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The added effect of thioridazine in the treatment of drug-resistant tuberculosis.

The review by Grosset et al. in a recent issue of the
Journal is highly interesting, and rightly pictures a
bright horizon for the improved treatment of tuberculosis. However, there are alternative compounds
that can already provide considerable relief in compassionate
application of treatment for multidrugr
esistant and extensively drug-resistant tuberculosis
(MDR/XDR-TB) in the short term, and may offer an
important additional effect in treatment regimens due
to a special working mechanism, such as effl ux pump
inhibition. The review did not, for example, discuss
the successful use of the neuroleptic thioridazine (TZ)
in MDR/XDR-TB treatment, although it has been
widely examined and published. Our correspondence
therefore addresses this omission and summarises in
vitro, ex vivo and mouse studies of TZ, as well as the
use of TZ in treatment of TB patients as monotherapy
or as an adjunct in combination with drugs to which
the causative Mycobacterium tuberculosis was initially
resistant.
It has been known for many years that phenothiazines,
and especially the traditional neuroleptic
chlorpromazine (CPZ), possess in vitro activity against
M. tuberculosis. However, because the mode of action
occurs at concentrations that are not considered
tolerable in humans, interest in CPZ as an antituberculosis
agent did not develop. Moreover, although
these have been highly infrequent, the compound has
been associated with serious side effects. Nonetheless,
with the emergence of MDR-TB in the late
1980s, CPZ regained interest as an anti-tuberculosis
agent. In New York, new TB cases quadrupled during
this period, more than half of these caused by MDR
strains. This re-emphasised the need for alternative
treatments for TB, and at the time it was demonstrated
that CPZ enhanced the killing of newly phagocytosed
M. tuberculosis in human macrophages at clinically
tolerable concentrations. This observation regenerated
interest in phenothiazines. Soon after, the milder
phenothiazine, TZ, also showed considerable in vitro
activity against all tested MDR-TB isolates. Although
the concentrations needed to inhibit the in
vitro replication of MDR-TB isolates were still too
high for clinical application, concentrations that enhanced
the killing of newly phagocytosed MDR-TB
bacteria were considered clinically tolerable, revealing
an important added effect of this class of drugs.
After in vitro studies, animal models are the next
step in research on the effi cacy of drugs. TZ appeared
highly effective as a sole drug in the treatment of both
susceptible and MDR-TB in the Balb/C mouse model,
and showed an added effect in combination with other
drugs. In the coming period, TZ and other drugs
with a similar working mechanism, such as SILA421,
could be tested for their added value in treatment of
TB in combination with the promising new drugs
TMC207, PA824, PNU100480 or SQ109. In addition,
higher dosages of rifampicin (RMP) are currently
being tested in a drug trial in Tanzania and South
A frica, and the utility of phenothiazines or similar
drugs to acquire higher intracellular RMP concentrations
at even lower dosage is worth exploring.
The recent report on totally drug-resistant tuberculosis
(TDR-TB) from Mumbai exemplifi es the urgent
need for alternative treatments for TB; in the
short term TZ may therefore be more important than
realised. Patients diagnosed with TDR-TB have already
been exposed to virtually all available fi rst- and
second-line drugs without a favourable response, and
physicians have run out of regular options. New TB
drugs are therefore desperately needed to treat this
category of patients. However, until the new drugs
become available we will have to work with all drugs
currently at hand.
Given the above, we fi rst tested the safety and effi –
cacy of TZ as salvage treatment in four Indian patients
confronted with XDR (nearly totally) TB. We
found it well tolerated and safe, even in malnourished
patients who had failed treatment with all other
drugs, and we documented clinical and radiological
improvement in three of the four patients. In this
small series, TZ was applied out of compassionate
use, and treatment was started too late to achieve full
bacteriological cure. Larger trials with TZ added on
to standardised or individualised XDR-TB regimens
at an earlier stage are foreseen. TZ has also been
added to the salvage treatment regimens of three of
the 15 cases of TDR-TB described by the Hinduja
Hospital in Mumbai; these patients are also showing
clinical, radiological and in two cases even a microbiological
response.
