1. health and fitness
2. drugs

Perspective
MDR-/XDR-TB management:
what it was, current standards
and what is ahead
Expert Rev. Resp. Med. 3(2), 133–145 (2009)
Ignacio Monedero and
Jose A Caminero†
†
Author for correspondence
Servicio de Neumología,
Hospital General de Gran
Canaria Dr Negrin,
35010 Las Palmas de
Gran Canaria, Spain
Tel.: +34 928 450 563
jcamlun@
gobiernodecanarias.org
Despite killing nearly 2 million people every year, TB is arguably the most neglected disease in
terms of the funding and research it receives. In many ways, multidrug-resistant TB is a result
of this disregard. In high-burden countries, not many improvements have been implemented in
the diagnosis and treatment tools of TB since the 1960s. Following this period, fluoroquinolones,
developed for other infections, are the only highly active new drugs against TB. Multidrug- and
extensively drug-resistant TB is booming worldwide as a result of insufficient control measures.
Furthermore, the prevalence of this disease is substantially facilitated by the HIV epidemic. After
a deadly and well-reported extensively drug-resistant TB outbreak occurred in HIV-infected
patients in South Africa, the threat of an untreatable TB epidemic is receiving increased attention
internationally. Nevertheless, drug-resistant management has lacked research and funding over
several decades and we are now faced with many controversial issues and little research-based
evidence. There are no clinical trials comparing different treatments, and current management
is based on personal experiences and agreement between experts. The major challenge for the
next few years is to improve the evidence base in order to develop more rational recommendations
that adequately address the current problem and avoid making a bad situation worse.
Keywords : diagnosis • drug-resistant TB • future • MDR-TB • TDR-TB • totally drug-resistant • treatment
• tuberculosis • XDR-TB
TB is probably one of the most long-standing [1]
and harmful diseases in human history [2] . In
the 1950s, a cure was possible for the majority
of patients through a combination of drugs [2] .
However, the uncontrolled use of anti-TB drugs
throughout the following 50 years has resulted
in the escalation of Mycobacterium tuberculosis
strains that are drug resistant (DR). As a result,
TB in certain patients has cure rates similar to
those of the pre-antibiotic era.
Initial resistance was to streptomycin (SM)
and para-aminosalicylic acid (PAS), the first
anti-TB drugs [3] . Subsequently, strains resistant
to isoniazid (INH) and especially, strains with
INH resistance linked to SM and PAS resistance,
appeared, which were the three TB treatment
bases. Certain TB cases started to be referred to
as ‘incurable’. Studies with different drug combinations were performed in an attempt to cure
such patients [4] .
Rifampicin (RMP), the most powerful antiTB drug up until the present day, was developed
in 1963. Its generalized and sometimes improper
use during the late 1960s and 1970s furthered
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10.1586/ERS.09.6
the development of resistant strains. Even more
dangerous was the development of strains resistant to both RMP and INH, the most potent and
effective anti-TB drugs [2,4] . These strains were
defined as multidrug-resistant TB (MDR-TB).
Despite the large benefits of the directly observed
treatment short-course (DOTS) strategy, which
was introduced worldwide in 1992, concerns
about incurable TB grew during the 1990s.
During this last decade, the management of
MDR-TB cases has been an international priority, as a result of approximately 500,000 estimated new cases each year [5] . There are world
regions where the situation is particularly severe,
such as the former Soviet Union Republics [6] .
Despite some progress in the control of
MDR-TB [4] and the development of an international approach for treating the disease,
even more severe forms of TB, extensively
drug-resistant TB (XDR-TB) [7–9] and totally
drug-resistant TB (TDR-TB), have evolved [10] .
Drug resistance is thus putting previous progress in the development of TB treatment at risk,
and accordingly demands new practices and
© 2009 Expert Reviews Ltd
ISSN 1747-6348
133
Perspective
Monedero & Caminero
approaches. In addition, HIV is fuelling the epidemic, creating
fatal nosocomial outbreaks [9] . The old TB is again highly lethal
in many regions.
Consistent evidence for the appropriate management of
DR-TB does not exist, given that the vast majority of patients
during the 1960s, 1970s, 1980s and 1990s were treated as
individual cases in reference centers in developed countries.
Data are limited and almost nonexistent in relation to crucial aspects, such as treatment, while there are no randomized
controlled trials (RCTs) evaluating different drug combinations. Management of these patients is particularly challenging
since it is based on experts’ opinions, which are occasionally
controversial [4] . Basic agreements on which to base standardized treatments for MDR-TB are only a recent achievement [11] .
However, many issues remain where intensive research is needed
to optimize diagnosis and treatment.
Within this perspective, we seek to review the current knowledge on MDR-/XDR-TB and the fundamental consensus. In
addition, we present a critical view of the most controversial
issues, as well as a speculative 5-year future prediction of the
MDR/XDR epidemic. To conclude, the authors provide their
opinions on potential interventions of the most pressing concerns
in the control of the epidemic.
Resistance origins: the bacteriological rationale of
TB treatment
The prognosis of TB patients changed significantly approximately
60 years ago with the onset of chemotherapy. Although PAS was
the first drug investigated [3] , studies with SM were much more
prominent during the 1940s and 1950s. These investigations
became crucial in the development of the bacteriological bases
for TB treatment. Shortly after the description of SM, clinical
trials using it as a monotherapy were conducted in the UK [12]
and the USA [13] . The case fatality was reported to be considerably
reduced. However, it was also observed that patients improved
over the first few months and subsequently deteriorated in many
cases, due to the development of SM resistance. SM trials had
a considerable impact on research for the next 20 years, which
predominantly focused on methods for preventing the emergence
of drug resistance. Further studies demonstrated that the addition of PAS to SM significantly lowered the risk of acquiring
resistance [14] .
