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African Journal of Health Sciences
The Kenya Medical Research Institute (KEMRI)
ISSN: 1022-9272
Vol. 15, Num. 1-2, 2008, pp. 6-13
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African Journal of Health Sciences, Vol. 15, No. 1-2, Jan-Mar, 2007, pp. 6-13
Multi drug
resistant tuberculosis: a challenge in the management of tuberculosis
Evans Amukoye
Center for Respiratory
Diseases Research; Kenya Medical Research Institute (KEMRI), P. O. Box
54840-00200 Nairobi, Kenya; e-mail: crdr@todays.co.ke
Code Number: jh08003
SUMMARY
Multi drug resistant tuberculosis (MDR-TB) will not
usually respond to short course chemotherapy. Unless the individual infected
with this bug is treated appropriately, they can continue spreading resistant
strains in the community and further fuel the tuberculosis epidemic. Diagnosis
requires drug sensitivity testing and the capability to do this is not widely
available. Multi drug resistant tuberculosis has been reported all over Africa but the prevalence is still low. The treatment is not only expensive but also quite
prolonged and compliance cannot be overemphasized. The recent outbreaks of
extensive drug resistant TB further complicate the management and control of
the disease. This is a perspective on challenges of managing MDR TB and its
effect on the control program the information presented is gathered from
published data.
Introduction
Tuberculosis (TB) is one of the fastest growing epidemics.
Worldwide over 1 billion people are infected with dormant TB. Nine to eleven
million people have active TB predominately in Asia, Africa, and Latin America,
and almost 3 million people die of TB annually, including half a million
children. WHO estimates that 4.5 million people are co-infected with the human
immunodeficiency virus (HIV) and TB. TB flourishes where there is poverty,
malnutrition, overcrowding, and deficient health care [1]. In Kenya the notification rate of all forms of TB over the past 5 years has been increasing by
an average of 14%. Reported cases of Tuberculosis have risen from 10,000 in the
1980s to over 100,000 in 2004 [2]. The increase has been driven mainly by the
high prevalence of HIV in the population. It is estimated that up to 60% of TB
patients are co-infected with HIV in Kenya [2]. MDR TB, which has been
demonstrated to occur in indigenous Kenyans, could complicate management of TB
and erode the gains made by DOTS if its prevalence is left to grow in the country [3].
Definition
Multi-drug resistant (MDR) Tuberculosis refers to
resistance in vitro to at least Isoniazide (INH) and rifampicin (RIF). Resistance to at least two drugs other than the combination of INH and RIF is known as polyresistant tuberculosis and monoresistance is the resistance due to only
one anti-tuberculosis medication [4]. This definition is based on the fact
that INH plus RIF is the most important combination and resistant to them will
lead to failure of short course chemotherapy even though resistant to other
drugs could also lead to failure. MDR TB may be due to acquired resistance,
that is strain of M. tuberculosis that was initially sensitive to DOTS
drugs, but becomes resistant to drugs within an individual in the setting of
low drug levels, intermittent therapy or effective monotherapy. Primary
resistance is infection with a strain in M. tuberculosis that is
already resistant to important first-line drugs [4].
Cases of MDR TB have been documented throughout
the world including in the United States, South America, Central America,
Africa, Mexico, Russia and the former Soviet Union, Western Europe, Eastern
Europe, the Caribbean, Asia, New Zealand and Austria. The problem has been
growing over the past several years and mathematical modeling suggests that
unless a concerted effort is made to stop MDR TB, it will become a major public
health problem on several continents [3-14].
Causes
Effective therapy for disease due to M. tuberculosis
was discovered in l943, when streptomycin (SM) was identified. It was noticed
that patients with TB who initially improved on SM often failed therapy; they
no longer then responded to the drug, even at higher doses. Although a single
potent drug could often eradicate the majority of tubercle bacilli, natural
mutants resistant to that drug survived to become the dominant strain [15].
This mutant was then transmitted to other members of the community. INH and
paramino salicylic acid (PAS) were developed shortly after SM, but when used
alone, they would also develop acquired resistance [16,17]. It was then
recognized that combinations of antituberculous drugs could prevent the
development of drug resistance and thus, treatment regimens including more than
one antituberculous drug became the standard of care.
It is worth reiterating that MDR TB, a relatively
new threat to health, is an entirely man-made phenomenon; antituberculous drug
resistance is the result, ultimately, of poor therapeutic practices [18]. If
TB-control efforts had been well organized decades ago, it is likely that the
dimensions of this problem would be significantly smaller. Thus, the
introduction of systematic and effective control of drug-sensitive TB, through
DOTS, is our best weapon against the generation of drug resistance [19].