Current drug choices for treating XDR- or TDRTB
are scarce. Information on the safety, tolerability
and effi cacy of alternative regimens is therefore of
utmost importance. A retrospective study was performed
among 17 adult pulmonary XDR-TB patients
without the acquired immune-defi ciency syndrome
admitted to a referral treatment centre for infectious
diseases in Buenos Aires, Argentina, from 2002 to
2008. Drug combination schemes to treat these patients
were tailored on the basis of drug susceptibility
testing and the patient’s drug tolerance. A combination
of linezolid, moxifl oxacin and TZ was applied in the treatment of 12 of the patients. TZ was initially
administered at a daily dose of 25 mg for 2 weeks,
after which the dose was increased to 25 mg weekly
until it reached 200 mg /day, under strict cardiac monitoring
for eventual cardiac adverse events. Eleven patients
met the recovery criteria with more than 2 years
of follow-up after treatment completion. TZ was
discontinued in one patient with pancytopaenia and
in another with allergic dermatitis. Although cardiac
adverse effects have been reported previously, no
prolongation of QT interval or any other heart complication
was observed.
The activity of TZ against the drug-resistant strain
of M. tuberculosis that resides in the pulmonary macrophage
of the alveoli is assumed to occur via two
distinct mechanisms. First, it enhances the killing of
M. tuberculosis within the phagolysosome by inhibiting
the cellular effl ux of potassium, thereby promoting
the acidifi cation of the vacuole and activation of its
hydrolases. Second, because TZ inhibits the effl ux
pumps of mycobacteria, which are partially responsible
for their resistance phenotype, antibiotics that
would normally be extruded by these effl ux pumps
because the intended target concentration cannot be
reached are retained due to the inhibition of the effl
ux pumps by TZ. Whereas the fi rst mechanism
avoids selection of mutated bacteria, the second mechanism
ensures the effectiveness of the drugs when TZ
increases the intra-cellular drug concentrations.
Treatment of TB is increasingly hampered by the
emergence of anti-tuberculosis drug resistance. The
rate of resistance is high not only in retreatment cases,
but also in new, previously untreated cases. This
indicates transmission of resistant M. tuberculosis
strains with presumably a higher level of intrinsic
resistance to withstand exposure to drugs. The genetically
conserved Beijing genotype strains have frequently
been associated with drug resistance in the
countries of the former Soviet Union and Asia. It was
recently shown that some of these strains have elevated
rates of RMP-r esistant mutants, and this may
be a highly conceivable explanation for some of the
resistance problems currently faced in these regions.
However, in Europe also, the Beijing genotype in particular
is associated with transmission of MDR/XDRTB.
To combat the emergence of resistant TB, new
drugs are in the pipeline. However, existing drugs,
improved treatment regimens and more effi cient dosages
should also be explored in the short term to prevent
morbidity and mortality. In particular, the synergistic
effects of drug combinations have not been
addressed suffi ciently. TZ may have an added effect
on the effi cacy of all drugs due to its specifi c mode of
activity, which yields higher intra-cellular concentrations
of drug.
In conclusion, at the time of writing, only TZ has
proven effective in the therapy of XDR-TB. The adjunct
use of TZ in combination with antibiotics to which the infecting organism was initially resistant is
highly promising, and is recommendable out of compassionate
consideration. In such cases, appropriate
measures should be taken to limit or prevent any
cardiopathy associated with TZ treatment, although
the drug is generally safe to use. In the USA, unsuccessful
treatment of a single MDR-TB case can
cost as much as $500 000,20 whereas for a few hundred
dollars an XDR-TB patient can be successfully
treated with TZ. This drug should be considered in
low-income regions of the world where the prevalence
of MDR/XDR-TB is high. Moreover, because of
its dual mechanism of action, TZ is expected to result
in similar cure rates in TDR-TB patients. A more
scientifi c approach, with greater numbers of patients,
should determine the true effi cacy of TZ and similar
drugs. This should not withhold the application of
these drugs in compassionate use today.

