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Alfred Lardizabal:Anti-TB medications are associated with adverse effects ranging from mild to

severe. This web-based seminar will specifically cover side effects of first line drugs used to treat tuberculosis and provide strategies for managing adverse events.

Slide 2This afternoon our faculty members are Dr. Robert Belknap from Colorado and Dr. Henry Fraimow from New Jersey. Dr. Belknap will provide an overview of managing side effects.

Slide 3We're about to begin and we're glad to have Dr. Bob Belknap. Bob is an assistant professor in the Division of Infectious Disease at the University of Colorado and is an infectious disease specialist working for Denver's Public Health Department. He has several years in conducting TB research, including the CDC sponsored TB Trials Consortium and the TB Epidemiologic Studies Consortium. I'll now turn the program over to him. Bob?

Slide 4Robert Belknap: The objectives are that at the end of the talk today, you'll be able to list the

common side effects associated with first line TB medications, describe the monitoring for and diagnosis of adverse drug reactions and discuss approaches for managing adverse drug reactions to minimize toxicity and to ensure treatment completion.

Slide 5So the first case for all of you is a 73-year-old patient who had rheumatoid arthritis and developed pulmonary tuberculosis while taking TNF-α inhibitor. Her past history was significant for chronic difficulty with nausea and dysphasia but her baseline liver function test were brought back normal.

Slide 6She was started on Isoniazid (INH), Rifampin (RIF), Pyrazinamide (PZA) and Ethambutol (EMB) and her cultures grew pan-susceptible tuberculosis. Her

chronic nausea however, worsened on the four drug therapy and she did report occasional vomiting. Two weeks into therapy her alanine transaminase (ALT) was repeated and was 57 on the upper limit of normal being 40.

Slide 7The first question I have for all of you is what would you do now? Your options are to continue on the current treatment and repeat the ALT in a week. Stop all medications. Stop the INH and PZA. Or continue treatment but add an antiemetic. And I didn’t put in the last choice which was none of these. You might choose to do something different…

Alfred Lardizabal:I think all the votes are in. 48% has continued treatment but add antiemetic.

Robert Belknap: Yes. And 41% continue the current treatment or repeat the ALT and 9% said they would stop all drugs at this point. So I'll tell you what we actually did at this point was to add an antiemetic and continue her treatment and unfortunately, despite the antiemetic, she didn’t tolerate the therapy and it appears Pyrazinamide was also discontinued. That was deemed to be the cause.

Slide 8 A couple I think important definitions and clarifications. Gastrointestinal symptoms when we talk about those, we're really talking about some or all of nausea, vomiting, loss of appetite, which sometimes gets missed if not asked specifically, or abdominal pain.

While all of those symptoms can be or can occur in the setting of hepatotoxicity they can also occur in the absence of actual injury to the liver. Hepatotoxicity we're defining in this case as drug-induced liver injury that is manifested as changes in the liver function tests.

The liver function tests that are commonly measured to evaluate this are the ALT, aspartate aminotransferase (AST), and/or the bilirubin.

Slide 9Hepatotoxicity can occur in any patient although there are definite risk factors that increase a likelihood of a person having hepatotoxicity from TB treatment.

Age is a factor and the older a person is the more likely they are to have drug- induced hepatotoxicity and for kind of traditional reasons and to have a relative at that point 35 years has been used in sort of determining who may be at greater risk versus lesser risk.

Certainly alcohol consumption is a very important for hepatotoxicity. Chronic viral hepatitis, pregnancy or being within the first 3 months post-partum, taking any concomitant hepatotoxic medications, and this can include over-the-counter herbal supplements and having a prior abnormal ALT or bilirubin in the absence of any of the other things also increases the likelihood of hepatotoxicity.

Slide 10For diagnosis the preferred test is an ALT. It's felt to be more specific for drug-related liver injury than the AST is. AST can be elevated for other reasons. Baseline testing is not recommended for all patients starting latent TB treatment but should be done for any patients starting treatment for active disease.

Patients who have one of the risk factors I mentioned or any other reason to suspect they might have underlying liver disease, for example they may have symptoms without a prior diagnosis. You would want to check that baseline ALT in that patient prior the starting therapy as well.

Then certainly anyone who has new or worsening GI symptoms should have a prompt ALT with or without holding the medication. The decision to hold the medication may be based on the degree of symptoms, other risk factors the person had, and whether or not you're talking about active versus latent tuberculosis. Generally with latent tuberculosis I'd have a very low threshold to hold the medication because the loss of efficacy by holding doses for a little while, latent TB is very low.

But active tuberculosis, especially if a person is very early in therapy, you've got to balance that out with the contagiousness and the risk to persons they're going to be around and be exposed to.

GI symptoms without hepatotoxicity is in fact very common during TB treatment and I've listed sort of relative frequencies for different drugs.

But I think we see this more commonly with Pyrazinamide greater than Isoniazid, Rifampin and the Fluoroquinolones. I feel patients complained of GI symptoms at about the same rate and then Ethambutol and aminoglycosides are very uncommon for those to be a cause of GI symptoms. The symptom monitoring while on treatment should occur continuously so in a patient who is getting directly observed therapy (DOT), certainly that's an opportunity to ask about any of these symptoms and address them if they are present.

And then obviously at monthly follow-up visits patients should be asked directly about all of those GI complaints.

Slide 12Managing GI upset or GI symptoms after you've excluded hepatotoxicity there are a number of options. One of the first and sometimes the easiest is to change the timing of the dose. So if a patient is taking the medications very early in the morning you might try changing it to the afternoon or evening, depending upon again perhaps the schedule of the clinic the schedule of any outreach workers if we're talking about directly observed therapy.

I think it's generally a good idea if you give the medications either with food or make sure that they've had some food in their stomach prior to taking it. That tends to decrease the GI upset that occurs. For some folks it's the pill burden. A change from daily therapy to intermittent therapy, they're twice weekly or three times weekly, leads to an increase in the number of pills taken with each dose.

