Managing MDR TB Treatment Side Effects Barbara J. Seaworth, M.D. Medical Director Heartland National TB Center Pacific Islands TB Controllers Association Conference, September 14, 2017 Honolulu, Hawaii
Disclosure Dr. Seaworth has no financial disclosures This presentation will include the off label use of fluoroquinolones and linezolid
Objectives Identify common toxicities of second line TB drugs Implement monitoring for toxicity due to second line TB drugs Recognize how to modify treatment to ensure a good outcome
Anti-tuberculosis Drugs (ATS/CDC/IDSA) First-Line drugs Isoniazid Rifampin Rifapentene Rifabutin* Ethambutol Pyrazinamide Second-Line Drugs Cycloserine Ethionamide Levofloxacin* Moxifloxacin* PAS Streptomycin Amikacin/Kanamycin Capreomycin Linezolid* Clofazimine* Bedaquiline Delamanid* Meropenem/Clavulanic acid* *Not FDA approved for TB
New Grouping of MDR-TB Drugs Group A Group B Group C Group D Fluoroquinolone Second-line injectable Other Core Second-line Add-on agents Levofloxacin Moxifloxacin Gatifloxacin Amikacin Capreomycin Kanamycin (Streptomycin) Ethionamide/ Prothionamide Cycloserine/ Terizidone Clofazimine Linezolid D1: Pyrazinamide Ethambutol High-dose INH D2: Bedaquiline Delamanid D3: P-aminosalicylic acid Imipenem/Meropenem Amoxicillin/Clavulanate (Thioacetazone)
Adverse Drug Events GI upset: PZA, rifabutin, fluoroquinolones, ethionamide, PAS, bedaquiline, (any drug) Central Nervous System: INH, fluoroquinolones, amikacin, ethionamide, cycloserine Musculoskeletal: PZA, fluoroquinolones, rifabutin
Dermatological Any drug Allergic reactions Flushing, photosensitivity, hyperpigmentation, lichenoid drug reactions Systemic DRESS Syndrome rifampin, PZA, INH-(any) Hematological most but especially linezolid Miscellaneous Adverse Drug Events Hypothyroidism ethionamide, PAS QT interval prolongation - FQNs, bedaquiline, clofazimine, delamanid
Sometimes our interventions can be dangerous
Toxicity Monitoring Face-to-face clinical assessments are the cornerstone of clinical monitoring for treatment adherence and adverse events. Patients should be categorically told to immediately stop medications (INH) for nausea, vomiting, abdominal discomfort, or unexplained fatigue and to contact the clinic for further evaluation Document, document, document!
Adverse Drug Events Side Effects or Toxicity? Patient likely cannot differentiate they both feel bad! Evaluate risk to patient and if medication needs to be stopped. Risk of long term harm to patient Risk of treatment failure/poor outcome if no replacement Work with patient to tolerate side effects
Strategies for Managing Adverse Reactions Prior to initiating a treatment regimen discuss the benefits and risks of therapy. Assure patients that every possible attempt to make their treatment as easy as possible will be made, but emphasize that having enough effective drugs in the regimen is essential to achieving a cure. Discuss the importance of having enough strong medications in the treatment to ensure lasting cure
Strategies for Managing Adverse Reactions Quickly recognize and respond to the symptoms a patient expresses Evaluate cause of symptoms; exclude other causes Develop a plan to address along with patient if possible Continue with planned regimen to manage side effects: Encourage patient to continue medication with knowledge that side effects often become more tolerable with time Stop and substitute another drug if needed and this is possible Encourage adequate hydration Correct electrolyte deficiencies Do not continue an inadequate regimen
RX: Amikacin, Levo, LZD, Ethionamide, Cycloserine Culture neg in 1 st mo. RX Nl LFTs; Held all 9/27/16, restart Amik, moxi first then LZD, then, cyclo OK, but with ethionamide new N/V so left with 4 drug but good regimen? Possible cycloserine, but long term history of this Watch closely 4 drugs needed Likely LZD but with only 4 drugs need this S/P 9 months of amikacin, so stopped PAS added Cavity gone, but must stop LZD and ethionamide Moxifloxacin, Cycloserine, PAS Terrible Regimen but little disease, yr 2 RX
Responding to GI Upset Exclude hepatitis If symptoms resolve and no evidence of liver toxicity, when possible re-institute at a lower dose and/or different time give with anti-emetic 30 minutes prior to dose take with small snack, tea, soda If ethionamide or PAS can divide dose Antacids may be helpful in some patients
Common causes of GI symptoms Gastritis Hepatitis/ hepatotoxicity Biliary disease/pancreatitis Other infections - UTI Peptic ulcer disease Clostridium difficile colitis Inflammatory bowel disease Lactose intolerance Acute renal failure or nephrotoxicity GI TB especially if early in treatment or unrecognized TB meningitis Diabetic gastroparesis Pregnancy Other medications/etoh