The added effect of thioridazine in the treatment of drug-resistant tuberculosis.

The review by Grosset et al. in a recent issue of the
Journal is highly interesting, and rightly pictures a
bright horizon for the improved treatment of tuberculosis. However, there are alternative compounds
that can already provide considerable relief in compassionate
application of treatment for multidrugr
esistant and extensively drug-resistant tuberculosis
(MDR/XDR-TB) in the short term, and may offer an
important additional effect in treatment regimens due
to a special working mechanism, such as effl ux pump
inhibition. The review did not, for example, discuss
the successful use of the neuroleptic thioridazine (TZ)
in MDR/XDR-TB treatment, although it has been
widely examined and published. Our correspondence
therefore addresses this omission and summarises in
vitro, ex vivo and mouse studies of TZ, as well as the
use of TZ in treatment of TB patients as monotherapy
or as an adjunct in combination with drugs to which
the causative Mycobacterium tuberculosis was initially
resistant.
It has been known for many years that phenothiazines,
and especially the traditional neuroleptic
chlorpromazine (CPZ), possess in vitro activity against
M. tuberculosis. However, because the mode of action
occurs at concentrations that are not considered
tolerable in humans, interest in CPZ as an antituberculosis
agent did not develop. Moreover, although
these have been highly infrequent, the compound has
been associated with serious side effects. Nonetheless,
with the emergence of MDR-TB in the late
1980s, CPZ regained interest as an anti-tuberculosis
agent. In New York, new TB cases quadrupled during
this period, more than half of these caused by MDR
strains. This re-emphasised the need for alternative
treatments for TB, and at the time it was demonstrated
that CPZ enhanced the killing of newly phagocytosed
M. tuberculosis in human macrophages at clinically
tolerable concentrations. This observation regenerated
interest in phenothiazines. Soon after, the milder
phenothiazine, TZ, also showed considerable in vitro
activity against all tested MDR-TB isolates. Although
the concentrations needed to inhibit the in
vitro replication of MDR-TB isolates were still too
high for clinical application, concentrations that enhanced
the killing of newly phagocytosed MDR-TB
bacteria were considered clinically tolerable, revealing
an important added effect of this class of drugs.
After in vitro studies, animal models are the next
step in research on the effi cacy of drugs. TZ appeared
highly effective as a sole drug in the treatment of both
susceptible and MDR-TB in the Balb/C mouse model,
and showed an added effect in combination with other
drugs. In the coming period, TZ and other drugs
with a similar working mechanism, such as SILA421,
could be tested for their added value in treatment of
TB in combination with the promising new drugs
TMC207, PA824, PNU100480 or SQ109. In addition,
higher dosages of rifampicin (RMP) are currently
being tested in a drug trial in Tanzania and South
A frica, and the utility of phenothiazines or similar
drugs to acquire higher intracellular RMP concentrations
at even lower dosage is worth exploring.
The recent report on totally drug-resistant tuberculosis
(TDR-TB) from Mumbai exemplifi es the urgent
need for alternative treatments for TB; in the
short term TZ may therefore be more important than
realised. Patients diagnosed with TDR-TB have already
been exposed to virtually all available fi rst- and
second-line drugs without a favourable response, and
physicians have run out of regular options. New TB
drugs are therefore desperately needed to treat this
category of patients. However, until the new drugs
become available we will have to work with all drugs
currently at hand.
Given the above, we fi rst tested the safety and effi –
cacy of TZ as salvage treatment in four Indian patients
confronted with XDR (nearly totally) TB. We
found it well tolerated and safe, even in malnourished
patients who had failed treatment with all other
drugs, and we documented clinical and radiological
improvement in three of the four patients. In this
small series, TZ was applied out of compassionate
use, and treatment was started too late to achieve full
bacteriological cure. Larger trials with TZ added on
to standardised or individualised XDR-TB regimens
at an earlier stage are foreseen. TZ has also been
added to the salvage treatment regimens of three of
the 15 cases of TDR-TB described by the Hinduja
Hospital in Mumbai; these patients are also showing
clinical, radiological and in two cases even a microbiological
response.