The nausea and sometimes vomiting that occurs is actually related to the number of pills swallowed with each dose and going back to a daily dosing can alleviate that for certain patients. If antacids, if you suspect that it, that the person may be having acid reflux or that that may be contributing, then antacids can be used. If you're going to use an antacid it's recommended that

they take that either two hours before or two hours after the medications so that there's not any impact in throughout absorption.

For a number of folks, one of the issues that you'll observe and I certainly run into not infrequently, is patients who have had some GI symptoms start to anticipate those. And so when you're questioning them about this, they may say, “I start to get nauseated as soon as I see the outreach worker pull up,” or “As soon as I pull up to the clinic I start to get nauseated.”

Well that's obviously not an effect of the medication. That's a psychological effect of the fact that they've experienced that before and they're expecting to experience it again. And so an anxiolytic medication can help at times. And finally antiemetic medications…

Slide 13 I've listed some more of the more common antiemetics that can be used. Ondansetron (trade name Zofran®) is generally a good option; it's well tolerated.

It works fairly well and it's relatively recently become generic, so it's more affordable than it once was. And you can see the kind of the usual dosing and twice a day as needed, all of these would be given as needed. And usually the way I recommend folks to take them if they're going to work is to make sure they take the antiemetic about an hour before the planned time for their TB dosing. That way the medication has had an opportunity to be absorbed into their system and should be effective at the time they take their drugs.

I listed Hydroxyzine down there which is not traditionally thought of I think as an antiemetic. It's more of an antihistamine medication has antiemetic properties and also has anxiolytic properties. I certainly stay away from prescribing anxiolytics like benzodiazepine, I will use Hydroxyzine with relative frequency and good success for managing some anxiety associated nausea has an antiemetic effect and then also in cases where an antihistamine is needed.

Some other options to consider, if you know that the person has pan- susceptible disease, Ethambutol really has little if any role in the treatment of the disease at that point. Discontinuing Ethambutol reduces the pill burden and may allow people to tolerate without impacting sort of the total duration of therapy that you have to give.

Another consideration I think if you're going to have to stop a single medication, Pyrazinamide is the one that seems to cause the most problems, and by discontinuing that patients are able to tolerate the other three; it does mean that your therapy will need to be extended to at least nine months.

And then in very severe cases holding all medications except the Ethambutol and then adding a Fluoroquinolone so this would be an example of someone certainly in the initial phase of TB treatment who is likely still contagious and may still be symptomatic where holding all of the medications is not considered a good option. You could hold the three and still keep them on a two drug combination with the plan to, as quickly as possible, begin adding back drugs one at a time.

And in that scenario I would generally add back Rifampin first because it's our most potent medication in the regimen. Typically Isoniazid second and then may or may not add back the Pyrazinamide depending upon how the individual is doing.

Slide 15So the next case for you guys to consider this was a 40 year old gentleman alcoholic, diagnosed with smear positive pulmonary TB. And on baseline laboratory testing he had an elevated AST of 78, ALT of 88, for both the upper limited normal was 40, alkaline phosphatase (Alk Phos) and total bilirubin were normal. His platelet count was slightly low. He was started on Isoniazid, Rifampin, Pyrazinamide and Ethambutol.

Question for you guys. Two weeks later his AST and ALT were rechecked and his AST was now 546, ALT 328, Alk Phos 223 and total bilirubin 0.6. What would you do?

Stopping INH and PZA, holding all the medications, switching to Levofloxacin and Ethambutol, or continue the medications for referring for alcohol treatment. Most folks preferring holding all medications.

So what we did in this case actually was hold the medications except we did give the patient Levofloxacin and Ethambutol. And this was because the patient had smear positive pulmonary TB and was only two weeks into treatment. So we stopped the INH, Rifampin and Pyrazinamide but we didn't want to stop all the drugs because the concern that 1) as a TB could progress, but 2) the patient would remain infectious.

Slide 17So in terms of diagnosing and managing hepatotoxicity and this overlaps a bit certainly with the management of the gastrointestinal symptoms. First off, routine laboratory monitoring is not recommended for all patients on treatment. So it's not required or necessary that every patient on active TB treatment get periodic laboratory evaluation.

But the patients that should and should generally get it repeated are patients who have a baseline abnormal liver function test or those that have a risk factor for hepatotoxicity.

And then as I mentioned previously, all patients with the GI symptoms should have an ALT check. And so if they have symptoms at baseline, even with a normal ALT you likely should recheck it within two to four weeks or certainly if they develop new or worsening GI symptoms then you want to recheck then.

When to hold the medications, there are some specific guidelines that CDC has put out around these. And the recommendations are to stop medications if the ALT is greater than three times the upper limit of normal and the person has symptoms.

Or if they're asymptomatic but the ALT is greater than five times the upper limit of normal. So this will change depending upon the labs, but in general the upper limit of normal is around 40. So you think of an ALT of about 120 in someone who has symptoms or an ALT of 200 or greater in someone without symptoms.

If you do this – if you do have to hold medications, you might consider changing them to what we think of as a more liver-friendly regimen and so a Fluoroquinolone, an Ethambutol and/or an aminoglycoside can be – can generally be given safely.

Slide 19Next case is a 43-year-old who had non-alcoholic cirrhosis and was diagnosed with tuberculosis during a transplant workup. The patient actually was complaining of some pleuritic-type chest pain and had a CT scan done looking for a pulmonary embolis and was found to have an incidental cavitary lesion and turned out to have smear positive pulmonary TB.

So we started the patient on Rifampin and Ethambutol and monitored. The liver function tests remained stable. And the question is what medication would you add next? The options are Isoniazid, Levofloxacin, Pyrazinamide or Moxifloxacin. You've got a couple choices in terms of the Fluoroquinolones.