Directly Observed Therapy, Short Course (DOTS)
refers to a specific type of tuberculosis-control program, requiring the
following elements: 1) government commitment to a National Tuberculosis
Program; 2) passive case-finding in general health services by sputum smear
microscopy examination of samples from suspected TB cases; 3) standardized
short-course chemotherapy administered to at least all smear-positive TB cases
under specified case-management conditions with therapy being directly
observed; 4) regular uninterrupted supply of all essential antituberculous
drugs; and 5) a monitoring system for program supervision and evaluation. A
strategy to manage MDR TB that takes advantage of the many strengths of the
DOTS strategy is known as DOTS-Plus [19,20].
Failure of DOTS to adequately treat drug-resistant
TB (whether polyresistant or MDR TB) lead to generation of further resistance
and ultimately the circulation of highly resistant strains of M.
tuberculosis. The result of the generation of high-grade drug resistance
by inadequate therapy is not only grave for the patient, but for the community
at large, as drug-resistant strains are spread by the same airborne,
person-to-person mechanism as a susceptible strains of TB Drugs. DOTS is
ineffective for curing either form of MDR TB and for preventing further spread
of drug-resistant strains in the community. It is worth to note that not all
re-treatment cases of tuberculosis have MDR. In Malawi of 164 culture positive,
81% (122) were fully sensitive and only 4% (6) had MDR [21]
Factors that favor the development and spread of MDR-TB are
incomplete or inadequate therapy that can select for drug-resistant mutants of M
tuberculosis. Prolonged infectiousness of patients due to delayed
diagnosis of MDR TB and to the absence of effective therapy also allows ongoing
transmission of drug-resistant strains to susceptible contacts. Patients with
cavitary lesion have a tendency to have a more chronic illness and higher
chance of having MDR and should be isolated especially from immuno-compromised
HIV patients [7].
Patients infected with primary drug-resistant TB
treated with short-course chemotherapy are less likely to be cured. Patients
sick with drug-resistant TB exposed to short-course chemotherapy can further
acquire resistance through inadvertent monotherapy (the amplifier effect)
[22]
Kenyan
situation
Since the introduction of short course chemotherapy in
Kenya in 1993, the treatment success rate has been about 80%, the death rate
reduced from 1% to 0.4%. In 2003 7% of all TB treatment were on re-treatment
regime [2]. Though there is usually a higher drug resistance in the
re-treatment population, it may not be evidence of MDR and outcome of
re-treatment may be good, as shown in a study done in Malawi [21]. A
well run control program such is available in Kenya is important in reducing
secondary (acquired) drug resistance. In 1995 MDR was not reported in general
population but was isolated among the refugees. [3] This is no longer so as
patient seeking culture services at the Kenya Medical Research Institute
(KEMRI), 11.4% of the 983 specimen tested positive for MDR tuberculosis
[23,24]. This was the first time MDR was documented in indigenous Kenyans,
even though there have been sporadic reports of MDR from public and private
sector. KEMRI has undertaken a survey of drug resistant Tuberculosis and the
results will soon be published. In Ethiopia, our neighbour,
Multi-drug-resistance (MDR) TB was reported to be about 1.2% of new cases and
12% of re-treatment cases [25].
Situation
in children
It is difficult to diagnose MDR tuberculosis in children
and this results in delay in treatment. In South Africa the median age of
diagnosing tuberculosis was 4.5 years at first TB diagnosis and 6.2 years on
MDR culture confirmation. Delay in starting appropriate MDR treatment after TB
diagnosis was a median of 2 days if MDR TB source cases were taken into
account, but 246 days if the drug susceptibility pattern of the source case was
not considered, and 283 days if there was no known tuberculosis source case.
Seventeen children had smear positive tuberculosis, of which 13 had cavitatory
pulmonary disease. Eight children had central nervous system TB. Thirty-six
children were treated for MDR tuberculosis, of whom four died. Obtaining a
detailed contact history and their culture and sensitivity result is essential
in reducing the delay in starting treatment. Delay of starting appropriate MDR
anti-tuberculosis treatment has potentially serious consequences [26].
