/American Thoracic Society

(ATS) has released an update on the previous recommen-

dations for the treatment of tuberculosis (TB) among adults

and children

(1)

. The most notable changes. These recommen-

dations include the need for a) in vitro drug susceptibility

testing of Mycobacterium tuberculosis isolates from all

patients and reporting of these results to the health department,

b) initial four-drug regimens for the treatment of TB, and c)

Cermin Dunia Kedokteran No. 137, 2002

initial directly observed therapy for persons with TB.

Adherence to these recommendations will help prevent the

occurrence of more cases of drug-resistant TB, reduce the

occurrence.

WHO strategy combines case detection through sputum

smear microscopy, registration of each patient detected, and

standardized multidrug treatment under DOTS. This strategy

will detect 70% of TB cases and cure 85% of those newly

detected cases. By making sure that patients take their full

course of medications, it will prevent MDR-TB from

emerging. Dr. Arata Kochi (WHO) announced that more than

100 countries have implemented to some extent the

recommended DOT.

The United States implements the DOTS strategy in more

than 90% of the total population, but the status of the TB

epidemic in this country varies from community to commu-

nity

(7)

However, only 17% of the world's TB patients are

receiving DOTS, in which trained workers and volunteers

observe and record patients swallowing the correct dosage of

anti-TB medications for the entire 6 or 8 month therapeutic

course

(2)

Decisions regarding the use of expanded or universal

DOT should be based on a quantitative evaluation of local

treatment completion rates. If the percentage of patients who

complete therapy within 12 months is less than 90% or

unknown, the use of DOT should be expanded. If greater than

or equal to 90% of patients beginning therapy complete a

recommended course of therapy within 12 months, the

expanded use of DOT may not be necessary. However, even in

these circumstances, consideration should be given to extend-

ing the use of DOT to increase the treatment completion rate.

All patients with TB caused by organisms resistant to either

INH or RIF and all patients receiving intermittent therapy

should receive DOT.

A program in which DOT is routinely used for all patients

had a completion rate of 98%. Although expanding the use of

DOT may require additional resources, intermittent, directly

observed regimens are cost effective (CDC unpublished data).

DOT can be conducted with regimens given once a day, 2

times/week, or 3 times/week.

Post-treatment Evaluation

An individual who was treated for TB resistant to at least

isoniazid and rifampin should be evaluated every six (6)

months by symptom review and sputum for AFB smear, cul-

ture and drug susceptibility testing, and chest x-rays (if pulmo-

nary TB) for two (2) years after completion of treatment.

Other individuals also may be followed at those intervals

after treatment completion, including those who:

were treated for TB resistant to isoniazid alone; or

rifampin alone

are HIV-infected, or otherwise immunocompromised

(with any strain of TB, whether susceptible or drug-resistant);

and

have completed a full course of anti-tuberculosis treat-

ment.

PROGNOSIS

Multidrug-resistant TB (MDRTB), associated with high

death rates of 50% to 80%, spans a relatively short time (4 to

16 weeks) from diagnosis to death

(10)

. Delayed recognition of

drug resistance, which results in delayed initiation of effective

therapy, is one of the major factors contributing to MDRTB

outbreaks, especially in health-care facilities

(11,12)

. In most

countries, MDRTB has increased in incidence and interferes

with TB control programs, particulary in developing countries,

where prevalence rates are as high as 48%. The high infection

and death rates pose an urgent challenge to rapidly detect

cases

(1)

Multidrug-resistant strains of Mycobacterium tuberculosis

seriously threaten tuberculosis (TB) control and prevention

efforts. Molecular studies of the mechanism of action of

antitubercular drugs have elucidated the genetic basis of drug

resistance in M. tuberculosis. Drug resistance in M. tuber-

culosis is attributed primarily to the accumulation of mutations

in the drug target genes; these mutations lead either to an

altered target (e.g., RNA polymerase and catalaseperoxidase in

rifampicin and isoniazid resistance, respectively) or to a

change in titration of the drug (e.g., InhA in isoniazid resis-

tance). Development of specific mechanism-based inhibitors

and techniques to rapidly detect multidrug resistance will

require further studies addressing the drug and drug-target

interaction

BIBLIOGRAPHY

Ashok Rattan, Awdhesh Kalia, Nishat Ahmad. 1998. Multidrug resistant

Mycobacterium tuberculosis : molecular perspective. Center for Disease

Control Emerging Infectious Diseases, 1998; 4 (2) : 195-207.

Brown P. Drug resistant tuberculosis can be controlled, says WHO. BMJ

2000; 320 : 821.

Bureau of Tuberculosis control, New York City. Section VII : Evaluation

and Treatment of Drug-resistant Tuberculosis Policies and Recommen-

dation, 1996.

4. Lambregts-Van Weezenbeek. Drug Resistant Tuberculosis. In

Tuberculosis, edited by Wilson R. Eur Respir Society, vol. 2, Monograph

4, July 1997 : 298-326.

5. Iseman D. Drug therapy. Treatment of mufti-drug-resistance tuber-

culosis. N Eng J Med 1993; 329 : 784-91.

CDC Prevention Guidelines. Initial therapy for tuberculosis in the era of

multidrug resistance - Recommendation of the Advisory Council for the

elimination of tuberculosis. MMWR 42 (RR-7); 1993 : 001-8.

Mike Bykowski. DOTS may contain tuberculosis epidemic. International

Medical News Group. Pediat News 1999; 33 (5) : 22.

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