We added the Fluoroquinolone and I gave you two choices there– in part for my own curiosity to see if folks had a preference in terms of Levofloxacin or Moxifloxacin. We certainly did, we added Levofloxacin and as you can see at the bottom of the slide the reason we added Levofloxacin is because the medication is cleared by the kidneys as opposed to Moxifloxacin which is cleared by the liver.

And that – those really are the main differences between these two drugs. If you look in the literature, you can find reports and evidence that in vitro, in the lab Moxifloxacin appears to have greater activity than Levofloxacin although there haven't been any clinical trials to support that Moxifloxacin is better.

And so my own approach is to look; 1) to see if the person has either liver disease or kidney disease that might lend to using one or the other drugs based upon that. Or otherwise to go with the one that is more readily available and cheaper.

Slide 20The other potential side effects from these drugs are really quite similar. GI symptoms can occur; so nausea, upset stomach although not typically hepatitis. Central nervous system (CNS): headache, dizziness, insomnia. There is a black box warning related to tendon inflammation or tendinopathy and associated tendon rupture.

This is usually the Achilles tendon. It tends to occur more commonly in older patients and also patients who are taking steroids and then QT prolongation. By itself Fluoroquinolones don't tend to cause cardiac arrhythmia but if you have a patient with a known underlying cardiac disease or is taking other medications that can cause QT prolongation, the addition of Fluoroquinolones could make that worse so you want to be aware of that and at least have thought about it, have asked the questions prior to starting the drug.

Slide 21Alfred Lardizabal:Bob, do you think we could before you get to your next slide perhaps pause to

answer a few questions that relate to these two cases? The first case- a question was sent in through the chat line. For the first case you ended up stopping the Pyrazinamide?

Robert Belknap: Yes, we stopped the Pyrazinamide. And so the question was I think so did we treat the patient for nine months? So we did. If we – in any case where we can't get eight weeks of Pyrazinamide into the patient either because of

toxicity or it turns out that they have resistance, then we extend therapy to nine months.

Robert Belknap: The question I see is given budget constraints before adding an antiemetic in a choice between twice weekly therapy under DOT or daily therapy out without which would you choose- daily therapy without antiemetic or twice weekly therapy with an antiemetic?

Good question, certainly a challenging scenario. I'd say that my bias is certainly for directly observed therapy in all cases of pulmonary tuberculosis. And we do it for most or you know we try to do it for all but certainly do it for most of our extrapulmonary cases in part because you know the folks that started the clinic here and certainly who trained me were strong advocates for directly observed therapy.

And I agree with them on that. So given those two options I would likely choose trying to treat with an antiemetic and continuing the twice weekly therapy if able. And in the cases where we've not been able to do that, we've gone to daily therapy but continued to directly observe.

And sometimes that involves making arrangements with a patient so that they come into the clinic for two or three of their doses and we'd have outreach go out for the others. And that makes it more feasible at times.

But our own practice in our own clinic we would not go to daily self-administered therapy as a way to manage GI side effects.

Alfred Lardizabal:OK. If I could pose a question as far as the last case, the 43-year old with non-alcoholic cirrhosis? You ended up treating with Rifampin, Ethambutol and Levofloxacin, is that correct?

Robert Belknap: Yes.

Alfred Lardizabal:For how long did you treat?

Robert Belknap: Good question, so how did you treat on that case? So there is not data on how efficacious is a regimen where a Fluoroquinolone has been substituted for the

Isoniazid. In most scenarios, I will treat for nine months, and in certain settings, 12 months.

So in someone with smear negative or extra pulmonary disease I'm generally comfortable treating with a Fluoroquinolone, Rifampin and I keep the Ethambutol going throughout because the other information that we don’t really have is are Fluoroquinolones protective against acquired resistance?

So we know that they're active and there have been a number of published studies demonstrating that the Fluoroquinolones can be used in place of INH and the regimens at least early on in therapy are as effective. They so far haven't appeared more effective to allow us to shorten treatment to less than six months.

But again we also don't really know in the continuation phase is if a Fluoroquinolone and Rifampin equivalent to INH and Rifampin. Because this patient was being evaluated for liver transplant and was potentially going to be severely immunocompromised if she was able to get a transplant I opted to treat her longer rather than shorter. And so she is still on therapy and will be completing 12 months soon.

Slide 22The next case for you guys to consider is a 85-year-old patient, born in Laos whose diagnosis again was smear positive pulmonary TB.

Started on four drug therapy and the baseline labs got delayed initially but were checked a week later and the AST was 357, ALT 150, Alk Phos was 48 and total bilirubin 0.8. And at that point, the providers discontinued Isoniazid, and Pyrazinamide and continued the patient on Rifampin and Ethambutol and planned on a 12 month course.

After three months, the patient moved to Denver, or in this case he is moving to your jurisdiction and rechecked and the AST/ALT showed they were normal.

The question is would you re-challenge him with medication? Would you re-challenge Isoniazid, Pyrazinamide, both or neither?

The majority of folks would re-challenge this patient with Isoniazid. Next was 24% said they would re-challenge with both and 9% said they would re-challenge with neither, Isoniazid or Pyrazinamide.

Slide 24One of the things is- don’t be too quick to give up on first-line treatment in the setting of a transaminitis. And a few things to keep in mind, 1) you know, this patient's labs were delayed by a week but one of the things we see in more severe forms of tuberculosis, and certainly if there is any possibility of disseminated tuberculosis, is that the disease itself can cause abnormal liver function tests.

We also know that about 20% of patients who are on treatment will have a transition asymptomatic increase in their AST and this did not become clinically significant and doesn’t necessarily require any changes in treatment. And you always want to consider alternatives or confounding factors such as alcohol or viral hepatitis, and so taking a complete history.

With alcohol, it's important not just to assess their current use but also their past use of alcohol because someone may tell you they quit drinking and unless you ask further and find out when they quit drinking and also importantly how much they drank before they quit, you may not have a good sense for underlying liver disease that could be present.

