Jaime E Ollé -Goig

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Editorial: The treatment of multi-drug resistant tuberculosis – a
return to the pre-antibiotic era?
Jaime E. Ollé-Goig
Catalan Association for the Control of Tuberculosis in the Third World (ACTMON), Barcelona, Spain
keywords tuberculosis, multidrug-resistance, DOTS-Plus
We as scientists have an obligation to address the
ethics of transnational research, the distribution of
drugs of the so-called ‘diseases of poverty’… (Beyers
& Chan-Yeung 2003)
When the eyes don’t see the heart doesn’t feel
(Spanish proverb)
When Magdalena was 15 years old she was diagnosed
with smear-positive pulmonary tuberculosis (TB). She lived
with her mother, a stepfather and 13 siblings in a very
humble dwelling in an Andean country. Her stepfather
would often beat her because she was unable to perform
her assigned domestic chores. As a result, she would flee
and abandon her treatment. She was prescribed several
regimens which she took erratically. Three years later she
was still smear-positive; the chest X-ray showed multiple
cavities in both apices and drug susceptibility testing
confirmed resistance to isoniacid (H), rifampicin (R),
ethambutol (E) and streptomycin (S). The following year
she became pregnant and died of respiratory insufficiency
6 months later.
Peter is a 45-year-old primary school teacher in an
Eastern African country; he lives with his wife and
several children. In September 2000, he was diagnosed
with smear-positive TB and was given the category I
regimen (2HRZE/6HE; Z ¼ pyrazinamide); at the com-
pletion of treatment he was still smear-positive. Despite
taking the category II regimen (2HRZES/1HRZE/5HRE)
twice, he remained smear-positive. He saw a consultant
in the capital who prescribed the entire gamut of second-
line TB medications. The only drug which Peter was able
to find was ciprofloxacin, which he took for several
months. His latest drug susceptibility tests have demon-
strated resistance to H, R, E, S and ciprofloxacin; the
chest X-ray shows multiple cavities, especially in the
left lung. He remains weak, emaciated, dyspnoeic and
smear-positive.
These two patients from different continents had two
characteristics in common: first, they suffered from a very
serious form of TB; and secondly, they could not be treated
adequately for lack of medication. Let us briefly examine
the reasons underlying their clinical condition and lack of
effective treatment.
Resistance to TB medications
All patients harbouring large numbers of bacilli have some
mutant organisms resistant to one anti-TB drug. The
number of these resistant bacilli is minimal compared with
the population of susceptible bacilli and will be of little
clinical significance as long as the patient is not exposed to
an inadequate therapeutic regimen. Large numbers of
resistant bacilli are the consequence of human intervention,
which, by selecting the few naturally existing resistant
bacilli, afford them a microbiological and clinical role they
would not have under ‘normal’ conditions (no exposure to
anti-TB drugs).
Resistance cropped up almost as soon as the modern era
of TB treatment began, more than 50 years ago, when
streptomycin was administered as monotherapy (Crofton
& Mitchinson 1948). Many patients with meningitis were
cured, but those with pulmonary TB and large bacillary
populations rapidly became resistant. Because naturally
mutant bacilli are resistant to only one drug (resistances to
different drugs are not linked and are therefore highly
unlikely) the detection of resistance to more than one anti-
TB medication implies a multi-step selection process: the
patient must have received a sequence of several non-
curative regimens. The result is a sick person who, through
faulty human intervention, has been transformed from a
patient suffering from a fully drug-susceptible disease into
a patient suffering from a multiple drug-resistant disease.
Resistance to the two most effective drugs, isoniacid and
rifampicin, is termed multidrug-resistance (MDR); its
treatment is far from easy and frequently results in failure
or even death (Garcı́a-Garcı́a et al. 2000; Lockman et al.
2001; Mukherjee et al. 2004).
MDR-TB in the world
Little attention was given to MDR-TB until the last decade,
as it was not considered to be an important problem. A
Tropical Medicine and International Health doi:10.1111/j.1365-3156.2006.01770.x
volume 11 no 11 pp 1625–1628 november 2006
ª 2006 Blackwell Publishing Ltd 1625
group from Denver had given due attention to this issue
(Iseman 1993) but it was not until several outbreaks took
place in the United States (Dooley et al. 1992; Pearson
et al. 1992; Frieden et al. 1993; Salomon et al. 1995) that
the world began to take notice.
Two surveys by the WHO and the International Union
against Tuberculosis and Lung Disease using standard
guidelines revealed that resistance to TB medications was
universal but varied greatly between countries and specific
areas. MDR-TB was detected in several ‘hot spots’ but had
a very uneven distribution in the world (Espinal et al.
2001). These surveys generated important data and dem-
onstrated the urgent need to address this issue on a global
scale and, more specifically, in areas with scarce resources.
Globally, MDR-TB is not decreasing. In 2005, more than
1% of patients diagnosed with TB who had never received
treatment were MDR (World Health Organization 2005).
Access to second-line anti-TB medications
Under the auspices of WHO, a Working Group on DOTS-
Plus for MDR-TB was formed in 1999 with the main
objective of preventing further spread of this man-made
phenomenon. Securing second-line drugs at significantly
reduced prices was one of the Group’s major achievements.
It was decided that second-line drugs should be made
available only to specialized units linked to a laboratory
capable of performing reliable drug susceptibility tests. At
present, a project for treating patients with MDR-TB has
to be submitted through a National Control TB Pro-
gramme with its government’s support and follow the
guidelines developed for establishing DOTS (directly
observed treatment short course)-Plus projects. Then, if
approved by a Green Light Committee set up by WHO and
comprising several institutions, cheap second-line drugs
will be made available under strict supervision (Gupta
et al. 2001, 2002).
Pending issues
