Multidrug-Resistant Tuberculosis (MDR TB) and Extensively-Drug
Resistant (XDR) TB —
Webinar - August 17, 2007
Moderator: Lee Reichman
August 17, 2007
1:00 pm CT
Operator: Good afternoon and thank you all for standing
At this time, all participants are in a listen-only mode until
the question and answer session of today’s conference.
I would like to remind all parties this call is being recorded.
If you have any objections, you may disconnect at this time.
I would now like to turn the call over to Dr. Kenneth Castro, Director,
Division of Tuberculosis Elimination at CDC.
You may begin.
Kenneth Castro: Thank you.
Welcome to the Web-based seminar on Multi- and Extensively Drug-Resistant
This session is done in joint sponsorship between CDC and the four
Regional Training and Medical Consultation Centers.
These centers offer training, education, and medical consultation
services in the United States. Tuberculosis experts from each of
these four centers have joined us today as faculty for this Web-based
By way of background, following more than ten years of experience
with three model tuberculosis centers, in 2005 CDC funded four Regional
Training and Medical Consultation Centers, which are geographically
located throughout the United States:
In California, the Francis J. Curry National TB Center is located
in San Francisco; in Texas, the Heartland National TB Center is
located in San Antonio; in Florida, the Southeastern National TB
Center is located in Gainesville; and in New Jersey, the Global
Tuberculosis Institute is located in Newark.
Each of these four centers serves its designated region. The states
served by each center are color-coded to correspond to each of the
regions outlined on this map.
In recent months, the public health problems posed by multi- and
extensively drug-resistant tuberculosis have gained public attention.
We want to ensure that all our partners have the most up-to-date
information on this topic, thus the rationale behind this Web-based
Today’s learning objectives are indicated on this slide,
and include, first, a description of the global and national epidemiology
of multi- and extensively drug-resistant tuberculosis; second, a
description of the development of
drug-resistant tuberculosis; third, a description of the laboratory
diagnosis of drug-resistant tuberculosis; fourth, the listing of
the general principles of treatment of persons with multi- and extensively
drug-resistant tuberculosis, then discuss the challenges in managing
contacts of multi- and extensively drug-resistant TB cases, and
lastly, identify resources for education, training and expert consultation
on management and treatment of multi- and extensively drug-resistant
Today’s agenda is outlined on this particular slide.
Please note that questions are going to take place at the end.
So please write and save all questions until that time, when we
have allotted approximately 30 minutes for discussion. During that
time, we will be joined by several additional tuberculosis experts.
Continuing education credits are available for this Web-based seminar
free of charge. For information about continuing education credits,
please go to the Web site which appears on you screen right now
The process of continuing education requires that we provide disclaimers,
statements to indicate that none of our presenters have financial
interest related to this Web-based seminar.
In addition, the presentations today do not include discussion
of a product under investigational use except that Dr. Seaworth
may discuss the use of fluoroquinolone and linezolid therapy for
patients with multidrug-resistant TB. These drugs, although FDA
approved, are not FDA-approved for this specific purpose.
So now I'd like to turn the Webinar over to Dr. Lee Reichman, who
will act as the moderator for today’s session.
Lee Reichman: Thank you, Ken. Good afternoon everybody.
Thank you very much for attending our Webinar.
The first speaker will be Masae Kawamura. Masae is the director
of the TB Control Section of the San Francisco Department of Public
Health, and she is the Principal Investigator of the Francis J.
Curry National Tuberculosis Center at the University of California
San Francisco, and she will talk on MDR and XDR TB: Global Problem,
Masae Kawamura: Hello? Am I in? Thank you, Lee.
In the next 10 minutes, I will briefly review the current epidemiology
of global and domestic multidrug-resistant TB.
Before we get into the epidemiology, I'd like to start by saying
that MDR TB is every TB controller’s nightmare because of
the seriousness of how it challenges our most important control
strategies. And it’s a problem that was well recognized by
Lee Reichman. He wrote a book called Timebomb seven years ago. And
it’s only now coming into the public eye. And it’s really
a problem that is inescapable to us in the United States with the
global nature of travel and commerce.
Let’s begin with some definitions. MDR TB is when the TB
isolate is resistant to both isoniazid and rifampin. XDR TB is MDR
TB with additional resistance to fluoroquinolone and one of the
three injectable agents -- amikacin, kanamycin and capreomycin.
Now, a brief note that XDR TB patients are usually resistant to
all of the first-line agents.
Now, there are two kinds of drug-resistance, primary and secondary.
Primary resistance refers to an infection in an individual that
is already drug resistant.
Secondary drug resistance is when the resistance developed during
Now, what's the significance of MDR and XDR TB, well there is no
short course treatment regimen available, and it requires the use
of very toxic drugs. And with XDR TB, there is significantly poor
So what's the global incidence of MDR TB? The WHO estimated that
the number of MDR TB cases went from roughly 273,000 to 424,000
between 2002 and 2004, a very short two-year period. Proportionately,
it nearly quadrupled from 1.1% to 4.3%.
Remember, we are now in 2007, and the world hasn’t changed
that much in terms of TB control. And so we can certainly predict
that things are much likely worse, especially with XDR being detected.
The second bullet points out that prior treatment is the biggest
risk factor for MDR TB. And prior treatment accounts for 43% of
all of the MDR TB cases in the world. China, India, and the Russian
federation account for 62% of the MDR burden.
And please note that the exact number and prevalence of XDR TB
is really not known at this time.
This map shows that MDR TB is all over the world, but is not evenly
distributed. As the light green areas indicate that 3% to 6% of
the incident cases are MDR and this includes China, the most populous
country in the world.
The yellow countries have the highest rate of MDR TB of over 6%,
and this includes the Russian federation and countries of the former
Soviet Union. Some of these countries actually record a greater
than 14% prevalence of MDR TB.
Estonia, which is close to Finland -- I'm sorry, I don’t
have a pointer -- is 17.4%, and Azerbaijan and Kazakhstan have a
prevalence of 14.6%. I wouldn't want to be TB controller there.
This map shows you where XDR TB is currently found in the world.
And so again, it’s found all over the world. But essentially,
it’s actually where second-line TB drug have been introduced.
Why do we have this current MDR, XDR TB epidemic? Well I think
the first thing is that there is suboptimal TB control practice
out there in the world, poor DOT or no DOT at all, poor infection
control practices and healthcare facilities to no infection control
at all, and treatment without the benefit of drug culture, excuse
me, without drug susceptibility or cultures and that’s what
I called “treatment in the dark.”
The second bullet points out that MDR TB is actually the precursor
to XDR TB, and poor use of second-line TB drugs leads to XDR TB;
and with the introduction of these drugs to low and middle-income
countries, we are now seeing that happen.
And HIV amplifies disease and transmission. We know that for all
forms of TB. But when you throw MDR and XDR in the mix, you end
up with situations like what we’re seeing in KwaZulu-Natal,
South Africa, where 52 out of 53 XDR cases died within a 16-day
median. Devastating - a devastating disease in HIV.
And this - the last bullet is one of the most worrisome ones to
me is that it’s a fact that in 2005, only 2% of the estimated
culture proven MDR TB cases were actually treated with second-line
So if I'm calculating this correctly, 98% of these cases were not
treated. And so we can expect spread and transmission of these forms
Let’s switch our focus now to the United States and examine
our current situation.
Since the US-born HIV-related MDR TB epidemic in the early 90s,
primary MDR TB has significantly decreased from 2.5% in 1993 to
about 1% in 1998. The number of cases has plateaued to about 100
per year for the past seven or eight years or so.
This graph actually shows how primary MDR TB was contained among
the US-born in the blue line and as that occurred, the proportion
of foreign-born MDR cases, represented by the pink line, increased.