The subsequent discovery of INH and its addition to the regimen including PAS and SM in the 1950s resulted in a highly
effective regimen that was able to cure the great majority of TB
patients [15] . It was around this time that the ‘bacillary populations theory’ was rationalized [16] . Since then it is commonly
accepted that, of the total bacilli load, there are a number that
can remain metabolically inactive (dormant) over a period of
years. Eventually, these would become active again, resulting in
disease (relapse). These forms are difficult to kill and require longterm treatments to sterilize the lesions. At the same time, metabolically active bacilli are responsible for the disease symptoms
and also the development of resistance. TB resistance appears by
selection of natural mutant strains after a drug selective pressure
134
driven mainly by monotherapy (inappropriate prescription) or
suboptimal adherence to the treatment protocol [17] . In the overall bacillary load held by a patient (from 106 up to 109 bacilli),
the number of natural mutant resistant bacilli to a single drug is
very low (just one or two bacilli on average). However, if these
few natural mutants are selected by one or both of the previous
mechanisms, they would expand into a full monoresistant population. In the case of being exposed again to a different single drug,
new mutants would be selected over the previously resistant and
so forth. To avoid drug resistance appearance and amplification,
TB needs to be treated with several drugs concurrently. Not infrequently, monotherapy and amplification is expressed clinically as
the addition of a single drug to a failing regimen [17] .
Since the mid 1950s, TB has been considered a curable disease
in almost all cases, with low treatment side effects. Furthermore,
these reactions were significantly reduced after the discovery of
ethambutol (EMB) and its addition to the regimens instead of
PAS [18] . However, EMB neither increased the efficacy of the
treatment schedule nor shortened its length (at least 18 months).
The discovery of RMP embodied a revolutionary change in the
treatment of TB [2] . The introduction of this drug resulted in earlier sputum conversion [19] . However, the main progress was that
treatment length was reduced to 6–9 months [20] . This new successful strategy was termed ‘short-course chemotherapy’ [21] . This
regimen consisted of INH and RMP for 6 months with a 2-month
intensive phase with pyrazinamide (Z). It demonstrated efficacy
of over 95% in patients with drug-susceptible TB. The adverse
reaction rate was lower than 2–3% [22] . This is Category I treatment; the regimen for new cases from the WHO [23] .
The bacteriological reasoning, previously explained, provides
two fundamental approaches: the use of several drugs avoids the
development of resistant strains, while long treatment periods
kill dormant populations, reducing the risk of relapse [2] . It was
demonstrated that the combination of three effective drugs was
sufficient to avoid resistances; however, this was described in ideal
conditions where all M. tuberculosis strains were totally susceptible. The circumstances have had notable changes over these
three to four decades; a considerable proportion of patients holding M. tuberculosis drug-resistant strains have not previously been
treated [6] . There is common agreement that, unless there are ideal
conditions and evidence that there is no resistance within the
community, TB treatment should include at least four drugs [4] .
This rule should be applied to all TB cases. This is the principal
reason that justifies the addition of EMB in the intensive phase
of Category I.
If there is resistance to INH (the most active drug for killing
metabolic forms of bacilli) and RMP (the most powerful sterilizing drug), longer and less effective treatments are required. In
this case, it is necessary to use the remaining most potent drugs to
kill active and dormant bacilli. These are fluoroquinolones (FQs)
and second-line injectable agents (second-line aminoglycosides
and polypeptides). Again, if resistance emerges to any FQ and
any second-line injectable over an already MDR-TB case, the
treatment possibilities become seriously limited. These strains
are defined as XDR-TB [24] .
Expert Rev. Resp. Med. 3(2), (2009)
MDR-/XDR-TB management
MDR-TB as a public health problem: the impact of HIV
With the advent of RMP, in many wealthy countries that had
strong primary healthcare services, TB was tackled and research
was stopped. At the same time, as it has been outlined previously,
patient resistance to RMP and INH began to appear. These were
isolated problems in settings where high numbers of patients were
treated. In an attempt to treat these limited cases, drugs developed
in the 1950s and 1960s were used. Drug resistance management
remained without substantial changes over several decades.
Gradually, the inefficient individual treatment of those few
cases created a vast prevalent group in some countries. Nonimplementation of DOTS, irregular or poor-quality treatments
and other circumstances converted this individual problem into a
public health concern (Box 1) . Outbreaks of MDR-TB began to be
reported. Finally, in the 1980s, the appearance of HIV changed
the TB landscape. It is known that macrophages and CD4 lymphocytes are the main cell targets for HIV, which are also the
principal barriers put up by the immune system to stop TB disease progression. Therefore, HIV acts synergistically to destroy
the principal protection against TB. In fact, people living with
HIV/AIDS are more likely to get infected and are 100–140-times
more likely to develop the disease and also to die as a result of
it [2,25] . Well-documented outbreaks of deadly MDR-TB among
HIV/AIDS patients occurred in many settings and increased
concerns regarding the disease and the attention paid to it on a
global scale [26–28] . TB-control programs were strengthened in
developed countries. At the same time, there was a steady introduction of antiretroviral therapy (ART) and great efforts were
made in HIV-prevention, focusing on risk groups. The situation
was partially controlled, while in developing countries, little or
no information was available.
Simultaneously in the 1980s, FQs were discovered and proved
useful not only for susceptible TB, but also for resistant strains [29,30] .
Invariably, FQ discovery has thus far been the main achievement
in MDR-TB treatment [31,32] , but the irrational use of these drugs
for other infections and among TB patients has aggravated the
problem, thus promoting the emergence of XDR-TB.
Due to concerns surrounding the increase in DR-TB, WHO
and The Union started projects to survey the global drug-resistant
TB burden. To date, there are four world DR-TB reports that
clearly indicate the extent to which the problem is growing annually [6] . Regardless, the issue only reached the international agenda
in 2006, when the Centers for Disease Control and Prevention
presented the rise of XDR-TB [33] . Shortly after that, a well-documented deadly XDR-TB outbreak in South Africa occurred [9] .
The death rate was as high as 98% among HIV-infected patients
in less than 4 weeks from diagnosis. Moreover, the genetic studies
revealed that the strains were the same, hence the transmission
was person-to-person, most likelyy within a health facility. These
circumstances promoted the issue to the top of the international
agenda, as the HIV collectives and the pharmacy industry considered that ART achievements could be hampered by untreatable TB, with a return to sanatoria times. In October 2006, a
meeting was held where actions where taken and XDR-TB was
redefined [24] .