Patients with MDR-TB, such as Magdalena or Peter, who
live in a country where no DOTS-Plus projects have been
approved, will be unable to obtain effective drugs. The
resolution of their disease will depend entirely on its
natural course. Faced with this situation, several contro-
versial issues merit discussion.
Availability of cheap second-line drugs
Cheap second-line drugs are unvailable (unless through
Green Light Committee-approved projects) because of the
fear that their inadequate use will create further resistance.
This argument is not fully justifiable as the only people who
need second-line drugs are those patients who already have
some degree of resistance; patients with fully susceptible
bacilli receive the more effective first-line drugs. ‘The
possible loss of second-line anti-TB drugs due to resistance
does not take us back to the 1940s’ (Brown 2004): our
patients are already in the pre-antibiotic era and will remain
there until their demise! It is ironic that because of the
concern of contributing to the difficulties in managing a
serious clinical condition – which we may have created – we
refuse curative medications to patients suffering from this
condition. WHO has established that no intervention
against MDR-TB should be undertaken unless it can be
implemented countrywide (Espinal et al. 1999). This is
tantamount to refusing treatment to all patients with TB
(drug-resistant or not) in a particular country unless a well-
functioning National TB Control Programme is in place.
Prevention is better than treatment
This argument, based on epidemiological and cost–benefit
considerations, may be valid for those taking decisions
away from the field. For a sick individual, discussions
about prevention come too late and are irrelevant. Health
personnel in close contact with patients find it hard to
explain to them that their illness should have been
prevented; that if they had not followed an inadequate
regimen (because of poor adherence or because of faults in
the health system) they would not harbour bacilli which we
cannot eliminate with our available tools; and that the
needed medications exist but that we cannot obtain them
because of a poorly performing National TB Control
Programme unable to deliver the much needed drugs
correctly.
No DOTS-Plus until an effective DOTS Programme
is in place
Several programme managers are of the opinion that no
attention should be paid to patients suffering from
MDR-TB as long as the number of successful treatments
among susceptible patients does not reach a significant
proportion. A patient who has failed with the first
treatment (category I) and who may have resistant bacilli
will be given the re-treatment regimen (category II) as a
last chance and if no cure is achieved not much else will
be offered. This regimen not only fails to cure MDR-TB
but can further increase resistance (Espinal et al. 2000;
Furin et al. 2000; Noeske & Nguenko 2002; Han et al.
2005), as only streptomycin is added to the original
regimen. There have already been calls for its discon-
tinuation (Espinal 2003). Although this reasoning may
Tropical Medicine and International Health volume 11 no 11 pp 1625–1628 november 2006
J. E. Ollé-Goig The treatment of multi-drug resistant tuberculosis
1626 ª 2006 Blackwell Publishing Ltd
seem logical (Why try to cure the ‘difficult’ patients
while we are unable to cure the ‘easy’ ones?) I do not
share this view: treatment of patients with TB under a
National TB Control Programme is not a zero-sum
equation. Adequate care of the small numbers of patients
with MDR-TB does not necessarily have to impinge on
the treatment of the large number of susceptible patients
(Sterling et al. 2003). In fact, the technical and financial
support required for treating patients with MDR-TB
could strengthen the National TB Control Programme
(Kim et al. 2003) and, eventually, the entire health
system.
Transmission of MDR bacilli
An important issue that requires urgent action is the fact
that patients with MDR-TB not receiving treatment are
excreting highly dangerous bacilli until the day their
disease spontaneously cures itself or until they die. It has
been shown that MDR bacilli are effectively transmitted
from person to person and may cause infection and disease
(Kritski et al. 1996; Schaaf et al. 1999; Van Rie et al.
2000; Teixeira et al. 2001). The treatment of contacts of
patients with MDR-TB poses several problems as studies
demonstrating the effectiveness of any particular treatment
are scarce and no consensus has been reached on the best
prophylactic regimen (Fraser et al. 2006).
Do patients with MDR-TB have a right to be treated?
The world has not shied away from offering complex
regimens with potentially toxic and expensive medications
that must be administered for life to people with HIV. The
‘3 by 5’ initiative of WHO and partners aimed to put on
treatment no less than 3 000 000 persons (Mukherjee
2004). There is no reason why people with other infections
should be denied rights that have been recognized for HIV
patients. Why is it that what is a good for AIDS patients is
not a good for others also? (Ollé-Goig 2004).
We urgently need to face the multiple issues related to
MDR-TB. It is imperative to find a solution to the dilemma
of universal access to second-line drugs in order to save the
patients with this form of TB, which carries a very poor
prognosis when not treated. Neglecting this problem will
increase the disparities in the care of our patients, and our
goal of greater equity will be pushed further out of reach.
Dedication
I dedicate this article to the patients with MDR-TB who I
have cared for on the American and African continents
who could not obtain adequate treatment.
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Corresponding Author Jaime E. Ollé-Goig, Carretera de las Aguas 181, 08017 Barcelona, Spain. Tel.: +34-9-3205 5576;
Fax: +34-9-3487 6132; E-mail: olleuganda@yahoo.com
Tropical Medicine and International Health volume 11 no 11 pp 1625–1628 november 2006
J. E. Ollé-Goig The treatment of multi-drug resistant tuberculosis
1628 ª 2006 Blackwell Publishing Ltd


Editorial: The treatment of multi-drug resistant tuberculosis -a return to the pre-antibiotic era?

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Editorial: The treatment of multi-drug resistant tuberculosis -a return to the pre-antibiotic era?

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