Slide 25In the example with the 85-year-old, we re-challenged him with Isoniazid. He tolerated it and we were comfortable treating him and completing a course in nine months as opposed to giving him the Rifampin or Ethambutol for 12 months.

Well he did restart the Isoniazid. After two months he came in complaining of a pruritic, erythematous maculopapular rash. He had no other symptoms; no fever, nausea, vomiting, anorexia. His ALT was normal. The rash had

been stable for about a month by at the time he reported this. Then the question is what would you do?

Slide 26Certainly a relatively common scenario for patients who come in complaining of rashes. And it’s important to note that all TB drugs can cause a rash and the management depends really on the type and severity.

One of the first things to consider is- is there something other than medications that could be causing this rash. So are there other medications that the patient recently started taking and you want to ask very specifically about any over-the-counter or herbal medication. Patients don’t always think of these when you ask about what drug your taking.

Are there new chemicals? Have they recently changed soaps, shampoos, detergents that they use to wash their clothes? With whatever work they're doing- are they exposed to chemicals there?

And then ask about insect bites and assessment for possibility of bedbugs. I recently had a couple, a man and wife who were new immigrants, and had been diagnosed with latent TB and both started on Isoniazid and both presented back at one month complaining of rash. And they had itching, and they had these small erythematous bumps in different places on their bodies.

In talking to them, I asked about the possibility of bedbugs and asked if anyone in the apartment where they lived complained of this. And as soon as the word “bedbugs” was mentioned they both looked at each other and then said, “No, it can't be that because they just sprayed last week.”

So that was a pretty good indication that we had the diagnosis and the Isoniazid was not the cause. So they were able to continue on therapy and with some help we were able to contact their landlords and discuss the issue with them.

Slide 27With regard to minor rashes, or itching without rash, the rash is often maculopapular. Patients will sometimes complain of an acute flushing. So

acute feeling of warm and turning red, generally 30 to 45 minutes after a dose and that is typically associated with to Pyrazinamide.

And for these more minor rashes, they can be managed symptomatically, so the use of antihistamines, topical steroids in some cases, continue the medications and as I already mentioned you want to consider other potential causes.

Slide 28Petechial rash-so if someone comes in and they got usually on the lower extremities or dependent portions, but can be other places, this type of a rash is suggestive of thrombocytopenia and so we automatically begin thinking of Rifampin, which can cause thrombocytopenia. Checking a platelet count if a patient has a petechial rash, it's important in holding the medications if their platelet count is abnormal. Abnormal meaning low.

Generalized erythematous rash- these are more suggestive of a hypersensitivity rash and it’s particularly important when it's associated with fever, or with any involvement of the mucous membranes so if they have eye symptoms or sores in the mouth then this is a potentially very serious drug reaction.

You want to stop all medications until their symptoms resolve and then typically restart one medication at a time. Once you’ve got them back on a reasonable regimen, don’t re challenge them with all the drugs.

Slide 29Hypersensitivity is best described with Rifampin, although can occur with Isoniazid and other medications. This is a difficult syndrome that can present with a real range of manifestations, and unfortunately not a clear clinical diagnostic criteria or good laboratory diagnostic tests.

It’s associated with rash, flu-like symptoms, thrombocytopenia or hemolytic anemia, acute renal failure or even hypotension and shock. These symptoms, especially the flu-like symptoms associated with Rifampin tend to be more common with intermittent dosing. But certainly in the case of any patient

with severe reactions, you want to discontinue and likely not re-challenge them with Rifampin.

Slide 30As I mentioned there is not a definitive diagnostic test for more minor-type flu-like symptoms. We'll often time, if a person is on intermittent therapy change them to daily therapy. There are some reports in the literature of patients who've been switched from Rifampin to Rifabutin with resolution of those types of symptoms.

For a more severe reaction, diffused rash, hypotension, renal failure, I would recommend discontinuing Rifampin and would not re-challenge them with any rifamycins.

Slide 31The next patient is 69-year-old who is newly diagnosed with pleural TB and started on the standard four drug therapy. One week into treatment he complained of acute worsening of his chronic knee pain and stated that the Hydrocodone/ acetaminophen (Vicodin) he had been taking the past was no longer working.

Slide 32What medication is likely to the cause of his knee pain?

People on the call are fairly well attuned to Pyrazinamide and the effects of – the potential side effect of Pyrazinamide.

Slide 33So acute gout- so Pyrazinamide causes an increased uric acid level, essentially in all patients. And previously has been used – uric acid monitoring had been used as a way of evaluating adherence to self-administered therapy in patients who were supposed to be taking Pyrazinamide.

It rarely actually causes a new onset gout. So although it increases the level in everyone, very few patients who have not had gout before will have their first outbreak or first episode of gout as a result of Pyrazinamide.

If a patient has a past history of gout, however, it's far more likely and in –oftentimes is an indication to avoid Pyrazinamide. One important thing to keep in mind in the management if a patient does develop acute gout is that Colchicine should be avoided as treatment in – when using TB medications because the levels are unpredictable.

They are increased by Isoniazid and decreased by Rifamycins. But we can't determine – those interactions are not necessarily equal. And, in fact, in this case the Isoniazid effect can be greater and lead to Colchicine toxicity.

Steroids are safe to give; so this question does come up regularly if a person has gout or has some other process that needs steroids and is getting TB treatment. And the answer generally is steroids are safe to give as long as you've got the person on adequate TB treatments.

And certainly steroids are recommended in the study of meningeal and pericardial TB; NSAIDs are also safe and a good choice for the management of acute gout.

Slide 34The other option and I think some of the folks chose Rifamycin.

And since I didn’t give you a history of gout, the Rifamycin absolutely could have been the cause of his worsening, chronic knee pain. Rifamycin is one of the big considerations always to keep in mind when starting a person on Rifampin, Rifabutin or Rifapentine are the drug interactions.

So the Rifamycins cause an increase in hepatic enzymes that are involved in drug metabolism. Rifampin is a very potent inducer and more potent than Rifabutin of these enzymes and Rifapentine probably falls somewhere in between.