And currently, 75% of all MDR TB is foreign-born. And the rate
of MDR TB among the foreign-born is actually three times that of
the US-born accounting for 1.5% of their cases versus 0.5% for US-born
The ten-year plateau in foreign-born MDR TB cases is actually not
surprising because most or all of these cases are imported and therefore
And so I think we can predict that the future rise and fall in
foreign-born MDR TB cases will follow patterns of global migration
and immigration into the United States.
Looking now specifically at XDR TB, from the survey done, you can
see that there were 88 cases of XDR TB between 1993 and 2007 --
81 were officially counted and 7 not counted. Fifty-seven percent
or 50 of these cases were primary or occurred in patients that never
had TB before. In other words, these cases occurred as a result
This map of the United States shows where XDR TB can be found by
state. If you look at New York, New York followed by California
had the most cases reflecting the epidemiology of the past -- the
HIV-related MDR TB outbreaks in the early 1990s in New York City.
And looking at California, you're seeing the current epidemiology
of immigrant XDR TB in California.
This bar graph shows primary XDR TB cases between 1993 and 2007.
Here, you can see that XDR TB is actually not new in the United
States. When we had a lot of MDR TB, we had more XDR TB, and that
was in the early 1990s.
And currently we have about one to six cases per year. And that
actually seemed really reassuring, but what is not reflected here
is probably a growing trend of pre-XDR TB cases. And that’s
certainly what we’re seeing in California.
These are cases that are resistant to all first-line agents and
are just one drug away from being XDR. And I’m sorry I don’t
have a slide to show you here.
This slide shows that XDR TB is a disease of minorities. And if
you take a look at the pie chart up there, the largest group is
Hispanic with 35% of the pie.
Most or all of these XDR cases are from Mexico. And the rest of
the pie is evenly broken up by African-Americans, (Blacks), Asians,
and whites at 21% each.
On the bottom of this slide, this table shows how the epidemiology
of US-born XDR TB has changed. Prior to year 2000, the majority
of XDR cases where US-born, and that switched to a minority of only
25% after 2000.
Since that time, 75% of the XDR occurs among the foreign-born.
The outcomes of XDR TB in the US, which has arguably the best TB
treatment in the world, is incredibly poor. Even if those that are
still on treatment complete, at best, only 44% will complete their
treatment. And a full third will die while they’re on treatment.
The total number of deaths in this cohort with known outcomes was
17 or 52%. And that rate really rivals the era prior to antibiotics
for tuberculosis. And even if the whole cohort is included, the
death rate is still a dismal 35%.
So what is the domestic impact of the global epidemic of MDR and
XDR TB? Well I think this picture is worth a thousand words and,
you know, human beings will be acting as carriers of these deadly
strains and arriving daily and reactivating later.
And if you look, you’ll see that migrating populations are
- have the United States as a favorite. It’s a major destination
site. And in fact, the migrating population in the 1990s increase
four-fold from the 60s and 70s.
So I’ll end with the “have germ will travel,”
and so we need to be ever vigilant and really do all that we can
to stop this global public health threat from advancing.
Unfortunately, I think it will get worse before it gets better,
and we all need to be mentally prepared and clinically prepared
to deal with XDR TB.
Lee Reichman: Thank you, Masae.
Our next speaker is Thomas Shinnick, Mycobateriology Laboratory
Branch, Division of Tuberculosis Elimination at CDC, and he will
speak on the laboratory aspects of drug-resistant tuberculosis.
Thomas Shinnick: Thank you, Lee.
Before discussing the laboratory aspects of drug-resistant tuberculosis,
I’d like to spend a few minutes describing how a drug-resistant
bacteria actually arise in the human host.
Mycobacterium tuberculosis bacteria become resistant to anti-tuberculosis
drugs by acquiring mutations that confer resistance. In such mutations,
such as the one shown here, arise spontaneously as the bacteria
proliferate in the host.
Rifampin-resistant mutations arise at a frequency about 1 in 10
to the eighth. Isoniazid and pyrazinamide-resistant mutations arise
at a frequency of about 1 in 10 to the sixth.
So prior to the beginning of treatment, the population of bacteria
in a TB patient already contains drug-resistant tuberculosis.
So if one treats this population of bacteria with three drugs,
one kills all the bacteria. However, if you treat with only one
drug such as isoniazid, you select for the isoniazid-resistant bacteria
and you end up with the population of bacteria that are isoniazid
Those bacteria, if they continue to multiply in presence of isoniazid
will also develop spontaneous mutations as they grow to large numbers
in the host, in this case, picking up a second resistance.
Then if you treat with two drugs such as the - adding a single
drug to a failing regimen, one actually selects for the strains
that have mutations both to isoniazid and rifampin, and one ends
up with the population of bacteria that contains - that are resistant
to two drugs and this circle here would be bacteria that have acquired
a spontaneous mutation to yet a third drug.
So this sort of amplification of a resistance can occur one drug
at a time leading first to MDR TB and then ultimately to XDR TB.
The role of the laboratory is to detect drug resistance as soon
as possible to enable the clinician to design an effective multidrug
regimen and thereby to prevent the acquisition of drug resistance.
The current recommendations are that all initial M. tuberculosis
isolates should be tested against the primary drugs, and that includes
isoniazid, rifampin, pyrazinamide, and ethambutol.
And for the rifampin-resistant isolates, at least, the second-line
drugs should be tested, and the key second-line drugs to be tested
are fluoroquinolones, amikacin, kanamycin, and capreomycin.
The sort of methods that can be used for drug susceptibility testing
include culture-based method such as proportion method, the absolute
concentration method, and the relative ratio method, as well as
molecular methods, and there are quite a few new molecular methods
for the detection of rifampin resistance, for example.
In the United States, the most commonly used method is proportion
method for the first-line drugs, liquid media is the primary tool
proportion method is used.
For second-line drugs, the primary method is the use of solid media.
And for the agar proportion method or the proportion method on solid
media, bacteria are plated on media that contain either no drugs
or media that contain the critical concentration of a particular
Those plates are then incubated while waiting for the bacteria
to form colonies and the colonies become visible, for agar plate
that takes about three weeks. One then counts the colonies. An isolate
is considered resistant if the number of colonies on a drug containing
media is more than 1% of the colonies on the drug-free media.
So to distinguish the resistant bacteria from the susceptible bacteria,
the isolates are usually tested against the critical concentration
and usually tested only against critical concentration. And this
concentration is also sometimes called the breakpoint concentration.
And what this is, if this were an ideal world, the critical concentration
would be the concentration of a drug at which all susceptible strains
would fail to grow and all-resistant strains would grow.
So if you saw a colony on a drug containing plate, you would know
that the bacteria were drug-resistant. If there were no colonies,
you would know that bacteria were drug-susceptible. However, the
world is not ideal, and it is difficult to find a drug concentration
that actually meets these definitions for many of the anti-tuberculosis
So we often have to settle for the concentration that best discriminates
between susceptible and resistant strains. And how this is determined
is shown on this slide.
The experiment to determine what is the concentration drug to use
in the laboratory involves measuring the percentage of presumably
drug susceptible bacteria --that’s shown by these dotted lines,
and presumably resistant bacteria shown as the solid lines here,
that are susceptible to inhibition by growth by various concentrations
For example, this concentration of rifampin inhibits about 85%
to 90% of susceptible strains and 5% to 10% of presumably resistant
strains. By the way, presumably susceptible strains are those that
come from previously untreated patients, and presumably resistant
strains are those that come from patients who have failed therapy
with that drug.
For rifampin, the susceptible strains are very easily distinguished
from the resistant strains over a wide range of concentrations.
The best discrimination is shown by this vertical line and that
represents the critical concentration of rifampin that is used in
LJ media, which is 40 micrograms per mil.
For isoniazid susceptible strains are also very easily and readily
distinguished from resistant strains, but over in much narrower
range of drugs.
And for the laboratory, this means that care must be taken to precisely
measure the drug containing media -- the drug that is in the media
to avoid having too little drug, which could lead to having these
susceptible strains being incorrectly classified as resistant or
having too much drug, which would lead to these resistant strains
being misclassified as susceptible.