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Perspective
Box 1. Common factors associated with selection
of TB resistance in the community.
• Poorly implemented directly observed treatment
short-course strategy
• Poor adherence and supervision of treatment
• Nonstandardized treatments
• History of frequent shortages of drug supplies in the country
• Poor quality of anti-TB drugs
• TB treatment mainly performed in the private sector
• Inefficient hospital infection control
• High prevalence of highly virulent strains of
Mycobacterium tuberculosis
• HIV infection in some settings
Adapted from [37].
Currently, the estimated number of MDR-TB cases worldwide is the highest ever reported (489,139 cases) [5,6] . The
global proportion of resistance among all cases has grown to
4.8% (95% CI: 4.6–6.0). China and India alone carry approximately 50% of the global burden, and the Russian Federation a
further 7%.
To date, XDR-TB has been reported in 49 countries since
2002 [6,34] . Data on DR-TB are unknown for more than
100 countries due to the unavailability of quality laboratories.
Estimates have a high level of uncertainty and are probably underestimated in unsurveyed countries [5] . Most MDR-/XDR-TB
patients remain undiagnosed and untreated [6,35] . Airborne
spread of XDR-TB in a world with greater human movement
and more relaxed border control is increasingly a global concern.
Risk factors for drug-resistant TB
Identifying the individual factors leading to MDR-/XDR-TB is
crucial to address suitable case-finding strategies. To date, the
better documented worldwide risk factor for DR-TB is having
been previously treated for TB [5,6,35–37] . However, being a close
contact of a DR-TB patient is another major risk factor [38,39] .
In some settings, the private sector could be playing a relevant
role in drug-resistance acquisition, as it tends to manage TB
without DOTS and works outside of international and national
TB standards of care [40,41] .
HIV was not considered to be itself a risk factor for infection with MDR-TB at an individual and ecological aggregated
level [35,36] . Conversely, more recent but limited data seem to
suggest that HIV could be a risk factor [6] . Nevertheless, the
association between HIV and MDR-TB could be explained by
environmental factors, such as transmission in congregate settings [42] . Countries with a high burden of HIV are susceptible
to DR-TB. There is more information concerning individual
risk factors in Box 2 .
However, there are many other reasons for the global increase,
such as poverty, substandard national TB programs (NTPs), stock
ruptures, lack of access to primary public health services, inadequate
treatment regimens, irrational drug use and INH monoresistance
[35,37,43] . Many of these reasons are also listed in Box 1.
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Perspective
Monedero & Caminero
Box 2. Individual risk factors for TB-resistance.
• Failures of category II* and chronic patients
• Exposure to a known MDR-TB case
• Failure of category I treatment‡
• Failure of anti-TB treatment in the private sector
• Patients who remain smear-positive at the second or third
month of treatment
• TB relapses and retreatments after default
• Exposure in institutions that have MDR-TB outbreaks or a high
MDR-TB prevalence (e.g., prisons)
• Residence in areas with high MDR-TB prevalence
• History of using anti-TB drugs of poor or unknown quality
• Treatment in programs that operate poorly (especially
out-of-stock drugs)
• Comorbid conditions associated with malabsorption
• HIV in some settings
Category II: WHO standard treatment for previously treated patients.
Category I: WHO standard treatment for new patients.
MDR: Multidrug-resistant.
Adapted from [35,36,47].
*
‡
Approach to the diagnosis of patients with
drug‑resistant TB
One of the main challenges in DR-TB is the diagnosis, as clinical symptoms and basic TB diagnosis tools (sputum smear and
chest x-ray) of susceptible cases do not differ from resistant
cases. Currently, the principal method of discerning resistances
is through bacterial culture and drug-sensitivity testing (DST).
DST can be performed in Lowenstein solid culture or in morerapid liquid culture mediums. Nevertheless, both techniques are
lengthy (ranging from 10 days to 2 months) for clinical purposes.
Culture and DST are complicated and expensive techniques.
Moreover, DST must be performed only at quality-assured laboratories with good, safe facilities and equipment.
Additionally, in vitro DST often shows poor reproducibility
and lack of correlation with clinical response. This is especially
true for second-line anti-TB drugs (SLDs) [44] . DST validity
varies widely depending on the specific drug tested and the
resistance prevalence [4,45,46] . In fact, the latest WHO MDR-TB
guidelines do not recommend the use of DST for EMB, Z and
the drugs in group 4 and 5 to base individual regimen design
(Box 3) [47] . A complete history of anti-TB drugs used by the patient
and prescribed in the country is a fundamental tool to complement and confront the information provided by the DST. These
data could be relevant in clinical practice, as the use of an anti-TB
drug for more than 1 month is thought to be one of the main
resistance predictors. Fortunately, the most reliable DST results
are for INH and RMP [4,45,46] and many efforts are put towards
SLDs DST standardization.
However, these drawbacks, in addition to information and logistical problems, create critical clinical delays in resource-constrained
settings [2,48] .
A wide range of novel diagnostic techniques to obtain faster and
valid diagnoses have been introduced. Probably the most promising for high-burden countries (HBCs) is genotypic rapid DST,
136
which detects mutations linked to phenotypic drug resistance.
These tests are line-probe assays that provide quick (1–3 days)
and cheap results to identify resistance with a high level of reliability. The better-documented mutations are in the rpoB gene,
which is responsible for 95% of RMP resistances [49] . Moreover,
a positive rapid test for RMP resistance is a strong indicator of
MDR-TB [50,51] . The main advantages of quick RMP resistance
detection would be the early identification of patients at risk of
DR-TB, such as those with treatment failures and previously
treated patients. Thus, MDR patients could receive early treatment, avoiding amplification and achieving a prompt interruption
of MDR-TB transmission [47] . Recent studies on the commercially available Genotype® MTBDR (GT-MTBDR) and its new,
more sensitive version (GT-MTBDRplus) open the door for the
use of these techniques as MDR-TB screening tools in developing countries [52,53] . Sampled directly from the smear, the genotypic tests were trialled in a busy routine diagnostic laboratory
in South Africa against conventional liquid culture and DST on
solid medium [52] . It provided results in 1–2 days in 97% of cases.