And it will decrease the effective levels of multiple medications, including narcotic medications like the Vicodin that patient I mentioned was taking; but also things like oral contraceptives. HIV protease inhibitors become ineffective in the setting of Rifampin. And so it's contraindicated to give Rifampin in someone who is on HIV treatment with that.

And Warfarin will be – effectiveness will be decreased. That effect can be managed but usually requires significant increases in the dose of the Warfarin and very careful monitoring.

Slide 35Next for you guys is a 45-year-old with Type II diabetes for about 15 years with smear positive pulmonary TB and started on four drug therapy. And at a month the patient complains of decreased vision in her left eye and the question when the patient comes in to you is, is this related to the TB treatment?

Slide 36Talk about ocular toxicity. Optic neuritis is a potential side effect although relatively rare with Ethambutol and very rare as a side effect of Isoniazid.

The usual presentation is bilateral involvement and blurred vision. The first change is typically a decrease in color vision. But patients can often be asymptomatic. A fundoscopic exam in these folks is normal but certainly very important to do to differentiate from other ideologies of acute changes in vision.

Slide 37As far as monitoring for this, probably the most important is to instruct a patient that if they develop any changes in their vision they should report it to the clinicians immediately so it can be evaluated appropriately.

Do recommend doing baseline visual acuity and color vision using a Snellen chart and Ishihara test and then repeating those evaluations at monthly visits.

Slide 38In terms of managing if a patient does develop symptoms- then I would stop the Ethambutol immediately and typically refer them to an ophthalmologist for evaluation.

If their vision change is severe and certainly if it's severe and bilateral I would stop both the Ethambutol and the Isoniazid until either an alternative etiology

is found. Or if no alternative etiology is found, then wait until their vision improves before considering re-challenging them with Isoniazid.

And at that point you likely would not restart the Ethambutol. If it's determined that a person changing vision is due to something other than Ethambutol, then you might want to restart it. However, the challenge there is then ongoing monitoring for additional toxicity from Ethambutol is compromised.

And so if you don't need it, you may consider just dropping that from the regimen all together.

Slide 39The same patient is determined to have ocular disease due to diabetes and again, has smear positive pulmonary TB, comes in at two months and now is complaining of tingling in the hands and the feet.

Slide 40Peripheral neurotoxicity is a dose-related toxicity related to Isoniazid. Risk is increased in patients with conditions that cause neuropathy. The mechanism is that Isoniazid causes a functional pyridoxine deficiency.

It rarely requires Isoniazid discontinuation and generally is treated with pyridoxine supplementation. And so patients who have underlying risk factors, typically diabetes or a history of alcoholism, pregnancies and other indications where pyridoxine supplementation should be given initiation of therapy. Don't wait for them to develop their symptoms.

Slide 41So I’ve got a few slides just in summary. Through common side effects here and for your handouts I've listed the medication and then the side effects that can occur more commonly underneath them. So Isoniazid: GI symptoms, transient elevation of hepatic enzymes, drug induced hepatitis, peripheral neurotoxicity. I didn’t talk about in this but INH can also cause a decrease in seizure thresholds and rashes.

With Rifampin: GI symptoms, drug-induced hepatitis, rash, hypersensitivity, flu-like syndrome and most importantly, not a side effect but something to always keep in mind, is the hepatic enzyme induction. This occurs in all patients.

I didn’t list here something else that occurs in all patients certainly is the red discoloration of tears and urine. Very important to let people know that that is not a side effect, but something that they can expect to occur.

Slide 43With Pyrazinamide again GI symptoms, drug induced hepatitis, rashes can occur. It's oftentimes an acute fleshing with pruritus and doesn’t necessarily need to lead to discontinuation. The elevated uric acid will occur in most or all patients but doesn't generally cause a gouty arthritis unless they have a history of gout.

Pyrazinamide can also cause a non-gouty pain. It's usually multiple joints involved without significant swelling.

Slide 44Finally Ethambutol, which the most common, although still relatively rare is optic neuritis.

Typically retrobulbar, so behind the eye, which is why the funduscopic exam is normal. It can also cause peripheral neuropathy or rash.

Slide 45The important for the monitoring of this is patient education and it is probably the most important so that they report to you any symptoms early on and it can be addressed.

Face-to-face assessment and monitoring, I think is critical as well. You want to try to address and relieve the symptoms. When possible, try to avoid breaks in therapy and so again always important to assess if symptoms are severe enough to require that.

And if not, try to manage symptomatically but continue the medication and always emphasizing the importance of treatment completion even in the setting of difficult side effects or tolerability issues.

Slide 46And I've got a few references listed for you

Slide 47Alfred Lardizabal:I will pause for a few minutes and answer a few questions or comments from

the audience.

Robert Belknap: I see a question that says what about headaches. So standard four drugs and after about three months patients the temporal and frontal headache, no timing association to the med dosing and also complains of increased depression already on an SSRI. Certainly of the medications typically used, I'd say that Isoniazid is the one that more commonly is associated with some headaches, fatigue, CNS symptoms. Fluoroquinolones when used can also cause that. It's difficult to determine if the medications are a direct cause of the headaches.

And assuming there aren't reasons to suspect a more serious illness like a meningitis, either TB or otherwise, or that the headache could be related to CNS trauma or bleeding, then generally it requires the symptomatic management, and that's not always easy.

The medications in and of themselves have not generally been linked clearly to worsening depression as opposed the more related to the diagnosis and the challenges in terms of social isolation, loss of work, and all the other complications that come along with being diagnosed with tuberculosis. Certain there can be some drug interactions particularly with, as I mentioned, Rifamyacin.

I think if you've got a person with depression who is already being treated, the important thing is to try and work with their primary provider, whoever it is that has prescribed the SSRI, and get them back into therapy and follow up and have the dose adjusted as needed, or determine whether or not the SSRI is the best medication for them.