For ethambutol, the story is much more complicated. And that’s
because there’s a very large overlap in the inhibitory concentrations
that affect presumably susceptible and presumably resistant strains.
Even at the most discriminatory concentration shown here by the
vertical arrow, the so-called critical concentration, there are
concerns that strains may be incorrectly classified as susceptible
or resistant. You see there’s very many strains that could
be potentially incorrectly classified.
And these sort of difficulties in classifying strains may be one
of the reasons for different results in different laboratories when
strains are being tested against drugs such as ethambutol.
Other reasons for having discordant results include the precise
bacterial population that is being tested. One could test either
the primary isolate or a subculture and it’s quite possible
that the population of bacteria in a primary isolate is different
from what that might be in any culture. And part of that could be
due to differential growth kinetics that is drug-resistant bacteria
often have different growth rates than drug-susceptible bacteria
so that differences in growth rates could give differences in populations
of bacteria especially in subcultures.
There are also could be differences in results due to different
precise methods of producing inocula for the plates or the precise
method. For example, differences in the size of the inoculum or
whether or not - clumps are present in the inoculum could give you
results - differences in results with drug susceptibility tests.
It is also known that there are differences between the methods
and/or the media that is used. Bactec - drug susceptibility test
results are very similar but not identical to what is seen with
solid agar proportionate media, so one can have occasional differences.
There could also be laboratory errors
either due to cross-contamination of cultures or simple transcription
or labeling errors that could lead to discordant results.
And finally, there are possible discordant results due to both
problem strains and problem drugs. And by - what I mean by problem
strains, these are difficulties that typically arise because the
minimal inhibitory concentrations for these drugs are actually very
close to or approximately equal to the critical concentration that
is used with these particular drugs.
And here’s, for example, what I mean by problem drugs. Each
year, a panel of well-behaved strains is sent to the members of
the World Health Organization’s Supra-National Reference and
Laboratory Network as part of a proficiency testing program. These
state-of-the-art laboratories were able to accurately identify rifampin
and isoniazid resistance with sensitivities and specificities of
97% to 98%.
On the other hand, even these reference laboratories had difficulty
identifying streptomycin and ethambutol resistance strains with
sensitivities of only about 90%.
And this indicates that drug susceptibility testing with streptomycin
and ethambutol are so much less reliable than drugs susceptibility
testing with isoniazid or rifampin.
Unfortunately, drug susceptibility testing for many of the second-line
drugs is even less reliable than what we see here for streptomycin
In addition to these concerns about exactly how reliable and reproducible
and accurate drug testing is for individual drugs, not all Mycobacterium
tuberculosis strains are as well behaved as the strains that were
sent out in this proficiency testing panel.
And here’s what I referred to as difficult strains. As part
of a performance evaluation program, CDC has sent strains more than
a hundred laboratories for drug susceptibility testing.
Most strains were consistently identified as susceptible or resistant
by the hundred laboratories. However, for some strains, agreement
between the labs was less than 80%, that is, laboratories disagree
more than 20% of time for 3 of the 19 rifampin-resistant strains
tested, and for 10 of the 40 isoniazid resistance strains tested.
For example, if you look at strain 1, only about a third of the
laboratories found strain 1 to be resistant to isoniazid, 2/3 of
the laboratory is found to be susceptible.
And for strain 2, we have a similar story with rifampin resistance,
where about 2/3 of the laboratories found it resistant to rifampin
and about a third of them found it susceptible to rifampin.
And this sort of problem, the behavior of these strains, it illustrates
the problem that that strains that have MICs close to the critical
concentration for the laboratory.
So in summary, drug susceptibility test results must be available
as soon as possible in order to guide treatment choices and here
- in efforts to speed up the availability of drug susceptibility
testing results, many laboratories are turning to testing algorithms
that include molecular test for rifampin resistance, and that may
allow a more rapid treatment decision.
It’s important to emphasize that laboratory tests do not
replace clinical judgment, and for making informed judgments, clinicians
need to have data to - help them interpret the results.
And they need to know what the performance for that parameters
of the test is, how reliable a test is, for example, they need to
know that it’s ethambutol resistant - its ethambutol drug
susceptibility test results are a little less reliable than for
rifampin resistance. And they needed to know its potential impact
of prevalence of resistance on predicted value, et cetera.
Overall, the laboratory has an important role to play in preventing
and combating drug-resistance tuberculosis. But success will require
laboratories and clinicians to clearly communicate with each other
regarding test results and to consult with each other as to the
appropriate interpretation of test results.
And with that I’ll thank you for your attention.
Lee Reichman: Thank you very much, Tom.
The next presentation by Dr. Rey McDonald, Medical Director of
the Global TB Institute at the New Jersey Medical School and Dr.
Barbara Seaworth, Medical Director of the Heartland National TB
Center, include the case presentation describing a highly complex
case of TB spanning several years and illustrates how drug-resistant
TB may develop leading to poor treatment outcomes.
The patient originally presents with drug susceptible TB, but through
a series of management errors progresses to XDR. We chose a real
case from our referral practice rather than a fictitious but simpler
one. So we ask the audience to please bear with this real-world
The case study is being used as a tool to highlight principles
of preventing and treating MDR and XDR TB, which is the focus of
the presentation rather than the specific details of this very complicated
Dr. McDonald will present the case, and pause at specific points
in which Dr. Seaworth will comment on the case and the principles
of treatment of drug-resistant TB that are highlighted in each section.
Reynard McDonald: Thank you, Lee.
A 60-year-old homeless black male presented to a local hospital
in July of 1986 with a positive tuberculin skin test measuring 15
millimeters in induration and abnormal chest x-ray. The chest x-ray
revealed a right upper lobe cavity as you can see on this slide.
The initial bacteriology revealed that the sputum smears were positive
for acid-fast bacilli and the cultures subsequently grew M. tuberculosis
and were thought to be pan-sensitive, that is, it was sensitive
to rifampin, isoniazid, streptomycin, and ethambutol. Testing for
pyrazinamide was not done.
On July 19, 1986, the patient was started on self-administered
treatment with INH and rifampin in appropriate dosages. The patient
was non-adherent in taking his medications, however; and had a history
of alcohol abuse and was known to be uncooperative in keeping medical
Today treatment would be directly observed and would include initial
treatment with rifampin, INH, pyrazinamide, and ethambutol, however,
starting treatment with two drugs, in this particular case, rifampin
and INH for nine months, was an acceptable option in 1986.
In January 1987, approximately six months following the initiation
of treatment, the patient’s sputum smear remained positive
for acid-fast bacilli, and ethambutol was added as a single drug
to the regimen of rifampin and INH.
In November 1987, approximately a year-and-a-half after treatment
was initiated, the patient was again noted to be drinking heavily
and missing his medical appointments. INH and rifampin were stopped
because of hepatic toxicity and ethambutol was continued. Pyrazinamide
and streptomycin were added.
The patient was twice lost to follow and treatment was interrupted
in April of 1988 and December of 1989. Patient was a lost to follow
up from April of 1988 until March of 1989 when he presented to the
emergency room at a local hospital with a complaint of cough.
Treatment was restarted under self-administration with rifampin,
INH, pyrazinamide, and streptomycin.
Finally in December of 1989, patient was again lost to follow.
On this drug-gram, in July - on July 19 of 1986, treatment was
started with INH and rifampin as we previously stated.
Several months later, ethambutol is added as a single drug. M.
tuberculosis strain was sensitive to most of the first-line drugs
as we stated before, sensitive to rifampin, INH, streptomycin, and
ethambutol was noted.
Treatment was interrupted for several months in April of 1988 and
again in December of 1989.
Sputum briefly becomes smear and culture negative in early 1989,
but is again smear and culture positive for M. tuberculosis when
the patient is lost to follow on December 8 of 1989.
Dr. Seaworth, would you care to comment at this point?