Sensitivity, specificity and positive and negative predictive values
for MDR-TB detection were 98.8, 100, 100 and 99.7%, respectively, compared with conventional procedures. These molecular
techniques have demonstrated the potential to be used as screening tools for MDR TB, with substantial reduction in diagnostic
delays and substantial cost savings. Genotypic approaches could
also be a way to diagnose rapid development of resistance to SLDs.
Shortly, a rapid test for FQ resistance mutations will be available.
Nonetheless, other SLDs rapid tests are still under development.
Once more, the problem in HBCs is not only the cost of the
technology itself but the infrastructure, the maintenance and
human resources need. However, even with the useful rapid diagnosis, it would not be enough in low- and middle-income countries
(LMICs), as in many occasions just the time taken in the delivery
of results is doubled due to inefficient information mechanisms in
NTPs [48] .
Management of patients with drug-resistant TB:
lessons learned from past evidence
As previously stated, most of the evidence on which current recommendations are based date from the 1960s when RMP and FQ
were not yet discovered [4,54] . Moreover, the diversity of resistance
patterns within countries makes standardization even more difficult. On top of this, management of MDR/XDR-TB cases is
lengthy and quite complex. Thus, it should be only carried out
by experienced staff [2,4] . Nevertheless, in LMICs with very-high
TB burdens, the number of possible MDR cases is so high that
it cannot be managed by specialists alone [45] . Therefore, standardization is vital but, given the current tools and evidence, it
is not easy to create strong and universal recommendations. In
order to approach MDR-TB management, it is essential to take
into account the subsequent six controversial issues [4] . There is
a brief summary of these in Table 1.
The first challenge is how to approach diagnosis of MDR-TB
given that the DST has limited reliability. Comparing the information provided by DST plus the drug history enhances the likelihood
Expert Rev. Resp. Med. 3(2), (2009)
MDR-/XDR-TB management
of choosing the correct drugs. Detailed patient history and RMPand INH-resistance confirmation should always be performed prior
to MDR-TB treatment [4,45] . Whenever possible, DST to secondline injectables and FQ is strongly recommended.
Second, it is important to determine how many drugs should be
used. The answer differs greatly according to patient history and
the effectiveness of remaining susceptible drugs. There are substantial differences in resistance pattern among MDR/XDR-TB
cases. According to evidence from countries with a low pattern of
resistance to SLDs, three effective drugs were enough for an efficacious treatment, while in countries with great resistance to SLDs, a
low number of drugs used was associated with worse outcomes [55] .
As a common recommendation in NTPs, SLDs treatments should
include ‘at least four drugs’ to which the M. tuberculosis isolate
is known to be susceptible or, in the absence of DST, drugs that
the patient has never used before for more than 1 month [4,11] .
Occasionally, when several drugs could have their efficacy compromised or have very weak action, it may be justified to use more
than four drugs to strengthen the regimen [4] .
The third question to assess is which drugs to select on a rational basis. Drugs differ in efficacy and are classified into five groups
(Box 3) [4,47] . ‘At least four drugs’ should be used and selected starting from group 1 (oral first-line drugs [FLDs]) and moving on to
the next group when no adequate drug remains in the previous
group. Groups 2 (injectables) and 3 (FQs) are the basis of SLD
treatments. Only one drug from each group (2 and 3) should be
used, since all drugs from the same group have the same genetic
target. In addition, there is risk of cross-resistance and additive
toxicities while no additional efficacy is gained.
To complete the ‘at least four drugs’ rule, group 4 medicines
should be used, which have lower efficacy and are relatively toxic.
If there is no other option, drugs from group 5 should be used,
despite having very low or no documented efficacy. Z is frequently
used on SLD treatments as it is usually used in combination
with other drugs, and hence there is a chance of susceptibility.
However, Z should not be counted as one of the ‘at least four’
drugs given that the patient has used it before for more than
1 month and it is not possible to assume total susceptibility.
At this point, it is important take into account the possibility of cross-resistances. Be aware that all rifamycins have very
high levels of cross-resistance. At the same time, cross-resistance
between old-generation FQs seems to be almost complete (e.g.,
ciprofloxacin and ofloxacin). However, limited evidence suggests
that third-generation FQs (particularly moxifloxacin) do not have
complete cross-resistance with the older generations. Regarding
other drugs, ethionamide and protionamide have complete crossresistance while ethionamide and INH present crossresistance
when the inhA mutation is present [47] . Concerning injectable
agents, cross-resistance is complex and evidence for it very limited.
The most logical path on injectable use to avoid cross-resistance
seems to be to start initially with capreomycin, then kanamycin
and, finally, amikacin [56] .
In relation to the length of the injectables (intensive phase)
[4,47] , the evidence is especially controversial and no RCTs are
available. The most common recommendation is to continue
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Perspective
Box 3. Rational classification of anti-TB drugs.
Group 1: first-line oral agents
• Isoniazid (H)
• Rifampicin (R)
• Ethambutol (E)
• Pyrazinamide (Z)
Group 2: injectable agents
• Kanamycin (Km)
• Amikacin (Am)
• Capreomycin (Cm)
• Streptomycin (S)
Group 3: fluoroquinolones
• Ofloxacin (Ofx)
• Moxifloxacin (Mfx)
• Levofloxacin (Lfx)
Group 4: oral bacteriostatic second-line agents
• Ethionamide (Eto)/protionamide (Pto)
• Cycloserine (Cs)/terizidone (Trd)
• p-aminosalicylic acid (PAS)
Group 5: agents with unclear efficacy
• Clofazimine (Cfz)
• Linezolid (Lzd)
• Amoxicillin/clavulanate (Amx/Clv)
• Thioacetazone (Thz)
• Imipenem/cilastatin (Ipm/Cln)
• High-dose isoniazid (high-dose H)
• Clarithromycin (Clr)
Adapted from [4,47].
using injectables at least 4 months after sputum or culture conversion, defined as two consecutive negative smears and cultures
taken 30 days apart. After that, the injectable can be safely withdrawn when at least three effective drugs remain on the regimen.