Alfred Lardizabal:Let's take the last two questions here. And then move on. Is there any benefit in increasing vitamin B6?

Robert Belknap: There's certainly not any evidence that increasing the vitamin B6 in daily therapy to above 50 milligrams is of benefit. I don't generally recommend doing that. You know, 100 milligrams certainly if a patient's on intermittent therapy then, yes, I would go ahead and increase it to 100 milligrams. But looking to, looking at potential other causes at that point, because again the Isoniazid effect should be overcome and managed by the addition of the vitamin B6.

And then are there any adverse side effects seen in children which are different than those seen in adults? None that come to mind. In fact, the more children in fact tend to tolerate these medications far better than adults if you can get them into them. The challenge is always getting children to swallow the medications and often requires mixing them into other things and that, you know, the taste becomes maybe a more important issue to kids. But the tolerability is much better. So kids have fewer side effects overall from certainly the GI toxicity and hepatotoxicity is less common in children.

Alfred Lardizabal:So next I'd like to turn the program over to Dr. Henry Fraimow. And he's an associate professor of medicine at the UMDNJ Robert Wood Johnson Medical School. And he's also a medical consultant for the southern New Jersey Regional Chest Clinic. He's experienced in providing HIV and TB care and research activities on the use of antimicrobial agents and basic mechanisms of resistance. I'll now turn over the program to Henry who will present two TB cases related to today's topic. Henry?

Slide 49Henry Fraimow: Thanks for inviting me and I have two cases that I think will fit in nicely with

what was excellently presented to us so far. Both of these are recent, in fact current, cases from the southern New Jersey Regional Clinic.

The first case that I'm going to discuss is a patient who developed increasing liver enzymes while on therapy for severe tuberculosis, in fact should namely central nervous system tuberculosis.

She is a 62-year-old African-American woman with Sjogren’s Syndrome and autoimmune hepatitis and had been on chronic immunosuppressive medications to manage these with what will be listed on the next slide. In December of last year she was admitted to a local hospital with a protracted history of intermittent fevers, shortness of breath, increasing lethargy and then over the last week or two- headaches, neck pain, and progressive lethargy.

Slide 51Her past medical history is as shown. She has a history of well-controlled diabetes, a recent history of breast cancer which was treated with chemotherapy and radiation, as well as hypertension. And ultimately we discovered there was a history of a positive tuberculosis skin test, although this information was not available because she couldn't convey it to us when she was first admitted.

Her medications at the time of admission included Mycophenolate, which is an immune-modulating agent, also it's under its brand name is CellCept, and she was on prednisone 15 milligrams daily for management of her autoimmune hepatitis and she was also on blood pressure medications and some other medications and some other medications for pain and insulin and the Erythrodiol for her liver disease.

Slide 52On admission, she was febrile and lethargic. She was oriented only to persons and face. She had a stiff neck. Her admission CT scan of the head was normal. And she had a lumbar puncture which shows 151 white cells with a mildly elevated protein and a normal glucose, and all of those stains were negative initially.

Over the course of the next two weeks in the hospital, continued to do poorly. She had repeat lumbar punctures which were characterized by increasing lymphocyte counts and decreasing glucose values; and also had repeat MRI imaging studies of her head which showed enlargement of these white nodules scattered throughout the brain that were getting larger. And she had about 20 of these in various places.

Slide 54The decision was made that she needed a brain biopsy; and they went in and she had well-circumscribed lesions, each of these white things seen on the MRI was a nodular lesion that had necrotic material, and the acid fact stains from these that were sent to the laboratory were positive. And ultimately both from her brain biopsy and from her spinal fluid, she grew Mycobacterium tuberculosis and a diagnosis of central nervous system tuberculosis was made.

Slide 55As soon as these results were back, she was initiated on a four drug, anti-tuberculosis regimen. Her weight was around 70 kilos, I believe, so that's the basis of her dosing.

Her Mycophenolate was discontinued and prednisone was increased; as you've already heard prednisone is used for tuberculosis, tuberculosis meningitis. Her prednisone does was increased to help manage her tuberculosis and then after a couple of days she seemed to be tolerating her medicines and as happens in this day and age she was quickly booted out of the hospital and sent to a rehabilitation facility. Also was started at that time on a new seizure medication.

Slide 56About four days later she was readmitted to the hospital with elevated liver enzymes. The family, who were very attentive, reported that her appetite had been poor but had been poor for the last several months and that they hadn't noticed any new symptoms and there was no nausea or vomiting and no abdominal pain and that overall, they actually thought that she was slowly improving whether from the steroids or from her tuberculosis medications.

And this slide shows you the trend in her liver enzymes, looking particularly at the transaminases, the ALT and the AST. Her anti-tuberculosis medications were started on December 31st. She was discharged on January 7th and these were the enzymes that prompted her readmission.

Slide 58So what do people think is the most likely cause of the patient's liver enzymes?

Most people sort of felt the same way that we did- that they couldn’t really be sure although some people seem to feel pretty strongly that it's the Isoniazid.

Slide 59At this point, when she was readmitted to the hospital, the physicians taking care of her decided that it had to be her Isoniazid. They discontinued this and continued her other medications.

And her liver enzymes began to improve a little bit- discharged a couple of days later on a three-drug regimen and was discharged to follow up in our clinic and she was on a slow steroid taper.

Slide 60And this just shows you her trend in values during the hospital. She obviously got daily labs. Both of her transaminases are slowly decreasing. I didn’t mention the upper limit of the ALT value in our hospital is 40.

She then comes to the TB clinic for the first time, and at this time, four days after those last labs, her transaminases also have continued to decline a little bit.

Slide 61So the question is what would you do now?

She's got central nervous system tuberculosis which we consider to be a very severe infection. And she's on a regimen of Rifampin, Ethambutol and

Pyrazinamide. And at this point we have no drug susceptibilities. All we have is positive smears. And I think by this point, this spinal fluid culture is finally starting to grow.