Barbara Seaworth: Thank you.
When this patient was lost to follow-up 3.5 years after his initial
diagnosis, he was still culture positive as you noted. A crucial
factor that leads to this poor outcome was the failure of public
health and his providers to ensure adherence to treatment.
Drug-susceptible TB is readily treatable and curable. His alcohol
abuse, homelessness, and poor attendance at medical
appointments are characteristics associated with poor
adherence. These factors should have been recognized and
Directly observed therapy, a treatment strategy in which a trained
healthcare worker watches the patient take each and every dose of
TB medication is a standard of care for all TB patients in the United
States and is associated with significantly better outcomes. Directly
observed therapy should have absolutely been ordered for this patient.
The patient’s medical management was also inadequate. Although
treatment with INH and rifampin was an acceptable regimen, six months
into treatment the patient remains sputum smear positive and a treatment
At this point, new drug susceptibility study should have been ordered
and should be ordered whenever a culture remains positive after
But despite the glaring possibility of drug resistance, this risk
was not recognized and repeat drug susceptibility tests were not
A single drug was inappropriately added to his failing treatment
regimen. Because a failing regimen is a possible indication of developing
drug resistance, the correct action should have been to add at least
two and preferably three new drugs.
Ideally, one of these drugs should have been an injectable agent.
Now, I turn it back over to you Dr. McDonald.
Reynard McDonald: Thank you.
In April of 1999, approximately ten years later, the patient presented
with complaints of weight loss, cough and hemoptysis and was hospitalized.
His chest x-ray, as you can see on this slide, continued to reveal
a right upper lobe infiltrate and his sputum was smear positive
for acid-fast bacilli.
On 5-7-99, a decision was made to start treatment while awaiting
drug susceptibility test results. And directly observed therapy
was started with four drugs -- INH, rifampin, pyrazinamide, and
Drug susceptibility tests were obtained from a commercial lab on
a sputum specimen collected 4-29-99 and revealed resistance to INH
However, additional resistances to aminoglycosides, kanamycin,
and amikacin were also identified and resistance to one of the fluoroquinolones
Therefore, by definition, this patient would be identified as having
multidrug-resistant tuberculosis and though it was not a concept
at the time, XDR tuberculosis was also present.
On 7-16-99, although the patient appeared to be responding to treatment,
the treatment regimen was revised as follows:The isoniazid and rifampin
to which resistance had been identified or stopped, ethambutol pyrazinamide
was continued and three new drugs were added, streptomycin, ofloxacin,
and clofazamine, even though in retrospect the dosage of ofloxacin
was somewhat low and was given in a reduced dosage for approximately
On 1-14-2000, streptomycin was stopped and treatment continued
with ethambutol, PZA, ofloxacin, and clofazamine.
On 6-16-2000, the treating physician felt the treatment was adequate.
The patient had completed approximately 13 months of treatment and
was 12 months post-sputum culture conversion to negative.
Treatment with ethambutol, PZA, ofloxacin, and clofazamine was
stopped at this point, and I might add somewhat prematurely.
Unfortunately on 6-21-2000, five days after treatment stopped,
the state tuberculosis lab reported that the sputum sample collected
on 6-16-2000 was smear positive for acid-fast bacilli.
Dr. Seaworth, your comment.
Barbara Seaworth: Nine-and-a-half years after he was lost
as a treatment failure, he was again located. Non-adherence was
now addressed appropriately with the implementation of directed
The possibility of drug resistance was recognized by providers
and drug susceptibility tests were ordered. A standard four-drug
treatment regimen was started.
At this point, many experts may have considered using an expanded
regimen, in which two or three additional drugs are used in addition
to the standard four drugs because of the possibility of drug resistance.
Two months later, the laboratory confirmed resistance to isoniazid
and rifampin. By this time the patient had improved clinically and
was smear and culture negative.
However, INH and rifampin were stopped and streptomycin, ofloxacin,
and clofazamine were added.
By adjusting his treatment in response to the susceptibility results,
his providers followed an important principle in the treatment of
They recognized that even the good initial clinical response did
not justify continuation of what they knew as an inadequate regimen
based on laboratory susceptibility studies.
Have they simply continued, there would have been a further resist
of drug resistance and ultimate treatment failure.
The treatment regimen they did choose was too weak and too short
to adequately treat MDR TB.
We are having trouble advancing the slides, could you do that at
Barbara Seaworth: Thank you.
When initiating a revising therapy, it is important to always attempt
to employ at least three previously unused drugs to which there
is laboratory documented susceptibility.
The patient was treated with three drugs, ethambutol, pyrazinamide,
and streptomycin, which were compromised by their inclusion in the
failed treatment regimen.
Also ethambutol and pyrazinamide were the only drugs the isolate
was susceptible to during the initial nine weeks of his treatment.
And we know that PZA is not active against rapidly growing populations
of mycobacteria. Thus most of the population would only have been
treated with a single drug -- ethambutol.
The use of drugs to which there’s demonstrated in vitro resistance
is not recommended because it is very unlikely that these drugs
will be effective.
This patient had ciprofloxacin resistance and this should have
alerted the providers to the very likely possibility of ofloxacin
And last, bactericidal drugs with proven efficacy should be used
whenever possible and weaker agents only chosen when they are the
only possible alternative. In this patient, clofazamine was used,
which is a weak drug with unproven efficacy.
The regimen was fatally compromised when streptomycin was stopped
after only six months of therapy.
The Centers for Disease Control, American Thoracic Society, Infectious
Disease Society of America and most experts recommend at least 6
and preferably 12 months of injectable therapy after conversion
of cultures to negative.
This is especially important when the injectable agent is supporting
a weak oral regimen as it was in this patient.
Usually a total of 24 months of treatment following culture conversion
is recommended for multiple-drug resistance tuberculosis.
(A few selected) patients with limited disease may be adequately
treated with only 18 months of therapy, but this patient’s
long-standing disease and extensive drug resistant would have required
a longer treatment regimen. However, all treatments were stopped
prematurely after only 13 months.
Let’s look at this diagrammatic representation of the general
approach to designing a treatment regimen for multiple drug-resistant
The first step is to identify any first-line drugs, which have
proven or likely susceptibility.
This should generally be included even if they have previously
been used as part of a failed treatment regimen.
Next a fluoroquinolone, which is likely to be the most important
and active bactericidal drug in the regimen should be added if the
isolate is susceptible.
When a fluoroquinolone is not included in the treatment regimen,
it is less likely that the regimen will be effective.
The high mortality of XDR TB is especially related to resistance
to fluoroquinolone. Of the two fluoroquinolones listed here -- levofloxacin
and moxifloxacin -- moxifloxacin is generally regarded by most experts
to be the most active.
Finally, an injectable agent should be added. Any of these agents
is generally considered equally efficacious, but slight differences
in toxicity profiles exist.
Because the incidence of streptomycin resistance is greater than
10% in many areas of the world, it is always important to know that
there is documented streptomycin susceptibility before streptomycin
Once we’ve incorporated all the available drugs from Step
1, we turn to Step 2, and we add one or more of the oral second-line
drugs to crate a regimen of at least four and preferably five or
Whenever possible, we want to consider medical co-morbidities that
the patient may have. For instance, we would like to avoid cycloserine
in a patient with a serious seizure disorder or ethionomide in a
patient that had serious underlying hepatitis.
The last step is to add a third-line drug if an acceptable regimen
cannot be dealt from drugs available in Step 1 and Step 2. The drug
that is most likely to be helpful in this group is linezolid.
I’ll turn it back over to you, Dr. McDonald.
Reynard McDonald: Thank you, Dr. Seaworth.
On 8-18-2000 after a lapse of approximately two months, treatment
was with -- was restarted with ethambutol, PZA, ofloxacin, and clofazamine.
Several months later, streptomycin was added and continued for
approximately seven months.