Current drug choices for treating XDR- or TDRTB
are scarce. Information on the safety, tolerability
and effi cacy of alternative regimens is therefore of
utmost importance. A retrospective study was performed
among 17 adult pulmonary XDR-TB patients
without the acquired immune-defi ciency syndrome
admitted to a referral treatment centre for infectious
diseases in Buenos Aires, Argentina, from 2002 to
2008. Drug combination schemes to treat these patients
were tailored on the basis of drug susceptibility
testing and the patient’s drug tolerance. A combination
of linezolid, moxifl oxacin and TZ was applied in the treatment of 12 of the patients. TZ was initially
administered at a daily dose of 25 mg for 2 weeks,
after which the dose was increased to 25 mg weekly
until it reached 200 mg /day, under strict cardiac monitoring
for eventual cardiac adverse events. Eleven patients
met the recovery criteria with more than 2 years
of follow-up after treatment completion. TZ was
discontinued in one patient with pancytopaenia and
in another with allergic dermatitis. Although cardiac
adverse effects have been reported previously, no
prolongation of QT interval or any other heart complication
was observed.
The activity of TZ against the drug-resistant strain
of M. tuberculosis that resides in the pulmonary macrophage
of the alveoli is assumed to occur via two
distinct mechanisms. First, it enhances the killing of
M. tuberculosis within the phagolysosome by inhibiting
the cellular effl ux of potassium, thereby promoting
the acidifi cation of the vacuole and activation of its
hydrolases. Second, because TZ inhibits the effl ux
pumps of mycobacteria, which are partially responsible
for their resistance phenotype, antibiotics that
would normally be extruded by these effl ux pumps
because the intended target concentration cannot be
reached are retained due to the inhibition of the effl
ux pumps by TZ. Whereas the fi rst mechanism
avoids selection of mutated bacteria, the second mechanism
ensures the effectiveness of the drugs when TZ
increases the intra-cellular drug concentrations.
Treatment of TB is increasingly hampered by the
emergence of anti-tuberculosis drug resistance. The
rate of resistance is high not only in retreatment cases,
but also in new, previously untreated cases. This
indicates transmission of resistant M. tuberculosis
strains with presumably a higher level of intrinsic
resistance to withstand exposure to drugs. The genetically
conserved Beijing genotype strains have frequently
been associated with drug resistance in the
countries of the former Soviet Union and Asia. It was
recently shown that some of these strains have elevated
rates of RMP-r esistant mutants, and this may
be a highly conceivable explanation for some of the
resistance problems currently faced in these regions.
However, in Europe also, the Beijing genotype in particular
is associated with transmission of MDR/XDRTB.
To combat the emergence of resistant TB, new
drugs are in the pipeline. However, existing drugs,
improved treatment regimens and more effi cient dosages
should also be explored in the short term to prevent
morbidity and mortality. In particular, the synergistic
effects of drug combinations have not been
addressed suffi ciently. TZ may have an added effect
on the effi cacy of all drugs due to its specifi c mode of
activity, which yields higher intra-cellular concentrations
of drug.
In conclusion, at the time of writing, only TZ has
proven effective in the therapy of XDR-TB. The adjunct
use of TZ in combination with antibiotics to which the infecting organism was initially resistant is
highly promising, and is recommendable out of compassionate
consideration. In such cases, appropriate
measures should be taken to limit or prevent any
cardiopathy associated with TZ treatment, although
the drug is generally safe to use. In the USA, unsuccessful
treatment of a single MDR-TB case can
cost as much as $500 000,20 whereas for a few hundred
dollars an XDR-TB patient can be successfully
treated with TZ. This drug should be considered in
low-income regions of the world where the prevalence
of MDR/XDR-TB is high. Moreover, because of
its dual mechanism of action, TZ is expected to result
in similar cure rates in TDR-TB patients. A more
scientifi c approach, with greater numbers of patients,
should determine the true effi cacy of TZ and similar
drugs. This should not withhold the application of
these drugs in compassionate use today.