Responding to GI Upset Minimize use of non-steroidal antiinflammatory drugs Evaluate for other medication related causes Consider hospitalization if above not helpful; do so early to prevent psychological intolerance which is very difficult to overcome In hospital space medications, hydrate, antiemetics, IV medications
Responding to GI Upset When problem is diarrhea (especially with PAS) this usually improves with time Exclude C. difficile colitis Exclude gastro-intestinal TB May try pro-biotics Loperamide (Imodium) 2 to 4 mg initially then 1 to 2 mg after each loose stool Exclude lactose deficiency especially if patient hospitalized and has change in diet
Neurotoxicity Sensory peripheral neuropathy Optic (Retrobulbar) neuritis Central Nervous System
Adverse Drug Events Neurotoxicity Peripheral neuropathy Drugs: INH, Linezolid ( usually > 12 weeks use), Ethionamide, Cycloserine Fluoroquinolones and EMB have rarely been associated although neuropathy has recently been added as a black box warning for the fluoroquinolones. More common in patients with Diabetes Alcoholism HIV infection Hypothyroidism Pregnancy Inadequate dietary intake of pyridoxine (Vitamin B6) Usually symmetrical Initial symptoms: tingling, prickling, burning in balls of feet/tips of toes May progress to sensory loss, loss of reflexes, unsteady gait May also involve hands and fingers Pyridoxine prophylaxis 50-100 mg daily. Efficacy unclear
Peripheral Neuropathy Evaluation Lower Extremities Upper Extremities Patient s name: DOB: Date of evaluation: PATIENT S INTERVIEW Ask your patient the following questions: Question 1: Yes Do you have any pain in your feet? Question 2: Does your pain have any of these characteristics? Yes 1 Burning? 2 Freezing pain? 3 Electric shock-type sensation? No No Question 3: Do you have any of these symptoms in the area? Yes No 4 Tingling 5 Prickling 6 Numbness 7 Stinging/itchin g Question 4: Is the pain made worse with the touch of clothing or bed sheets? Yes No PATIENT S INTERVIEW Ask your patient the following questions: Question 1: Yes Do you have any pain in your hands? Question 2: Does your pain have any of these characteristics? Yes 1 Burning 2 Freezing pain? 3 Electric shocktype sensation? Question 3: Do you have any of these symptoms in the area? Yes 4 Tingling 5 Prickling 6 Numbness 7 Stinging/Itchin g Question 5 Is the pain made worse with the touch of clothing or bed sheets? Yes No No No No PATIENT S ASSESSMENT Question 5: 8 Hypoesthesia to touch 9 Hypoesthesia to prick 10 Extreme sensitivity to touch 11 Extreme sensitivity to prick Yes No PATIENT S ASSESMENT Question 4: 8 Hypoesthesia to touch 9 Hypoesthesia to prick 10 Extreme sensitivity to touch 11 Extreme sensitivity to prick Yes No
Management of Peripheral Neurotoxicity Correct vitamin and nutritional deficiencies. Address additional medical problems. Evaluate and correct electrolytes. Identify and stop (if possible) other medications that may cause peripheral neuropathy. Consider whether the dose of ETA or CS can be reduced without compromising the regimen. Consider decreasing dose of linezolid if symptoms progressive and distressing to patient, usually tolerate some peripheral numbness if needed but not painful neuropathy Monitor serum drug concentrations if doses lowered.
Management of Peripheral Neurotoxicity NSAIDs or acetaminophen may be helpful. Gabapentin (Neurontin) helpful for some. Adults initially 300 mg PO on Day 1, increase to 300 mg 2 x/day on Day 2, and 300 mg 3 x/day on Day 3. Titrate up to 1800 mg in 3 divided doses, as needed A low dose of tricyclic antidepressant (amitriptyline [Elavil] 25 mg PO at bedtime) can be tried if there are no contraindications. Carbamazepine (Tegretol), an anticonvulsant, at 100 to 400 mg PO BID, can be tried. Monitor CBC and liver enzymes.
Retrobulbar Neuritis Toxicity: Monitoring All patients should have baseline visual acuity (Snellen) and color vision discrimination (Ishihara). PATIENT EDUCATION Symptom check (blurred vision, scotoma) with DOT Monthly testing, increased risk with EMB in pts with renal insufficiency If patient reported symptom or abnormality detected in toxicity screening, Ophthalmology evaluation Hold medication potentially responsible (EMB, Linezolid)
Retrobulbar Neuritis Toxicity Decreased visual acuity or red-green color discrimination Dose related, Unusual at EMB dose 15 mg/kg. Increased risk with renal insufficiency. Usually occurs after 12 16 weeks of Linezolid
Central Nervous System Toxicity A variety of mild effects may occur early Drowsiness, headaches, poor concentration, irritability, mild mood changes, insomnia, & agitation. Caution patients to expect these effects and understand that they typically become less problematic after the initial weeks of therapy. Tolerance develops towards most of these effects and the patient learns to cope with them.