DOTs-plus
strategy
Evidence, and consequent estimates, suggested that the MDR
situation in developing Countries, especially in sub-Saharan Africa, is
deteriorating rapidly [27]. Similarly, major increases in tuberculosis have
been observed in the former USSR. It was estimated that some 7-8 million new
cases and 2-3 million deaths were occurring annually in the world. The global
targets of reaching 85% cure rates and 70% case detection among infectious
cases were established by the World Health Assembly in 1991. The WHO
declaration of TB as a global emergency in 1993 and the launch of the
five-element DOTS strategy in 1994-1995 resulted in countries adopting DOTS in
encouraging numbers. In 2000, 148 countries including all 22 highest burden
countries (HBC) responsible for 80% of cases worldwide, had adopted the new DOTS
strategy [27]
WHO
position statement on MDR TB is
- To achieve TB control worldwide
and to prevent the emergence of anti-tuberculous drug resistance, the WHO
considers implementation of sound TB-control based on the DOTS strategy as a
top priority.
- Recognizing that MDR TB is a
considerable threat to the effectiveness of DOTS in some areas of the world,
WHO strongly supports pilot projects to assess the feasibility of DOTS-Plus
interventions in a variety of settings, provided DOTS is in place.
- Based on the results of these
pilot projects, WHO and its partners in the newly established Working Group on
DOTS-Plus for MDR TB will formulate international policy recommendations on MDR
TB management. [19]
Effects of HIV
on MDR TB
History
of previous TB treatment, and not HIV infection, was the principal factor
associated with TB, which is resistant to at least one primary anti-TB Drug.
HIV co-infection can shorten the period from TB infection to disease leading to
lengthier periods of infectiousness. In a population-based representative data
on new and previously treated patients with TB collected within an
international drug resistance surveillance network, Espinal et al concluded
that prior but ineffective treatment is a strong predictor of drug resistance,
and that HIV is not an independent risk factor for MDR-TB [28].
The association between length of treatment and
drug resistance may reflect longer treatment as a result of treatment failure
in patients with drug resistance; it may also reflect irregular prior treatment
for TB, leading to drug resistance. However, as the HIV epidemic progresses in
a milieu of high TB prevalence, the link with drug-resistant TB warrants
constant monitoring and investigation [28].
Treatment of MDR TB
Management of MDR-TB relies on prompt recognition.
Traditional culture of Mycobacterium tuberculosis isolates on solid
media is slow, a commercialized molecular genetic test for a limited number of
target loci might be a good alternative for a drug resistance-screening test in
the context of an MDR DOTS-plus strategy [29].
DOT-plus strategy is more crucial in the
treatment of MDR TB because of the extended duration and the potential for
greater side effect. Emerging data suggest that in younger patients with little
co-morbidity, the occurrence of serious adverse effect is rare and does not
compromise treatment outcome. Trained individuals with experience in second
line drugs are preferred to supervise therapy, but administration of medication
in health centers could promote transmission of nosocomial MDR TB. A number of
studies have demonstrated the effectiveness of community health workers in
responding to serious challenges to health. The value of directly observed
therapy in the treatment of MDR TB can not be underestimated, this could
include mouth check after swallowing drugs, serum check where this is available
and/or examining for side effect such as bronzing of the skin with clofazimine
to ensure adherence.
The foundation of treatment consists four to five
drugs to which the infecting bug is (likely) susceptible. The regime should
include a parenteral drug, a first line drug to which the infective strain is
likely susceptible and a fluoroquinolone whenever possible. Choose bactericidal
(more efficacious) to which the patient has no allergy. Tuberculosis is
sometimes partially resistant to Isoniazide, in such situations it can be used
at a higher dose in conjunction with pyridoxine. Isoniazide cant be used in
higher doses in conjunction with pyridoxine in situations where TB is fully
resistant to it. Adjuvant treatments that can be used include the use of
cortcosteroids in patients with severe respiratory distress, central nervous
system involvement or laryngeal TB to try and prevent permanent sequelae of
chronic inflammation. Surgery has been recommended with good results in
patients with unilateral or focal disease that has no clinical response after 3
to 6 months of specific therapy. Other indications of surgery are high-grade
resistance with extensive parenchymal damage, recurrence of positive smear or
culture during or after treatment. [30].
Adverse drug reactions
The adverse drug reactions depend on drugs used. The
following are some of the documented adverse reaction: Nervous system-
includes headache, weakness, fatigue somnolence and insomnia. More serious
reaction includes seizure, peripheral neuropathy, ototoxicity, optic neuritis
and psychiatric reaction. Gastrointestinal side effects -are nausea, vomiting,
diarrhea, bloating, abdominal cramps and gastritis. Rarely gastric ulcer or
hepatitis may occur.