OK so it looks like we can go back to our patient. So it looks like most people felt that the thing to do would be to add a quinolone and that was, in fact, the first manipulation that we made to make sure that she was on an adequate baseline regimen while we were waiting for additional susceptibility data.

However, we weren't quite sure that the Isoniazid necessarily needed to be discontinued. And our feeling was that this was a much more important part of her regimen than the Pyrazinamide, which we thought if she wasn't on it maybe it wouldn't have any ultimate impact on the duration of her therapy, which was going to be prolonged regardless.

Slide 62So what we opted to do after she was tolerating the Levofloxacin, is we reintroduced, with careful monitoring of her liver enzymes, the Isoniazid initially at a dose of 100 milligrams daily and then to full dose. And at the same time we stopped her Pyrazinamide.

And so her new regimen now was INH, Rifampin, Ethambutol and Levofloxacin.

Slide 63And this just shows you her trend in liver enzymes from the time that these manipulations were made. You can see that there were transient blips in her transaminases particularly the AST at different times.

But on this regimen, she actually tolerated these drugs quite well.

Slide 64Before we move on to conclusions, any questions about this case or any comments anyone would like to make.

Alfred Lardizabal:It's certainly a complicated case and very hard to determine what is causing all the liver function changes. Certainly, the autoimmune hepatitis is a

confounding factor there. I'm glad you were able to get away with still using Rifampin and INH.

I think one important question would be the use of prednisone in this situation for both the autoimmune hepatitis and the CNS tuberculosis. What would be the appropriate dosing for steroids in this case? And bear in mind the interaction between prednisone and erythromycin.

Henry Fraimow: The dose that we opted to give was roughly around a milligram per kilogram per day. I think it might have been slightly higher. I think by the time – her weight – she was actually quite edemitive at this point so her weight might have actually been a little higher than her initial weight.

And then this was tapered by about 10 milligrams a day on a weekly basis. But she was never tapered off of steroids because she had been on long-term steroids for her hepatitis ever since – for the last several years prior to the admission.

Male: Is she going to stay on anti-TB drugs for 12 months because she had the CNS meningitis?

Henry Fraimow: Our plan would have been a minimum of nine months and most likely 12 months in this instance. And I think that was our intention was to continue for 12 months given the severity of the disease and how late in her course she was diagnosed.

Slide 65So let's move on to a second case which has some similar but slightly different issues. And this is a patient who also developed abnormal liver tests, as well as, possible neuropathy while on a pulmonary tuberculosis treatment regimen. And I believe that she is in the last weeks of her treatment course at this time.

Slide 66This is a 55-year-old Liberian-born woman who has been in the United States since 2002 and had been working as a nurse and was living in California at this time.

She has a history of chronic interstitial lung disease and intermittent steroids and, in fact, had been on a low dose prednisone for a fairly prolonged period by the time of this diagnosis.

She had recently gone on a trip to Ghana and actually became ill there with increasing cough and shortness of breath. And on her return she was hospitalized in California. She had negative sputum acid-fast smears but a bronchoscopic procedure revealed microbacteria and tuberculosis by nucleic acid amplification tests.

And cultures from both sputum and bronchoscopy ultimately grew bacteria M. tuberculosis.

Slide 67At this time she was initiated on a four drug regimen of Isoniazid, Rifampin, Ethambutol and Pyrazinamide and was started on B6 from the very beginning of her regimen.

After about two to three weeks, she began to complain of decreased appetite and malaise and after a couple of weeks her liver enzymes were noted to be elevated with a marked elevation of her bilirubin, mild elevation of her transaminases.

She was hospitalized in California and all of her tuberculosis medications were discontinued and under observation her liver enzymes improved.

Slide 68At this time, what is the most likely cause of her elevated liver enzymes? It looks like most people feel that this is related to the Isoniazid with several who think it may be a combination.

Slide 69So what should we do with her regimen at this point? All right, it's looking like the vast majority would start her drugs back one at a time and we could certainly argue or debate about which drugs would be started but I think that that seems to be where this group is going.

So actually this is not what was done. And remember this is all been done in California and they consulted there with the California Tuberculosis Program; and they decided after looking over her laboratory studies they were pretty convinced that this was Rifampin.

And they opted to restart everything but her Rifampin and continue her on this regimen. And we could debate at the end whether or not we would have done that or done something differently. But that was the decision that was made. During this time there were some transitions in her care.

She initially had health insurance and lost it in this transition from private doctors to the public health clinic, and somewhere during this time somebody counted up her PZA and said she's had 40 doses and this was discontinued leaving her on a regimen of Isoniazid, Ethambutol and B6.

And her liver enzymes were stable on this regimen. And then after being on this regimen for probably November and December, she appeared in New Jersey and her care was transitioned to our clinic.

Slide 71At the time of her initial evaluation, her liver enzymes were- transaminases were normal, she had negative smears and negative cultures and was on what we considered to be probably not an optimally adequate regimen; and we added Moxifloxacin to her regimen at this point with a plan to continue her regimen for a total of 12 to 18 months as she had been off of Rifampin for the vast majority of time and was only on INH and Ethambutol for a good chunk of her treatment.

Slide 72However, about a month ago she came to the clinic presenting with worsening paresthesias and numbness in both of her feet with no other findings other than mild sensory deficits on exam. She was concurrently seen by a neurologist who performed EMGs and nerve conduction studies that demonstrated mild lower distal extremity neuropathy.

What would you do at this point? Which of the medications is most likely to be causing her symptoms? Remember we're now about nine months into her treatment course and she has been on vitamin B6 the whole time.

And it looks like most of you would agree that this is going to be Isoniazid neurotoxicity, and that in fact was our impression as well. As well as the impression of the neurologist who saw her. However, the problems that we ran into were that we thought here symptomatology was relatively mild. However, the neurologist told her that she had to stop the Isoniazid immediately because it would cause irreparable, permanent damage and she would not even consider continuing on the Isoniazid.