Central Nervous System Toxicity Psychiatric effects Depression may lead to suicidal ideation if medication continues Cycloserine, ethionamide, INH and due to reaction to hyperpigmentation in some taking clofazimine Medication must be stopped and patient watched closely until no longer a threat to self if suicidal May be able to restart at lower dose Psychosis Most likely drug is cycloserine, occasionally FQNs & INH Consult a psychiatrist Patient may need to be hospitalized
Central Nervous System Toxicity Seizures Hospitalize patient Drugs most likely responsible cycloserine, FQNs, linezolid, INH, imipenem Serotonin Syndrome At least one of following: clonus, seizure, myoclonus, ataxia, incoordination, jawtrimus, rigidity, shivering, rigors, nystagmus, tremor/twitching, hyperreflexia Also - tachycardia, fever, mydriasis, diaphoresis, hyperactive bowel, diarrhea, agitation, delirium.
Serotonin Syndrome Clinical symptoms and signs that occur in the presence of excess serotonin activity. 3 different mechanisms - elevated serotonin levels: inhibition of serotonin metabolism (MAO inhibitor use) blockade of serotonin reuptake at the presynaptic neuron (SSRI and/or tricyclic antidepressant use) or increase in the release of stored serotonin (amphetamine use). LZD - weak, reversible, nonselective MAO inhibitor
Serotonin Syndrome (SS) LZD alone is not potent enough to cause SS may occur when LZD given with medications that increase the serotonin level or when diet is high in tyramine (cheese, cured meats, fermented soy products or sauce, red wine). Although rare, it can be severe and even fatal. Syndrome does not resolve unless the offending medications are withdrawn, recognition is imperative. Clinical picture varies from mild to severe
Serotonin Syndrome (SS) The syndrome develops soon after the introduction of the offending medication or an increase in a dose of a previously used drug. Physical exam should focus on assessment for clonus, deep-tendon reflexes, pupil size, mucosal dryness, bowel sounds, and diaphoresis. A good drug history including use of over-the-counter medications, herbal and dietary supplements, and illicit drugs (in addition to any recently prescribed drugs) is an essential part of the evaluation. The differential diagnosis includes anticholinergic poisoning, malignant hyperthermia, and neuroleptic malignant syndrome. The drug history will help to identify the cause. The SSRIs or tricyclics cannot be abruptly stopped and even if discontinued will continue to exert effects due to their long drug half-life. Supportive care, stop linezolid
Severe Systemic Drug Reactions Drugs should not be continued if systemic symptoms, fever, urticaria, mucous membrane involvement, blistering of the skin, edema of the lips or eyes, or wheezing or compromise of the airway. Consult with a TB expert, a dermatologist, and possibly an allergist for desensitization prior to rechallenge with any of the anti-tuberculosis medications.
Quinn d, Stern T, Linezolid and Serotonin Syndrome Prim Care Companion J Clin Psychiatry 2009
CID 2006
Hematological Toxicity of TB Drugs Drug Resistant Tuberculosis: A Survival Guide for Clinicians, 3 rd edition Curry International Tuberculosis Center
Hematological Abnormalities May be due to medications (TB or other) May represent underlying disease Chronic renal failure anemia Chronic liver disease anemia, low platelet count GI disease with blood loss anemia Disseminated TB involving bone marrow anemia, low white blood count, low platelet count
Adverse Drug Events Nephrotoxicity Drugs: aminoglycosides, capreomycin rarely rifamycins including rifabutin Monitoring - baseline serum creatinine, repeat at least monthly Lower initial dose in patients > age 59 yrs. (10 mg/kg) If baseline creatinine clearance < 70ml/min, avoid injectable drugs if possible or consider use of intermittent dosing initially Monitor peak and trough serum drug levels and adjust dose accordingly Encourage good hydration If creatinine increases, hold medication 1 2 weeks and watch If need to continue, restart at 2 3 x/week dosing Follow creatinine weekly
Ototoxicity All of the aminoglycosides and CM are toxic to the eighth cranial nerve. Can cause vestibular and auditory toxicity Usually do not occur together but may in 3 5% of patients Vestibular toxicity May manifest as tinnitus, dizziness, or unsteadiness. Fullness in the ears may be an early symptom of vestibular toxicity. Auditory toxicity Some degree of hearing loss occurs in > 50% of patients
Ototoxicity Vestibular Toxicity Perform baseline assessment of balance and ask about tinnitus and dizziness Educate patient about toxicity and request that they identify any change at time of DOT Monitor vestibular toxicity monthly and identify changes See toxicity checklist Toxicity may be limited if found early and injectable stopped May be permanent and patient can have severe problems if drug is continued once toxicity identified