Nevertheless, if less than three effective drugs are available or
belong to group 5, lengthy treatments with injectables should
be considered. Intermittent therapy (three times a week) can be
considered in the case of high risk of toxicity [47] .
The fifth controversial issue is the role of the surgery. Despite
the absence of RCTs, surgery is only indicated in very exceptional
circumstances [4,47] . The most accepted recommendations for surgery are that it should be used only when there are not four drugs
available, lesions are isolated and localized and when there is sufficient respiratory reserve [4,47] . Even in this situation, it must be
remembered that surgery has high morbidity–mortality and the
lesions are not sterilized [4] . An interesting and recent study performed in Peru concludes that the key factor for successful surgery
in MDR-TB programs in LMICs is the appropriate selection of
candidates [57] . These results are remarkable, as the previous literature addressing this issue were based in wealthy countries with
exceptional levels of support and expertise – circumstances that
could reduce the complication rates [32] .
The last issue is the manner in which to approach the ideal regimen in MDR-TB – in other words, whether to use standardized
or individualized treatments. Both are adequate, but it depends
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Monedero & Caminero
Table 1. Multidrug-resistant-TB management: fundamental aspects.
Step
Considerations
1. Diagnose
Compile and compare information
History of drugs: 1 month intake of a failed drug regimen could be a
strong predictor of resistance
DST: most reliable for R and H; also reliable for Km and FQ;
less reliable for E and Z; very low reliability for group 4 drugs
2. Number of
drugs
At least four effective drugs
3. Drug selection
Use FLDs if they are still effective
One injectable
One FQ
Use group 5 drugs until complete four effective drugs
If necessary, use group 5 drugs to strengthen the regimen, or when
no four effective drugs are reached with the previous groups
4. Length of
the injectable
At least 4 months after smear or culture conversion; longer if there
are no three effective drugs during continuation phase or are from
group 5
Finally, one of the most important and
unresolved questions is how to proceed with
MDR-TB infected cases. Currently, WHO
guidelines recommend close supervision,
but little is known about possible chemoprophylaxis [47] . This could again be a key issue,
especially in high HIV-burden countries.
Overall, addressing these six questions
enables the development of a rational
approach to MDR-TB programs and treatments. However, different countries would
require different strategies, depending on
the type and levels of resistance and the
resources available.
Prognosis
Invariably, MDR-TB and XDR-TB have
worse outcomes than pan-susceptible
TB for several aforementioned reasons.
5. Surgery
Consider only if:
Gradually, more factors are described in the
– Few effective drugs are available
literature that are linked to good and bad
– Localized lesions
outcomes (Box 4) [59] . However, MDR-TB
– Sufficient respiratory reserve
and XDR-TB definitions were established
6. Ideal regimen
Standardized: if there is no use of SLDs in the past
due to different treatment needs and
Individualized: use of SLDs in the past or contact of a MDR-TB
also due to different prognosis. Usually,
patient who had use of them (treat with the effective regimen of the
XDR-TB patients have a potential treatindex case)
ment success rate lower than 50% [31,32,55,60]
DST: Drug-sensitivity test; E: Ethambutol; FLD: First-line drug; FQ: Fluoroquinolone; H: Isoniacid;
and
clearly stand apart from MDR-TB
Km: Kanamycin; MDR: Multidrug-resistant; R: Rifampicin; SLD: Second-line drug, Z: Pyrazinamide.
Adapted from [4,47].
patients. In addition, two recent studies
have shown that the current XDR-TB defion the patient pattern of resistance, the economic NTP condi- nition is predictive of a poorer clinical outcome compared with
tions and the clinical conditions of the patient. For instance, in MDR-TB [60,61] . Nevertheless, the current XDR-TB definition
an HIV-infected or a critically ill patient, an individualized treat- leaves open the possibility of treatment with FQs and injectables
ment can be followed based on the drug history while waiting in the cases of incomplete cross-resistance throughout drug groups
for DST results. While for MDR-TB cases receiving only FLDs 2 and 3. Also, XDR-TB patients, by definition, could use FLDs
in the past, it is perfectly appropriate to use standardized SLDs other than RMP and INH, which lead to better outcomes [60] .
regimens, in MDR-TB cases receiving FLDs and many SLDs in Therefore, both groups under certain circumstances could obtain
the past, an individualized SLD regimen approach is preferred. In similar cure rates, as is currently being documented in Peru [58] .
the case of initial MDR-TB coming from an MDR-TB contact, Probably, a more suitable definition for XDR-TB is needed [54] .
the treatment should be based on the same pattern of resistance Concerning relapses after SLDs treatment, very little is known,
or effective regimen in the index case, if known [4] .
and studies on this question are also needed.
Concerning other issues, treatment fundamentals for children
do not differ from those for adults. Despite little evidence, all of Relevant & recent evidence on DR-TB management
the previous statements can be applied to children. At the same Concerning RCTs, there are several ongoing trials that are testing
time, the role of corticosteroid in MDR-TB remains equal to different treatment schedules in distinct settings. However, as yet
its role in susceptible TB: coadjuvant in cases of severe respi- there are no results available. A RCT on the effects of high doses of
ratory insufficiency, CNS and pericardial involvement [47] . On INH as an adjuvant therapy in MDR treatment has been published
the other hand, nutritional support and comprehensive and recently [62] . The study compared high INH (16–20 mg/kg/day)
psychosocial approaches are strongly linked to good outcomes versus regular (5 mg/kg/day) INH dose versus no INH (placebo)
on these lengthy treatments [47,58] . Nevertheless, comprehensive in MDR-TB patients, in addition to SLDs. The results stressed the
and psychosocial approaches are mostly only possible in highly positive benefit, especially in significantly increasing (p < 0.001) the
organized healthcare systems. Additionally, infection control speed of sputum conversion, maintaining the equal overall toxicity
(beyond the scope of this review) is likely to be one of the most in all groups. In fact, this is not the only publication addressing
cost-effective measures, especially in healthcare settings with a the use of FLDs in MDR-TB. One review has shown how, in cases
high HIV burden [47] .
with sensitivity to FLDs, their use increases the success rate [63] .