Then we had some decisions to make about what to do about her regimen which was now just Ethambutol and a quinolone.

Slide 74In conclusion about this case- there may be differences in patterns of liver enzyme elevations that you may see with Rifampin and Isoniazid.

Although it's not always clear that those are so specific that you can always make an assumption of what the causative agent may be. When you do discontinue an anti-tuberculosis agent, you have to look at the whole regimen and say well what does this mean for the rest of the drugs?

Clearly when this patient's Rifampin was discontinued, they didn’t realize that the PZA was no longer being used as 40 doses in combination with her Rifampin, but was a main component of her regimen. So you really have to be careful and reassess the whole regimen when you start dropping cornerstone drugs.

The other features in this patient are the neurotoxicity from her Isoniazid which occurred very late in her treatment course and on Vitamin B6. You really have to take into account patient's perceptions of their adverse drug reactions because they may have feelings about things that are extremely

important to them and that they won't tolerate that may be different than your perceptions as the care provider.

Slide 75All right we can open this up for any questions. ..

Alfred Lardizabal:I'd just like to underline your last bullet actually. The importance of providing patient education and I think both you and Bob had mentioned this as an important way to handle adverse reactions or complaints patients may have on their treatments.

Any questions on the last case?

Male: So what happened? Were the two drugs continued? Was something else added?

Henry Fraimow: After extensive negotiation with the patient who thought that she should be done with her treatment anyway because she'd been on them an awfully long time, we opted to just continue her two drugs and extend her treatment a little bit longer. She was about a month shy of what would have been a year of treatment although we had planned to try and continue for 12 months beyond when her cultures turned negative. And this was a negotiation because she really didn't believe that she needed to be on anything at this point.

Male: What drugs other than Rifampin can cause hematologic abnormalities and I think that was a left over question for Bob.

Robert Belknap: Sure, generally speaking, the other TB medications shouldn't cause hematologic abnormalities. So if you see someone that developed either an acute anemia or an acute thrombocytopenia, then Rifampin is the likely etiology but other medications don't generally cause…

Male: So, let's go ahead and finish up these other questions. I'll open this up to both the speakers. The question has to do with the positive effects of vitamin D therapy. Here it says in the prevention of TB, more as an adjunct to the treatment of TB. Is there any harm or the other corollary to the question- is there any benefit in introducing vitamin D to the treatment?

Henry Fraimow: It's an interesting question and certainly there's been a fair amount of research devoted to trying to figure out the role of Vitamin D, and importantly I guess the impact of using Vitamin D potentially, as an adjunctive therapy. And I'd say the short answer from that research has been that it's inconclusive. We do know that Vitamin D has a role; it's certainly not clear that supplementing Vitamin D in all patients with tuberculosis is going to improve their outcomes in any way.

Vitamin D is one of the vitamins that does accumulate; it’s fat soluble and so you can become toxic from Vitamin D so you do want to be careful and not necessarily over supplement the patients with Vitamin D. It's not something that I, that we, consider routinely. I think if you had someone and had reason to suspect Vitamin D deficiency or knew they were Vitamin D deficient, then replacing it makes sense for those reasons. But to just do it routinely for TB treatment, I don't think the evidence suggests that we should at this point.

Robert Belknap: I would agree with that. I think we also just don't have enough information on potential toxicity. Although, getting Vitamin D levels is also not something that's probably routine in our public health TB clinics. So it's not something that may be readily available. It may be more available for some patients than for others.

Henry Fraimow: I don't know of any reason to suspect that INH would increase Vitamin D levels.

Alfred Lardizabal: The next question has to do with noticing any differences based on gender, age or ethnicity. I guess this is with regards to developing adverse reactions to TB drugs. Perhaps Bob or Henry?

Robert Belknap: Yes, it isn't something that I'd say I've noticed or read in the literature to suggest that you can increased rate of, by gender or race specifically. I don't know. Henry-what is your feeling on it?

Henry Fraimow: I'm not sure there's a lot of good data, but you know anecdotally we seem to see a higher rate of significant dermatologic reactions in our Southeast Asian populations compared to some of the other populations. Again, whether it's

an actual higher rate or a poorer tolerance of what they get, I don't know. I mean there were clearly cultural differences in what different populations will tolerate in terms of toxicities compared to others.

But in terms of other specific toxicities I'm not sure I have any, know of any other good data.

Robert Belknap: Yes, I agree with the same, and I think that culturally there are differences to in the expectations for how side effects will be managed with some folks expecting you know an additional medication. Some people wanting medication stopped or all treatment stopped and some people being accepting when you educate them on it and understanding the risk, but I haven't seen a differential rate.

Alfred Lardizabal:And last question here has to do again with Rifampin and perhaps this is more pertinent to Bob's discussion. Can you explain why Rifampin is less likely to cause thrombocytopenia with daily dosing rather than intermittent dosing?

Henry Fraimow: In terms of the Rifampin side effects that have been definitively seen less commonly is flu-like symptoms. Thrombocytopenia is truly a relatively rare complication overall.

I can't say for certain that it is less common with daily dosing. Now why it might occur-would postulate it had to do with the, you know, it’s an immunologic reaction that leads to the destruction of platelets and you can have – if you're giving something continuously you can have essentially a desensitization to the medication to where the body tolerates it. Where if you give it more intermittently, that’s the more dangerous where you expose the immune system to it and take away and then re-expose it. That’s when people with certain allergic type immunologic reactions tend to have worse symptoms. But I can't say for certain that the thrombocytopenia specifically is worse intermittently.

Alfred Lardizabal:OK. Thank you. If any of the listeners have any additional questions please feel free to e-mail them to us and we'll forward them on for answers.

The New Jersey Medical School globally provides medical consultation to providers in the northeastern region. Please feel free to call us at 1-800-4TB-DOCS (482-3627).

Slide 77This concludes the conference this afternoon. Thank you all for your participation.

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