Drugs susceptibility tests were obtained from a national reference
lab, and as you can see on this slide, the resistance patterns were
Isoniazid was resistant, rifampin was resistant, kanamycin, amikacin
were again resistant.
However, now not only was there resistance to ofloxacin, but also
resistance to ciprofloxacin.
Somewhat confusingly, however, levofloxacin was still considered
to be susceptible. In retrospect, this probably represents total
resistance, however, to the fluoroquinolones.
Unfortunately, an eight-month delay occurred between the time that
the specimen was initially submitted to the lab and when the report
of this drug susceptibility pattern was finalized, primarily because
of the fact that the subculture was - had difficulty growing.
On 11-20-01, the treatment regimen was revised as follows:
Ofloxacin was stopped because it was recognized that there
was a resistance. Ethambutol and pyrazinamide, clofazamine were
continued and in an attempt to add at least two to three new drugs,
cycloserene was added.
Levofloxacin was added, however - additionally also added was rifabutin
against the advice of the consultant.
On this slide, you can see that on this drug-o-gram, May 7, 1999,
rifampin, INH, pyrazinamide, and ethambutol were started, but resistance
had occurred to rifampin and INH.
On July 16, 1999, rifampin and INH were stopped, and streptomycin,
ofloxacin, and clofazamine were added with improvement to the patient
in that the sputum smears and cultures became negative.
However, there was a break in treatment for two months during the
summer of 2000 when the treatment regimen was stopped prematurely
and treatment was not restarted until August 18th of 2000.
After the information regarding the second-line drug susceptibility
test was obtained in February of 2000, no new drugs were added until
November of 2001, and ultimately this was too little too late and
the patient died in January of 2002.
Dr. Seaworth, your comment.
Barbara Seaworth: Drug susceptibility studies confirmed
further amplification of drug resistance with reported resistance
to pyrazinamide. The patient’s management continued to be
When initiating or revising therapy, it is important to try to
use at least three new drugs to which there is laboratory confirmed
Instead of using three new drugs, treatment was started with the
same regimen that had just failed and consisted of only oral drugs.
Sputum cultures should be done monthly during treatment of MDR
TB in order to follow the patient’s response to therapy.
Sputum cultures remain positive for three months in this patient,
and then simply were not collected for an additional eight months.
It’s also important to repeat drug susceptibility test whenever
the culture remains positive for three months, and of course extended
drug susceptibility study should always be done on patients with
These studies were only done on four occasions during five years
of failing medical treatment.
Although expert consultation is recommended when treating patients
with MDR or XDR TB, expert consultation was not requested until
three months before this patient’s death, by which time the
patient was desperately ill.
The recommendations to the consultants were only partially followed
and his treatment included only a single drug likely to be effective
At this point, every available drug should have been used, but
even then, the possibility of a good outline - outcome, rather,
This slide represents many of the key principles to follow when
treating a patient with multiple drug-resistant or XDR TB. Most
of these principles were violated by his providers.
These principles include: Directly observed therapy should always
be used without exception, especially for MDR and XDR TB, a single
drug should never be added to a failing regimen, treatment should
be started or revised by using at least three drugs to which there
is proven or documented susceptibility, use enough oral drugs to
ensure that the regimen is adequately strong once the injectable
agent is stopped.
And if no other previously used active drugs, especially bactericidal
drugs are available, do not limit the regimen to just three agents.
Additional principles include the fact that intermittent therapy
should not be used when treating multiple drug-resistant tuberculosis.
Woman: (You’re) on the next slide.
Barbara Seaworth: Also do not use drugs that are reported
as resistant by the laboratory as they aren’t likely to be
Use the laboratory results to guide treatments. Remember, a good
response does not justify continuing an inadequate regimen.
Measure serum drug levels if it all possible, especially for bactericidal
drugs and the drugs that have major toxicities.
Rifampin shouldn’t be used unless you have documented susceptibility
to - rather rifabutin should not be used unless you have documented
susceptibility to rifabutin as the incidence of cross-resistance
with rifampin is significant.
And last, always consult an expert in the care of multiple drug-resistant
or XDR TB when you are caring for one of these patients. Again note,
that most of these principles were violated by his providers and
contributed to the development of XDR TB and ultimate death of this
patient. His disease should have been easily treatable and curable.
His management represented complete systematic failure.
I’ll turn it back over to you, Dr. Reichman.
Lee Reichman: And Dr. McDonald had a final comment.
Barbara Seaworth: Oh sorry.
Reynard McDonald: Thank you very much, Dr. Seaworth, for
One additional aspect concerning multidrug-resistant tuberculosis
is the use of adjunctive surgery. Surgery is sometimes necessary
to cure patients with MDR TB. The decision to perform surgery should
be individualized based on the degree of underlying drug resistance,
the presence of localized cavitary disease, and the patient’s
ability to tolerate surgery.
I think I’ll stop here, Dr. Reichman.
Lee Reichman: Thank you, Dr. McDonald.
The Management of Contact to Cases of MDR/XDR TB. Our next speaker
is, Michael Lauzardo, who’s the Principal Investigator of
the Southeastern National Tuberculosis Center at the University
of Florida and the Deputy Health Officer for Tuberculosis of the
Florida Department of Health.
Michael Lauzardo: Thank you, Lee.
The ideal management of contacts to MDR/XDR TB is unknown as there
are very few studies to provide guidance. Most of what we know is
based on anecdotes and a few reports of nonrandomized studies.
The practitioner caring for patients exposed to MDR cases is faced
with challenges that require interventions without much of an evidence
base to guide therapy. Nonetheless as providers, we need to move
forward in caring for these patients despite the lack of data.
My goal today is to address the management of contacts to MDR cases
while reviewing the fundamentals, as is well known, the spread of
M. tuberculosis involved with three-step process as is illustrated
in this medical illustration by F. Netter, MD © CIBA first, there
is obviously transmission of bacteria, establishment of infection
and then progression to disease.
In an attempt to address the management of contact to MDR, I'm
going to address specific questions at each of these steps necessary
for the spread of TB.
There are questions regarding fitness of MDR/XDR strains, for example,
are drug-resistant strains as transmissible as drug-susceptible
strains, are drug-resistant strains likely to progress to active
disease once infection is established when compared to drug-sensitive
There also questions regarding the relationship between the genotype
and phenotype of MDR/XDR strains. Are all MDR/XDR strains equally
And finally the most important question is questions regarding
the ideal management of contacts for these cases and should we follow
or actually treat these contacts. If we treat, what do we treat
First of all, are drug-resistant strains as transmissible as drug-susceptible
strains? A case-control study by Snider, demonstrated a contact
to patients with drug-resistant and drug-susceptible incident cases
of TB had an equal prevalence of positive tuberculin skin test results.
These results suggested that infectivity is not diminished by drug
In contrast, the animal study showed that isoniazid-resistance
strain caused significantly less disease in guinea pigs than drug-susceptible
Are drug-resistant strains likely to progress to active disease
once infection is established?
In the context of an effective TB program in San Francisco, Burgos
et al., found that strains that were resistant to isoniazid either
alone or in combination with other drugs were less likely to result
in secondary cases than with drug-susceptible strains.
In this setting and the setting of a very well functioning TB program,
isoniazid-resistant strains in MDR TB cases were not likely to produce
new incident drug-resistant TB cases. This presumed the fact on
the pathogenicity may be related to mutations in the katG gene.
Again, (Yeow), in a paper published in PLoS last year working in
San Francisco as well, found that a specific mutation in the katG
gene resulted in more secondary cases than those in other of INH-resistant
This table from the Burgos article (published in 2003) shows the
secondary case rate ratio of drug-resistant strains by HIV status
(in place of birth).
You’ll note that the overall secondary case rate ratio was
only 0.51 and this lower case rate ratio remained even after controlling
for HIV status.