138
Expert Rev. Resp. Med. 3(2), (2009)
MDR-/XDR-TB management
Regarding other sources of evidence, there are many personal
experiences and case studies available about DR-TB in the hospitals of developed countries. However, little is known about
MDR-TB in NTPs in developing countries, although some
illustrating experiences have brought important knowledge on
DR-TB management. For example, in 2002, the publication of
the Peruvian experience, showed that for the first time, standardized MDR-TB treatment was widely provided by a NTP
in a LMIC [64] . It was shown how MDR-TB treatment, under a
suitable NTP, was possible, and even highly cost-effective, with
acceptable success rates in resource-constrained settings. In 2004,
the results of a cohort of 58 MDR-TB cases using standardized
treatment in Bangladesh, which achieved outstanding cure rates
(69%), was published [65] . This study highlighted the success
of novel approaches to treating MDR-TB, such as high doses of
INH, clofazime use and the importance of early treatment of
SLD side effects during long treatments.
In 2005, the MDR-TB experience of Latvia was presented.
This country had an extraordinarily high MDR prevalence
and patterns of resistance to many drugs [55] . Three-quarters of
MDR-TB patients enrolled at NTP conditions obtained successful outcomes, even as a resource-constrained setting. Based on
an individualized approach, many fundamental issues arise from
this study. For example, it was shown how the survival rates were
linked to the number of effective drugs used and the pattern of
drug resistance. In addition, resistance to ofloxacin was linked to
poor outcomes, providing a view of how important FQs could be
for MDR-TB treatment.
More recently published, in 2008, are the treatment outcomes
of 603 MDR-TB and 48 XDR-TB patients in Peru. They were
treated in Lima between 1999 and 2002, being NTP-managed on
an outpatient basis [58] . In contrast to the previous evidence, the
striking result was statistically similar outcomes for MDR-TB and
XDR-TB patients (66.3 vs 60.4%; p = 0.36). It has been shown
how XDR-TB can be cured in HIV-negative LMICs populations.
It is also important to remark upon the comprehensive patient
approach adopted in Peru, which offers socio–economical and
psychological support. However, the high levels of political will,
multilateral collaboration and financial support of the Peruvian
NTP should be emphasized [34] . However, another recent cohort
study with more than 600 patients in Russia revealed remarkably different outcomes for MDR-TB and XDR-TB patients
[66] . Probably the reason for this discordance within experiences relates to different patterns of resistances (perhaps worst
in Russia) and the comprehensive outpatient approach used in
Peru. However, this particular approach is difficult to extrapolate
into other settings.
Future: mathematical models
In considering this global increase, one important question
arises: do resistant strains have the same infectious capacity as
susceptible strains?
Given that the major mechanism underlying DR-TB is mutation, the infectious capacity of the microorganism could be
reduced. For example, mutations on the rpoB gene (the main
www.expert-reviews.com
Perspective
Box 4. Predictors of good and poor outcomes in
the treatment of multidrug-resistant TB.
Predictors of poor outcome
• In vitro resistance to FLD and SLD
• Resistance to ofloxacin
• Cavitary and bilateral disease
• Treatment with less than two active drugs or the use of five or
fewer drugs for 3 months or more
• XDR-TB and MDR-TB versus not-MDR-TB
• Low BMI
• Capreomycin resistance of XDR-TB
• Kanamycin resistance
• Higher number of drugs received previously
• Having previously received treatment for MDR-TB
• Male gender
• Age older than 45 years
• Low hematocrit level
• Poor clinical condition
• HIV coinfection
• MDR-TB status knowledge at the time of diagnosis
• Extrapulmonary localization
• Underlying comorbidity
• Patients whose initial regimen was changed due to adverse
drug reactions
• Receiving category I versus category II treatment
• Alcohol consumption during treatment
• Poor adherence
• Positive sputum cultures after 2 and 3 months
Predictors of good outcome
• Fluoroquinolone therapy
• Absence of previous treatment with ofloxacin
• Surgical resection
• Inclusion of pyrazinamide and ethambutol in the regimen
(when susceptibility was confirmed)
• MDR-TB cases susceptible to at least one FLD
• To receive appropriate therapy for more than
2 consecutive weeks
• Negative sputum cultures after 2 and 3 months of therapy
• Patient admission
• Resistance pattern
• Younger age
• Hospitalized in a specialized centre
• Older patients
• New MDR-TB cases
• Treatment for 12 months
• Higher level of albumin
• Normal BMI
• Use of more than four drugs
FLD: First-line drug; MDR: Multidrug-resistant; SLD: Second-line drug;
XDR: Extensively drug-resistant.
Adapted from [59].
139
Perspective
Monedero & Caminero
mechanism conferring RMP resistance) have been shown to
decrease growth speed and lower virulence in vitro [67] . The term
fitness is more appropriate as this takes into account not only
virulence, but also trans­missibility. Nevertheless, experiences have
shown that prolonged patient treatment can result in MDR-TB
strains with no changes in fitness. Clinical experiences have
shown that DR-TB strains with no changes in fitness are also the
most common [68] .
Independent of virulence, according to estimations, MDR-TB
patients have three-times higher transmission than susceptibleTB patients, since those who have been unsuccessfully treated
live longer with the disease and consequently infect more
people [69] . Modeling epidemics of MDR M. tuberculosis of
hetero­­geneous fitness have shown that, even when the average
relative fitness of a MDR-TB strain is low, and a well-functioning control program is in place, a small subpopulation of a
relatively fit MDR-TB strains may eventually outcompete both
the drug-susceptible strain and the less-fit MDR strains [70] .
Furthermore, current trends and studies predict the possible
shift from susceptible to untreatable strains [71] . Mathematical
modeling suggests that current annual incident rates may climb
even with intensive efforts to control the disease [72] . This is not
an isolated problem in HBCs where most of the MDR-TB cases
come from. Globalization and population mobility predict a
worldwide increase in MDR-TB [73,69] .