Endocrine effect such as worsening of glycemic control in diabetics,
changes in menstrual period and hypothyroidism may occur.
Dermatological reactions such a skin color changes,
photosensitive, and dry skin are frequently observed, while anaphylaxis and
Stevens-Johnson syndrome are rare but potentially lethal. Renal and electrolyte
disturbances include acute renal insufficiency, nephrolithiasis, proteinuria
hypokalemia and hypomagnesemia.
Other minor adverse effects include
arthralgias, myalgias, cramps and candidal vaginitis. Dehydration and/or weight
loss, associated with gastrointestinal symptoms, may occur in the early months
of treatment. [31-38].
Duration of treatment
Treatment of MDR TB is long, it is recommended that
parenteral medication should continue for six months and oral medicine should
continue until there is 18 to 24 months of culture negative sputum (specimen).
Clinical response, radiological response and degree of resistance also
determine the duration of treatment. After terminating treatment routine follow
up and specimen collected for culture every 6 months for 24 months [39]. The
prognosis of patients treated for MDR TB has been improving as effective drugs
become available and as experience is gained in treating this condition. In a
study done in South Africa out of 443 patients infected with MDR TB after 5
years 44% had died, 15% had severe chronic respiratory disease, and only 33% we
cured. The situation has improved with almost an 80% cure in some setting where
DOTs- plus is practiced [40].
Extensive drug resistance (XDR)
Physician
working in Kwazula Natal, South Africa in 2005 noticed rapid deaths among
patients with co-infection of TB and HIV [41]. Gadhi et al compiled 1539
patients with tuberculosis from this area. MDR was detected in 221 of these
patients of whom 53 had XDR. All of those tested for HIV (44) were HIV
positive. 52 of 53 patients died with median survival of 16 days from the time
of diagnosis. 85% of the isolates had similar strain. 55% of these patients
had not previously been treated [42]. XDR tuberculosis is defined
as MDR (Resistant Rifampicin and Isoniazid) as well as resistant to at least
two of the 6 primary classes of second line drugs, one being a fluoroquonolone
and the other an injectable drug [43]. Centers for Disease Control (CDC) and
WHO in 2006 documented XDR in at least 17 countries. The data showed 10% of
MDR were XDR. Data from USA, Latin and Kofa showed that the XDR rates range
from 4% to 19% among MDR isolates [41].
Since a percentage of MDR is XDR it means that XDR must be existing in Kenya
though the number may be small as MDR is not yet a major problem in this
country. The cause of MDR and XDR is due to inappropriate use of first line
and second line drugs and the failure to diagnosis patients leads to increased
spread of the strains diseases. Therefore it is necessary to strengthen the
laboratory capacity and improve adherence to taking tuberculosis drugs or
otherwise face a situation in which the spread of TB will be driven by both HIV
scourge and MDR/XDR. Research into new drug sneed to be speeded up.
Conclusion
The
prevalence of MDR Tuberculosis is still low in Africa compared to Eastern
Europe, but it is growing and should be addressed in time. Even though the
price of treatment was brought down in countries such as Peru. The cost of
treating MDR TB in Kenya is estimated to be 1.3 million Kenya Shilling
(personal communication by NLTP manager) which is out of the reach of most of
its citizen. While HIV is fueling the TB epidemic in sub- Sahara, MDR does the
same in Eastern Europe. We are facing a situation in which we will have MDR,
HIV mixed in a milieu of poverty, a situation we dare not imagine.
Kenya should endeavor to reduce the emergence and spread of MDR-TB by
emphasizing on strict adherence to DOTs strategy. TB drugs should be
administered in DOTs registered centers. Any patient with evidence of long
standing disease such as demonstration of cavities on chest X-ray, should be
isolated until drug sensitivity result is known, as MDR-TB is common in long
standing disease. All patients with MDR-TB should be treated promptly therefore
the effort the National Leprosy and Tuberculosis Program to introduce DOTS-plus
is highly supported. The introduction of DOTS-plus could also remarkably reduce
the cost of treating MDR-TB.
The management of XDR will remain a challenge as there is a no effective
treatment and isolation for indefinite period could raise human right issues.
Health workers working with patients infected with MDR/XDR or even suspect TB
should have HIV tests regularly. Those found positive should opt to work in
less risky environments. I conclude by stating that MDR/XDR tuberculosis is a
growing threat in the control of tuberculosis and this is the time to act.
Acknowledgement
I
acknowledge with thanks tremendous support and permission from the Director,
KEMRI that has made this write-up possible.
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