In addition to these data, other molecular epidemiologic studies
observed that cases of TB caused by drug-resistant strains were
less likely to be in clusters. The implication is that drug-resistant
strains were less likely to be transmitted and/or to cause active
But there's conflicting data. Texeira and colleagues in 2001 working
in Brazil found 37% PPD positive rate among drug-susceptible contacts
and 44% PPD positives among contacts to MDR TB cases, 4% of the
contacts in all - in both groups had active TB disease. So this
was done in a very high-incident setting.
Conover and a CDC group again working in 2000 published in the
gray journal [International Journal of Tuberculosis and Lung Disease]
discovered 18.5% or 56 out of 303 contacts of the methadone treatment
program had converted their skin test, and again this is after contact
to an MDR case. Thirteen secondary cases were identified among 462
clients and staff, but limited HIV data was available.
I think when addressing the issue of likelihood to progress to
active disease among resistant strains, it’s also important
to remember the first experience with MDR here in the United States.
In 1991 the first documented MDR outbreak was published in the
MMWR. During 1990 and 1991, outbreaks of multidrug-resistant TB
in four hospitals, one in Miami, three in New York City, were investigated
by CDC in collaboration with local partners. The report summarized
the findings of investigations and gave recommendations.
And of the 87 patients involved in the four outbreaks, 94% were
HIV positive and a shocking 80% were dead within 4 to 16 weeks of
being diagnosed with TB.
These numbers are very similar to the recent experience in South
Africa with XDR.
Does MDR/XDR progress to active disease quickly? Yes, of course,
it can and these reports document that.
Was there an increased virulence? Probably not, and I think you
can extrapolate some of that to what went on in South Africa. It’s
unknown, but there probably wasn’t. The high mortality, morbidity
is most likely a reflection of the level of overall TB control ongoing
at the time.
Now we’ve seen that there are some debate about how likely
MDR is to progress to active disease, and we have seen that MDR
strains are capable of rapid spread despite questions of their relative
fitness compared to drug-susceptible strains.
But to answer why this is going on depends on various factors,
and these are going to be based on the pathogen, undefined virulence
factors, variability of virulence between genotype and size of the
There also going to be host-related for obviously the presence
of immunosuppression with HIV being the most important, and also
it’d be very difficult to substantiate, but widely suspected
ethnic susceptibility to various strains.
A number of different studies have suggested that different genotypes
of TB might be associated with drug resistance. There is some inconsistency
in the studies’ conclusions of the relationships between genotype
and phenotype. Some have shown strains to be more likely developed
resistance and others - and also be more likely to progress to active
In a study that was published in April of this year, again, in
the Gray Journal, that study done in Singapore found that MDR isolates
at 41 that were studied were more common among those - identified
to be Beijing strains than among non-Beijing strains.
The estimated transmission rate of MDR TB was 7.7%. The transmission
rate of drug-resistant TB was significantly higher among the Beijing
genotype strains than the non-Beijing strains, 12.9% versus 4.4%
with a very significant P value.
This and other studies are documenting the genotypic heterogeneity
of MDR strains and some of that heterogeneity may result in increased
Now, for the real question, “What do we do with contacts
to MDR? Should we treat or follow those patients that are going
to be contacted through some of our most difficult and challenging
cases with TB?”
Well the answer is yes, we should do both, obviously. The guidelines
for MDR and drug-resistance recommend following the patients for
at least two years. But now the data to support strategies for managing
the contact is very sparse.
Recommended regimens were supported by very little data, usually
oral regimens combining PZA with quinolone or ethambutol. I don’t
- and I don’t know of anyone who’s using injectables
as a long-term option for most of these patients with latent TB
infection after contact with MDR case.
Now, overall the non-injectable regimens that don’t include
injectables, tolerance is still very poor, that is, PZA and ethambutol
or PZA and the quinolone, it’s very poor - tolerance of those
regimens are very poor when compared to INH.
I’ve had more success recently using quinolone alone for
six months and that has been something that’s been tolerated
a little bit better. And again, just to emphasize the obvious is
that a regimen that is not tolerated is completely useless, whereas
on that is partially or maybe less effective and is well tolerated,
is probably going to have more bang for the buck.
Now, as far as outcomes and what is actually published literature,
there’s very little, and it’s going to be non-randomized
series are what’s out there and again, I may emphasize this,
there’s very little.
In the literature, there is very little looking at the contacts,
one of those papers was the paper - in one study that was done in
South Africa looking at children exposed to MDR adults and these
children had documented LTBI.
The children received multiple drug regimens by DOT depending on
the susceptibility pattern or the presumed source case.
Schaaf et al. followed 119 small children who were contacts to
active cases of MDR TB.
Sixty one or 51% of the children were infected, and 14 or 12% of
the total had active disease at the time of the evaluation.
Two or 5% of the 41 children who received preventive therapy developed
TB compared to 13 or 20% who did not for an odds ratio of 4.97.
In the Conover study that I mentioned earlier looking at the outbreak
in the methadone clinic, during two years of follow up after the
last case in the outbreak was diagnosed, no further cases of MDR
TB were identified.
INH was added as exposure to a drug susceptible organism was possible.
During two years of follow up, no further cases of MDR TB were identified.
Preventive regimens were determined by the treating physicians
and typically a combination of the two of the followings, as I mentioned
earlier, ethambutol, PZA, and ofloxacin. All
medications were given by DOT in that study.
So in conclusion, there is very little data to support our current
recommendations. Outcomes of contacts may be influenced by the specific
organism’s genetics, but the practical utility of this approach
is not established.
Looking for a regimen that is going to be tolerated is probably
the best option and those or based on quinolones if you have that
option and combining it with or without PZA.
However, experience with combined regimens with PZA has been poor
I would also strongly recommend consultation in managing the contact
of these cases. Someone who has had significant experience with
Close follow up is going to be prudent despite the fact that there
are some questions regarding the fitness of these organisms.
Once again, thank you very much for your time, and I’ll be
glad to answer any questions during the question and answer session.
Lee Reichman: Thank you, Michael.
To finish up, I’m going to talk a little bit about the lesson
- some lessons that we’re learning from XDR and MDR TB and
then talk about the resources available to our listeners from the
RTMCCs and CDC.
First of all, you’re all familiar with the US traveler who
had XDR and then MDR TB, who was very prevalent in the newspapers
a few months ago.
No matter what you think of him, he taught us several lessons,
and I think it’s worth repeating right now.
First of all, TB is not going away. It remains with us highly prevalent
Any one can get tuberculosis, not only poor people, not only minorities,
and not only the foreign-born.
TB anywhere is TB everywhere. All resistant tuberculosis, multiple
drug-resistant tuberculosis and extensively drug-resistant tuberculosis
is preventable by proper TB diagnosis and treatment.
Good public health can be silent, but when there is a glitch it
becomes major news.
We desperately need new tools for tuberculosis diagnosis. We desperately
need new drugs in treatment for regular drug
sensitive TB as well as drug-resistant TB.
And finally, you don’t want to sit on an airplane for eight
hours next to an untreated coughing person with any kind of TB,
be it drug-sensitive, multiple drug-resistant, or extensively drug-resistant
Now we’re going to talk about the services available to you
from the Regional Training and Medical Consultation Centers and
Centers for Disease Control.
At the height of this Webinar, there were 826 lines open. Assuming
if several of these were in groups, that’s a lot of people
who hopefully are interested and will do the right thing in treating
multiple drug-resistant and extensively drug-resistant tuberculosis.
But we have the RTMCCs and CDC available to help you. So for consultation,
be sure to notify your state and local TB programs of any TB case.
And always bring an expert consultation when managing a person with
drug-resistant TB and TB treatment failure --witness the case presented
Dr. McDonald and Seaworth.
Experts are available at your state TB program and also at the
four CDC funded Regional Training and Medical Consultation Centers.
And here they are and here is the contact (information) of the RTMCCs.
This slide will put up during the question period, so you don’t
have to take notes on it now.
And here’s the map that Dr. Castro showed showing the state
breakdown of which center handles which state.