Other mathematical models predict exponential increases in
XDR-TB internationally as a result of synergistic interaction
of acquired resistance due to SLDs treatment and transmitted
resistance [71, 74, 75] . Without tight control of MDR-TB epidemics, XDR-TB would quickly become uncontrollable [71] . One
of the models was created to compare DOTS with MDR-TB
program component (former DOTS-Plus) [75] . The model found
that in LMICs, suboptimal DOTS-Plus could quickly lead to
developing XDR-TB with decreasing effectiveness of the whole
TB program. Additionally, several clinical experiences and modeling programs identified that poor treatments can be worse
than no treatment. A narrow focus on MDR-TB therapy could
paradoxically make a bad situation worse [17,72] .
This problem could be partly solved by a substantial increase in
monitoring, evaluation and capacity building. However, this does
contribute to the other main risk: the diversion of resources away
from DOTS. If MDR-TB program implementation comes with
just a 5% decrease in regular DOTS effectiveness, the cumulative
number of deaths would be substantially higher than if DOTS
was implemented alone [75] . The consequences of the diversion
of funds and human resources could be the increase in deaths
in susceptible TB patients and the creation of more MDR-TB
as a consequence of DOTS failure [71,75–77] . In fact the success
of advocacy for MDR-TB treatments programs has forced some
governments to initiate MDR-TB treatment prematurely, before
robust DOTS strategies are already built [72] . On the other hand,
in hot zones (>10% of primary drug resistance), optimal MDR-TB
programs would have a great impact on lowering total TB mortality [71,75] . According to these models, best DOTS practice is highly
likely to control MDR-TB and can even prevent its emergence. In
140
agreement with the mathematical models, we consider that the key
in fighting MDR-TB is to not create it. However, once DR-TB has
emerged, even the best DOTS practice cannot contain DR-TB
outbreaks. In such cases, SLDs are required to prevent MDR-TB
outbreaks [77] .
Expert commentary
Multidrug-resistant/extensively drug-resistant TB is clearly
an emerging problem. Currently, there are more controversies
than certainties, but clearly more solid evidence validating various recommendations will come to light in the near future.
Moreover, increased political interest, funding, and research
and development are starting to flow towards TB for the first
time in several decades.
Interventions to increase early identification of resistant TB
could play an important role. For example, rapid detection of
the rpoB mutation could simplify and hasten the classification
of patients. If rpoB detection could be available at cheap prices
without high-tech requirements, it could substantially change
the procedures in LMICs. In particular, laboratory requirements,
capacity and delays are one of the major bottlenecks in MDR-TB
programs in LMICs.
The results of ongoing trials on current drug schemes could also
be very important for the future management of TB. The role of
FQs is increasingly studied. Ciprofloxacin is not recommended
anymore to MDR-TB as other FQs have shown much better profiles [47] . At the same time, levofloxacin 1000 mg (double regular
dosage) is showing similar efficacy to moxifloxacin with a reduction in total costs [78] . However, the actual role of the new FQs in
the initial phase of treatment remains unclear [30,78] . It is necessary
to address whether new-generation FQs, such as gatifloxacin and
moxifloxacin, could have similar sterilizing activity to RMP. In
that case, MDR-/XDR-TB treatment length could be substantially reduced without an increased relapse risk. In addition, it is
vital to confirm if the introduction of a new FQ could reduce the
duration of susceptible TB treatment to 4 months. An issue arising is the extent of the risk of cross-resistances and amplification
against the increase in adherence due to the length reduction.
Another interesting issue remaining is the unclear role of clofazimine [79] , a drug included in group 5 but that could probably
be placed in group 4. There is little evidence on this matter and
clofazimine, as well as high doses of INH [62] , could play a relevant
role in the near future, as was shown in Bangladesh [65] . In addition,
linezolid, a group 5 drug, could be a promising tool, especially in
XDR-TB treatment [80,81] . However, to date little evidence is available, especially regarding its effectiveness when using lower, and
therefore safer, dosages [82] . However, the price of this drug and its
grave side effects make it an unsuitable candidate for most HBCs.
There are several new and promising drugs in the pipeline [83] .
New rifamycins, such as rifalazil (KRM-1648), have shown efficacy and long-acting oral activity against M. tuberculosis. Rifalazil
is currently under Phase II clinical trials. Another good example
is the novel compound PA-824, which has demonstrated potent
activity against active and dormant forms. At this moment,
PA-824 is going through Phase II clinical trials. An additional
Expert Rev. Resp. Med. 3(2), (2009)
MDR-/XDR-TB management
Perspective
component currently in Phase II clinical trials is TMC207, which
seems to have a very specific antimycobacterial mechanism in
combination with a long life, which could allow weekly treatments
and possibilities to reduce the length of treatment. However, these
and other new compounds will not be completely tested within
the next 5–10 years. Therefore, it is very unlikely that new drugs
will be ready for clinical use in LMICs in the next 10–15 years.
Vaccination could certainly be the best tool to tackle TB and
many efforts are following this approach. Once again, this will
take at least 10–20 years to be introduced in LMICs.
There will be no ‘magic bullet’ to control MDR/XDR-TB [84]
and, hence, it is more realistic not to simply wait for new TB drugs
or vaccines. It is important to simplify DR-TB management and
gradually incorporate standardized treatments into the procedures
applied in the NTPs [4] . Low-cost and low-risk policies to optimize
current tools could be essential to prevent DR-TB scale-up and
improve its management. Some of these affordable interventions
to reduce the risk and dimension of the DR-TB problem could be:
• Strength DOTS. More than ever, high-quality DOTS is
necessary to cure susceptible patients and prevent MDR [37] ;
• Extend intensive-phase treatment by 1 month in sputum smearpositive cases at the end of the second month of treatment. An
additional month with four drugs could reduce the bacterial
load and, in the eventual case of monoresistance (especially to
INH), the likelihood of gaining resistance to RMP in the continuation phase would very probably be reduced. In the case
of extensive lesions or fibrotic lesions with bad drug pharmacokinetics, it would be beneficial, while, in the case of dead or
nonviable bacilli, no substantial change would occur;
• Wide use of fixed-dose combinations (FDCs). Recently, in the
39th World TB Conference, the provisional results from The
Union’s ‘Study C’ were publicly shown [85] . This RCT was
performed with high-methodology standards covering a population approximating 1400 patients in 11 different settings.
