Continuing Education Activities for Webinars

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Multidrug-Resistant Tuberculosis (MDR TB) and Extensively-Drug Resistant (XDR) TB

Webinar Transcript

Moderator: Lee Reichman
August 17, 2007
1:00 pm CT

Operator: Good afternoon and thank you all for standing by.

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 Tuberculosis.

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 seminar.

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 seminar.

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 tuberculosis.

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 (www.cdc.gov/tb/CE/webinars.htm)

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, Domestic Implications.

Masae?

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.

Next slide.

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.

Next slide.

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 treatment.

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 outcome.

Next slide.

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.

Next slide.

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.

Next slide.

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.

Next slide.

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 drugs.

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 of TB.

Next slide.

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.

Next slide.

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 cases.

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 not preventable.

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.

Next slide.

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 of transmission.

Next slide.

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.

Next slide.

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.

Next slide.

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.

Next slide.

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.

Next slide.

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%.

Next slide.

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.

Thank you.

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.

Tom?

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 resistant.

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 anti-tuberculosis drug.

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 drugs.

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 of drug.

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 and ethambutol.

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 presentation.

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 case.

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?

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 appointments.

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 addressed.

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 failure.

At this point, new drug susceptibility study should have been ordered and should be ordered whenever a culture remains positive after three months.

But despite the glaring possibility of drug resistance, this risk was not recognized and repeat drug susceptibility tests were not ordered.

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 ethambutol.

Drug susceptibility tests were obtained from a commercial lab on a sputum specimen collected 4-29-99 and revealed resistance to INH and rifampin.

However, additional resistances to aminoglycosides, kanamycin, and amikacin were also identified and resistance to one of the fluoroquinolones -ciprofloxacin.

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 five months.

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 observed therapy.

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 drug-resistant tuberculosis.

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 CDC, please?

Woman: Okay.

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 resistance.

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 TB.

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 is chosen.

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 six drugs.

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.

Next slide.

Drugs susceptibility tests were obtained from a national reference lab, and as you can see on this slide, the resistance patterns were similar.

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.

Next slide.

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 inadequate.

When initiating or revising therapy, it is important to try to use at least three new drugs to which there is laboratory confirmed susceptibility.

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 MDR TB.

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 -- cycloserene.

At this point, every available drug should have been used, but even then, the possibility of a good outline - outcome, rather, was unlikely.

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 effective.

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 your comments.

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.

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 strains?

There also questions regarding the relationship between the genotype and phenotype of MDR/XDR strains. Are all MDR/XDR strains equally virulent?

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 with?

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 resistance.

In contrast, the animal study showed that isoniazid-resistance strain caused significantly less disease in guinea pigs than drug-susceptible strains.

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 cases.

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 TB disease.

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 infecting inoculum.

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 disease.

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 pathogenicity.

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 of late.

I would also strongly recommend consultation in managing the contact of these cases. Someone who has had significant experience with MDR.

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 and transmissible.

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 TB.

Next.

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.

Next, please.

And here’s the map that Dr. Castro showed showing the state breakdown of which center handles which state.

Next, please.

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 Center.

Next, please.

We have additional MDR/XDR educational resources from the Division of Tuberculosis Elimination of CDC.

Next, please.

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 tuberculosis.

Next, please.

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.

Next, please.

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.

Next, please.

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.

Cue operator.

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 questions.

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 Holtz.

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.

So, questions?

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--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 decisions.

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 is open.

(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?

Thank you.

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?

((Crosstalk))

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.

((Crosstalk))

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 situation.

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, please.

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?

((Crosstalk))

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 state.

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?

((Crosstalk))

Charles Wallace: Could I do a follow up on that?

Lee Reichman: …(to comment).

Man: Yes.

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.

((Crosstalk))

Lee Reichman: Thank you, Charles.

Next question.

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?

Ann Loeffler: Yes, I’m here.

Hello?

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?

Ann Loeffler?

Ken: Lee, you may want to want to ask Mike Lauzardo, who was dealing with that topic.

((Crosstalk))

Lee Reichman: …my next fallback case.

Mike?

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 exacerbation.

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 very closely.

(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…

((Crosstalk))

(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 to…

((Crosstalk))

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.

END