Under the RTMCC training, we have a series of national Webinars
on legal interventions, laboratory diagnostic, TB/HIV, and genotyping.
I'd like to call your attention to the next one, which will be held
September 11, the National Webinar- Best Practices in TB Control
Legal Interventions, sponsored by the New Jersey Medical School
Global Tuberculosis Institute, and you can find out more about it
on our Web site.
We also have standup training courses in all the RTMCCs such as
clinical intensive, case management, contact investigation, program
management, and updates on topical issues.
We have educational products and resources as shown in this slide,
Drug-Resistant Tuberculosis Survival Guide for Clinicians from the
Francis J. Curry Center, the Multiple Drug-Resistant TB Care plan
from the Heartland National TB Center, the Electronic Drug-o-Gram
from the New Jersey Medical School Global TB Institute, and the
Medical Consultation Database from the Southeastern National Tuberculosis
We have additional MDR/XDR educational resources from the Division
of Tuberculosis Elimination of CDC.
We have the CDC Web site, which www.cdc.gov/tb/xdrtb/, which is
up-to-date listing of all things to do with extensively drug-resistant
And that has on it about XDR TB overview and XDR TB fact sheet,
the podcast, MDR TB fact sheet, and then most of these are translated
into all sorts of languages -- Spanish, Chinese, French, and Italian,
and you can just link right on there and get to the language.
So we have the CDC Web page continued more about XDR TB. We have
the morbidity mortality reports, fact sheets, drug-susceptibility
testing for TB, questions and answers, so if you don’t get
yours answered from this Webinar, you can go on there and find the
answer. TB and air travel guidelines for prevention and control,
state TB control officers, city TB control officers, the World Health
Organization XDR TB Web site.
Now, each of the speakers who spoke today had a lot of people,
so we thought we’d save time and put all the acknowledgment
on each slides so then the acknowledgement people who had helped
in the presentations of each of our speakers.
I’d like to add our own acknowledgements to all the people
at Centers for Disease Control, some of whom are on here, but especially
Amera Khan, Nick Deluca, Wanda Walton, Kashef Ijaz, and Ken Castro,
who are very helpful and Dan Ruggiero in putting this thing together.
And now, we will open the lines for questions. We’re going
to go until 20 minutes to 4:00, which will give us approximately
17 minutes for questions now.
And the operator is going to tell us how to do that.
Operator: Thank you.
If you would like to ask a question, please press star-1. Please
unmute your phone and record your name clearly when prompted. Your
name is required to introduce your question.
To withdraw your request, press star-2.
One moment, please, for our first question.
Lee Reichman: We have a panel of experts who will be handling
The panel includes Kevin Fennelly from New Jersey who is available
for transmission and protection among health workers, Ann Loeffler,
a pediatrician from the Francis J. Curry Center, obviously, on pediatrics,
Todd Braun, Nurse Consultant at Heartland, will talk on nurse case
- be available for nurse case management, Peter Cegielski and Tim
Peter is the Chief of the MDR team, and Tim Holtz is the Medical
Epidemiologist at CDC will be available for MDR and XDR in international
setting; Theresa Harrington, the Medical Epidemiologist in CDC,
and Anne Buff, an EIS officer at CDC, will be available for the
XDR outbreak investigation.
Operator: One moment, please, for our first question.
Our first question comes from (David Asmond). Your line is open.
(David Asmond): Yes, thank you.
The slides leading up to Slide 37 gave us information on how to
interpret resistance testing, vis-à-vis the sensitivity and specificity
of different agents.
I had a little bit difficult time following some of the details,
and I was wondering if you would just review briefly in a practical
way how we should interpret resistance testing for those agents
that were described.
Lee Reichman: Thomas Shinnick, are you there?
Thomas Shinnick: I’m here, Lee.
Basically what that slide - the couple of slides were showing is
that there can be variability between individual laboratories when
testing particular strain.
But typically what we see within a laboratory is that the results
are very reliable and reproducible that it is rare that if you found
a strain that’s resistant on day - the first time you test
it and come back a couple of weeks later and test it again, that
the susceptibility has not changed.
So what you need to do - or in general, what the clinician needs
to do is get to know their laboratory and understand the predictive
value of what the laboratory is telling you and so you know that
that laboratory’s results impact your treatment management
Lee Reichman: And I think, Tom, also that it’s very
important to be getting familiar with the laboratory, like the laboratorian
knows the clinicians. So it’s very, very good if the clinician
and the laboratorian can talk about the case, so the laboratorian
knows that the clinicians looking for, and then we found that this
kind of communication really enhances our care for each patient.
Next question, please.
Operator: Our next question comes from (Jackie). Your line
(Jackie): Hello. I have a question. How close are we to developing
a vaccine against tuberculosis so that maybe this would eliminate
the multidrug-resistant and the extreme drug-resistant tuberculosis?
Lee Reichman: Kevin, you want to take that?
Kevin Fennelly from New Jersey because he’s across the room.
I can see him. (Let’s see).
Kevin Fennelly: Well I’m not sure if that’s fair of
Lee. But my impression is that, we’re quite far away from
a vaccine. There’s been some exciting data presented at research
conferences. But I would be very surprised if we had a vaccine that
was ready for clinical use within the next ten years.
And even as we’ve seen with other drugs, you know, vaccines
may prevent some disease, but I suspect that within the near future,
we’ll still have to be dealing with the active cases and,
you know, deal with them as our experts have suggested here today.
Lee Reichman: Another question, please.
Kenneth Castro: (Hey), Lee, this is Ken Castro. Let me just
add to that - answer that.
There are at least three, possibly four vaccine candidates in Phase
1 clinical trials, and I would very much agree with Dr. Fennelly
that it will take some time for this to be field evaluated for both
safety as well as efficacy, and it will be sometime before we have
something that we can introduce as an effective measure.
However, it is very much part of the strategy that we’re
pursuing globally to deal with tuberculosis.
Lee Reichman: Thanks, Ken.
Next question, please.
Operator: Our next question comes from (Vincent Fears).
(Vincent Fear): Good afternoon.
I was wondering, can anyone provide an estimate in 2007 dollars
as to what it cost to treat a case of MDR to cure and .. for XDR?
Lee Reichman: Barbara Seaworth, do you have any idea?
Barbara Seaworth: I think that it varies depending on where
the patient is treated whether they’re treated outpatient,
inpatient, treated with surgery or without surgery. But certainly
it would cost at least $250,000 for a simple MDR patient and it
could cost three, four, five times that much for a complicated XDR.
Just treating this patient from the beginning even in 1993 must
have been incredibly expensive and unsuccessful.
Kenneth Castro: This is Ken Castro. Let me jump in and add
to what Dr. Seaworth has just stated.
Suzanne Marks from our unit who does some health economics has
estimated that on the average, it’s costing $483,000 for inpatient
hospitalization costs if you have extensively drug-resistant TB.
In prior years, we had estimated that you would average up to about
$200,000, $250,000 for treatment of persons with multidrug-resistant
TB. These are incomplete cost estimates because they exclude lost
wages and all the other indirect costs.
But certainly, what’s important is to underscore how one
person with extensively drug-resistant TB could bankrupt a local
health department resources that are right now in a very precarious
Lee Reichman: And I just should add that it makes it looks
pretty cheap to just plain old everyday treatment of tuberculosis
with six months treatment directly observed therapy contact follow
up. But that’s pretty cheap compared to the numbers that Barbara
and Ken just gave you.
Next question, please.
Operator: Our next question comes from (Dominic Asiano).
Lee Reichman: (Dominic)?
(Dominic Asiano): Do rifampin and streptomycin signal multiple
drug-resistant tuberculosis, is that true and what is the basis
of that statement if it is true?
Lee Reichman: The question was, “Do rifampin and streptomycin
together signal multiple drug-resistant tuberculosis?”
Barbara, can you handle that?
Barbara Seaworth: Yes.