Based on a noninferiority ana­lysis, it has been demonstrated
that FDCs have similar effectiveness and side-effect profiles as
loose drugs. FDCs have key logistic and practical advantages
and the obvious capacity to avoid monotherapy [86] . Added to
the currently reduced price, one can speculate that if FDC
uptake increases, especially in the private sector in LMICs, cure
rates could also increase and, at the same time, a substantial
proportion of drug-resistant TB cases could be prevented;
TB is again on the international agenda and now more than
ever joint efforts and funding are starting to be directed towards
research and development against TB. However, in the race
against DR-TB, we have started with decades of delay and been
helped only by outdated tools. A quick sprint is currently necessary
to overcome the disease before it is too late.
Unfortunately, DR-TB treatment lasts an average of 2 years, so
the impact evaluation of interventions and treatment outcomes,
especially relapses, could take many years. In addition, clinical
trials and the development and testing of new drugs or vaccines
could take decades. It is unlikely that significant changes in the
TB landscape will be witnessed in the next 5 years. During the
next 5 years, more experience on current diagnoses and treatment
will be gathered but, nevertheless, it is expected that some RCTs
will be completed that will improve the evidence on which current
recommendations are based.
Furthermore, the future of the TB epidemic will be linked to
HIV evolution, poverty and migration circumstances. All of these
are closely related to geopolitical and economical circumstances.
Nevertheless, even with obsolete tools in LMICs, there is still a vast
amount to be done. Optimizing current tools and strengthening
primary healthcare systems and DOTS programs could improve
or at least reduce the rise of the MDR/XDR-TB epidemic. Despite
warnings of mathematical models, there is a positive future if there
is continuous political will and the provision of funding towards
this disease.
• Engage all healthcare providers in TB, especially pneumologists and those in the private sector. The influence of the private
sector on DR-TB remains unclear but, without any doubt, it
plays a crucial role as NTPs are not enough in the fight against
TB. Formal and informal private sectors hold a substantial
number of patients worldwide and, thus, even in the absence
of DOTS, the daily use of FDCs under suitable protocols with
proper referral systems added to strong capacity building with
monitoring and evaluation activities could bring remarkable
benefits in cure rates and DR-TB reduction;
• Perform rapid DST (at least to RMP) to all failures, defaults,
relapses, TB patients contacts from a MDR case and to all
smear-positive cases in areas of high MDR prevalence. Rapid
test screening could improve early case detection, avoiding
unnecessary category II treatments, reduce further resistance
amplification and maximize prevention of MDR-TB infection
in the community. If the resources are available, another possibility to identify MDR-TB cases early could be performing
rapid DST to all smear-positive cases at the end of the second
month of the Category I regimen;
www.expert-reviews.com
• Moreover, in LMICs where initial INH monoresistance rates
are high, it could be reasonable to add EMB during the whole
continuation phase. In theory, adding EMB, which is a cheap
and well-tolerated drug, could reduce the risk of MDR development over initial INH resistance, protecting the RMP during
the continuation phase. We believe that the potential benefits
from adverted MDR-TB could outweigh the increase in cost,
side effects and toxicity in countries with high initial INH or
INH plus SM resistance rates.
Five-year view
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
141
Perspective
Monedero & Caminero
Key issues
• Drug-resistant TB is a manmade problem related to inadequate TB treatment or management. Efforts should be made to prevent
multidrug-resistant (MDR)-TB, which usually relies on good directly observed treatment short course (DOTS) practice, early casedetection and high cure rates in national TB programs (NTPs).
• Management of MDR-TB patients is long and quite complex. It should be carried out only by experienced staff. Even if resources are
unlimited, malpractice in NTPs can create more cases of MDR-TB and faster than they can be treated [17,84] .
• MDR-TB may not necessarily be less virulent. MDR-TB and XDR-TB will be universal if we do not act appropriately now.
• Optimizations of current tools (DOTS expansion, fixed-dose combinations use, public–private mix, adapted treatments for high isoniazid
resistance prevalence settings and rapid drug-sensitivity testing) appear to be, in the near future, the best option to prevent and
manage resistant cases. There is an urgent need for new drugs and quick and reliable methods of diagnosis. Nevertheless, new drugs
and vaccines could take decades to be developed and tested, and even more time to be implemented in developing countries.
• Summary of MDR-TB good practice:
– Perform a comprehensive patient drug history and confirm by DST resistance to rifampicin and isoniazid (and if possible to ofloxacin
and kanamicin in MDR-TB in high-burden countries)
– Use ‘at least four effective drugs’. If possible, use first-line drugs and include one fluoroquinolone and one injectable (beware of
cross-resistance between different drugs of the same group)
– Minimum length of injectable: from 4 to 6 months after sputum/culture conversion. Whole treatment should last 18 months after
culture conversion
– Close supervision and treatment of side effects
– Never add a single drug to a failing regimen
– Comprehensive and psychosocial approach
• Standardized versus individualized treatment. Both can be applied; however, the key factor is the appropriate patient selection. Patients
never having used second-line drugs are suitable candidates for standardized regimens.
• Different countries, depending on their resources and the characteristics of their epidemic, require different case findings and
treatment strategies.
• If well-performed and -managed, treatment of drug resistance is possible with more than acceptable success rates even in resourceconstrained settings. However, a narrow-view focus on MDR-TB treatment could make a bad situation even worse. More than ever,
high-quality DOTS is necessary.
approach to MDR-TB, not only at the
clinical but also at the programmatic level.
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Affiliations
•
•
Perspective
Jose A Caminero, MD
Servicio de Neumología, Hospital General
de Gran Canaria Dr Negrin, 35010 Las
Palmas de Gran Canaria, Spain
Tel.: +34 928 450 563
[email protected]
and
MDR-TB Unit, Tuberculosis Division,
International Union against Tuberculosis
and Lung Disease (The Union),
75006 Paris, France
Ignacio Monedero, MD, MPH
MDR-TB Unit, Tuberculosis Division,
International Union against Tuberculosis
and Lung Disease (The Union),
75006 Paris, France
Tel.: +33 144 320 360
Fax: +33 143 299 087
[email protected]
145