Actually the definition of multiple drug-resistant tuberculosis
requires that the isolate be resistant to both isoniazid and rifampin,
at least. And so streptomycin may or may not be resistant in that
particular instance. It’s based on INH and rifampin resistance.
Lee Reichman: Thank you, Barbara.
Next question, please.
Operator: Our next question comes from (Connie Keaton).
Your line is open.
(Connie Keaton): Yes. All I want to ask is to show that
screen again where you can get the CEUs.
Lee Reichman: That will be shown at the end. CEU information
will be shown at the end.
(Connie Keaton): Thank you.
Lee Reichman: Next question - thank you. The next question,
Operator: Our next question comes from Charles Wallace.
Lee Reichman: (Charles)?
Charles Wallace: Yes. I’d like to know what plans are under
way to manage XDR patients, who are not treatable and require quarantine?
How will you handle those particular patients?
Kenneth Castro: This is Ken Castro.
I should have expected that question from Dr. Wallace, who is in
charge of TB control in Texas.
We are - part of the discussions that are taking place is whether
we ought to consider the establishment of a few places throughout
the country with the appropriate airborne infection control isolation
facilities, not only for tuberculosis, but for some of the other
conditions that are of concern, for example, SARS comes to mind
as another condition for which you would want to prevent transmission
from person to person.
There is no decision that has been made. And obviously, that would
require - there are so many important resource implications with
that regard. But there are handfuls of centers throughout the country
that have those facilities.
The question is, who’s going to be funding the stay of a
given patient especially if you have to transfer a patient out of
I personally think that the Regional Training and Medical Consultation
Centers ought to be a good place to consider getting things started,
at least, two, if not three, of the centers have direct links to
facilities that could provide the appropriate isolation precaution.
In the absence of that, we would want to make sure that persons
with drug-resistant TB, who are potentially contagious, are not
exposing others. And in the most extreme of cases, once you’ve
exhausted the less restricted measures, you might need to consider
situation such as house arrest to prevent them from exposing others.
But that’s a last resort type of intervention.
I would welcome any input from any of the other panelists on this.
Charles Wallace: Ken?
Charles Wallace: Could I do a follow up on that?
Lee Reichman: …(to comment).
Lee Reichman: Go ahead.
(Charles Wallace): Yes, the follow up is, how do we work
being a border state -- Texas -- how do we deal with our neighboring
country, Mexico, Latin America, Central America, in managing TB
cases that may be extremely drug-resistant or extensively drug-resistant
in that country, but they cross the border on a regular basis?
Lee Reichman: Well just looking at the international settings,
can we call on Peter or Tim Holtz to comment on that?
Peter Cegielski: (I can). This is Peter Cegielski.
Yes, it’s true that border crossing and international migration
is very important in the epidemiology of XDR TB, as well as MDR
TB. I don’t know if specific additional measures to control
the movement of individuals with tuberculosis across the US-Mexico
border other than the measures that are in place for tuberculosis
patients in general.
There are resources to help ensure that patients who are initiated
on treatment on one side of the border continue their treatment
on the other side such as CURE-TB and TB Net.
And in addition to that, the World Health Assembly enacted international
health regulations in - they became effective in July 2007 that
enable governments to take action to restrict the movements of individuals
for public health measures.
Lee Reichman: Thank you, Peter.
Charles, just I think the point that the organizers would also
like to underscore that we’ve said a couple of times before
is a good TB control prevents XDR and MDR TB, and if we support
good TB control in these countries, there won’t be so much
problem of these people crossing the borders or hopping on airplane.
Charles Wallace: Lee, I agree with you. But I think one of the
problems is that, some of these countries don’t have quarantine
laws that we can effectively use to quarantine those kinds of patients,
that makes it very difficult.
Lee Reichman: Thank you, Charles.
Operator: Our next question comes from (Alma Gutierrez).
(Alma Gutierrez): Hi.
Lee Reichman: Hi.
(Alma Gutierrez): I do have a question. Actually two on
the treatment outcomes from MDR contact. How old were the children
who developed the disease?
Lee Reichman: Children, so Ann Loeffler. Are you there,
Ann Loeffler: Yes, I’m here.
Lee Reichman: Hello. Go ahead.
(Alma Gutierrez): Yeah. Because, you know, we do
have a case that there’s multidrug-resistance and this person
has a son and he’s nine years old and he doesn’t want
to take the preventive medication.
So we have some concern for him to develop the disease in the future.
Lee Reichman: Okay. Ann, can you handle that?
Ken: Lee, you may want to want to ask Mike Lauzardo, who
was dealing with that topic.
Lee Reichman: …my next fallback case.
Michael Lauzardo: Yes.
And so if I understand correctly, it’s a child who’s
a contact to an MDR case, but the mother does not want the child
to take the medications?
(Alma Gutierrez): Uh-huh, that’s correct.
Michael Lauzardo: Yeah, I mean, that’s one of the
challenges and why it’s so frustrating to take care of any
of these patients because there’s not a huge evidence base
to fall back on and say, you know, ma’am, your child has a
x% chance of developing active TB disease, and I know if I give
him this medicine, I can reduce that chance by so - such and such.
So that’s, you know, largely the challenge that’s there.
Again, individualizing therapy, if it’s something that is
susceptible to the quinolones, even though it’s a child, you
may still consider using quinolones for preventive therapy. We’ve
done that with several children with success and again, it’s
more of that anecdotal experience that people talk of.
A lot of the fears that people have had with regard to children
and the use of quinolones on a chronic basis has been diminished
largely by what’s published in the cystic fibrosis literature
and how those children have been treated mostly for their pseudomonas
So using those situations can be considered on an individual basis.
Now, as far as how far do you go, each state, it’s going
to be independent. In Florida, when we have a contact to a case
be it MDR or not, we will many times get child protective services
involved to have them determine whether or not the mother or parent
or caregiver is being reasonable.
And if they don’t want to take the medications because they
don’t want to give their child an untested regimen…
(Alma Gutierrez): Uh-huh.
Michael Lauzardo: …in my eyes, that’s being
very reasonable. There is nothing that’s truly tested and
that we can know. I would - at the bare minimum, follow the child
(Alma Gutierrez): Uh-huh.
Michael Lauzardo: Then give them the evidence that’s
there and then let them make their decisions, and hopefully they’ll
be making an informed decision.
(Alma Gutierrez): You know, the mother who’s…
(Alma Gutierrez): …even though she doesn’t want
to take - continue their medication, right, you know, I was so persistent.
But the son, you know, he starts taking the moxifloxacin and he
took it maybe for a month and then he stopped.
Michael Lauzardo: Yeah. Those are some of the many challenges
that we have, and it’s - that’s why it’s such
a challenge and that’s why following them is very important.
(Alma Gutierrez): So he might be breaking out on TB in the
future, most likely?
Lee Reichman: Absolutely. But that’s - as Michael
said, those are the challenges that we deal with all the time not
only with drug-resistant cases…
(Alma Gutierrez): Uh-huh.
Lee Reichman: If we started ten minutes later, we went ten
minutes later. But I’m afraid that we’re going to have
to cut off the questions now.
You have the continuing education news on the screen now, and before
you had the contact information for the RTMCC and CDC, if your question
was not answered, we have a lot of questions in queue, written questions,
we have a lot of other questions, broken questions, but unfortunately
we can’t get to them all.
I’d strongly suggest that you call or email your RTMCC or
more preferably CDC. And we thank you very much for your attention.
We thank you very much for joining this Webinar.
If you think this was an effective use of information sharing,
and if you think this is useful, please let us know and we will
schedule future Webinars.
And if you have other specific topics you want us to talk about,
we are your RTMCC. The one in your region is there to help you and
Lee Reichman: …can solve and to train, so get to know
them, work with them, and of course, as always, report your case
to your local TB control program and discuss it with them, too.
So thank you very much to everyone who’s on and everyone
who helped and good night - afternoon.