Assessment Tool for Ototoxicity DATE: QUESTIONS Hearing Vestibular Testing Report Ears full or stuffy Weak Nausea TYPE OF TEST Balance Walking Past Pointing Lateral Nystagmus Romberg Heel to toe walk RESPONSE OK: Left / Right IMPAIRED: Left / Right Left: Yes / No Right: Yes / No Yes / No None / Sometimes / Always RESULTS Ok / Teeters Falls? Left / Right Ok / Weaves / Stagger Yes / No Left / Right Yes / No Normal / Falls Does Well / Jerky Hesitates / Sways Past pointing A. Patient sits facing you, with his/her eyes closed B. Have him/her point their fingers, then place your fingers below theirs C. Hold your position, ask patient to raise both hands and return fingers to yours D. Deviation R & L from target fingers-past pointing Lateral Nystagmus A. Patient sits on exam table for 30 seconds B. Lies down, look for nystagmus (jerking of eyeballs side to side) C. Log roll patient to one side, wait 30 seconds, look for nystagmus, then try the other side Romberg A. Patient stands with feet together B. Encircle the patient with your arms, but do not touch C. Tell the patient I will not let you fall and have the patient close their eyes E. Falling is a positive Romberg sign Heel to toe walking A. Stand beside standing patient B. Demonstrate walking heel to toe Hertz (HZ) Frequency C. Do it together (be prepared to catch pt.) Right: X Left: O D. Observe for jerkiness, falling swaying D E C I B E L S 50 45 40 35 30 25 20 Audiogram 500 1000 2000 4000 6000 8000
Ototoxicity Auditory Toxicity Injectable drugs have direct toxicity to 8 th cranial nerve Streptomycin usually identified as having less auditory toxicity but not all studies agree Hearing loss is usually permanent Hearing loss may progress for months after injectable is stopped Monitor at 3 and 6 months after stopping drugs If possible stop injectable or decrease dose/ increase interval when early loss is detected Baseline audiogram should always be done Ask about prior injectable drugs, family history of hearing loss
USAID, KNCV Tuberculosis Foundation, Challenge TB
Ototoxicity Auditory Toxicity Normal hearing thresholds are at 25 decibels (db), or lower, in both ears. If hearing is not at this level the individual has hearing loss Damage to inner ear (cochlea) leads to sensorineural hearing loss (SNHL) nerve related Usually cannot be corrected surgically or medically Cochlear implants can be helpful Hearing aids often not very helpful Conductive hearing loss due to problem with ear canal, ear drum, or middle ear and little bones
Ototoxicity Auditory Toxicity Audiometry is the procedure that tests ability to hear various sound frequencies Can test air conduction and bone conduction Audiogram is the graph showing the result of a pure tone audiometry which determines faintest tones a person can hear at selected pitches or frequencies from low to high. Pitch or frequency is referred to in Hertz (Hz) Loudness is measured in decibels (db)
Ototoxicity Auditory Toxicity Hearing loss due to ototoxic drugs starts at high frequencies So does age related hearing loss Risk increased with HIV, genetic predisposition Baseline audiogram needed to identify hearing loss already present Repeat monthly and 6 months after drug stopped At speech frequencies 250 600 Hz and higher 8000Hz Serial audiograms best indication of hearing loss
USAID, KNCV Tuberculosis Foundation, Challenge TB
Ototoxicity Auditory Toxicity Screening audiometry suggestive of ototoxicity Decrease in hearing threshold by 20 db or more at any one test frequency Decrease in hearing threshold by 10 db or more at any two adjacent frequencies Loss of response at three frequencies where responses were previously obtained Monitor more frequently if tinnitus, dizziness or vertigo noted Exclude other causes ear wax, otitis media, perforation of tympanic membrane
Auditory Toxicity When Should Injectable Be Stopped? Tinnitus or unsteadiness attributable to vestibular toxicity Persistent vertigo and ataxia is intolerable, not reversible Moderate or severe hearing loss; earlier if possible Ensure adequate regimen if injectable stopped
WHO Classification
Baseline -normal Initial loss Progressive loss due speech
What Else Might Be Done to Prevent Hearing Loss? Damage to 8 th nerve due to reactive oxygen species Theoretically possible to mitigate these effects Iron chelation but many other toxicities Aspirin Research needed to guide these efforts
Fluoroquinolones Moxifloxacin>levofloxacin>ofloxacin>ciprofloxacin Bedaquiline QT interval prolongation Degree of risk not determined with recent studies Risk of torsades de pointes unknown (?small) Optimal screening and monitoring unknown Classic example of risk/benefit assessment
Rifabutin Toxicity Hematologic toxicity: neutropenia and thrombocytopenia Drug interactions: less severe than rifampin Uveitis: Rare, < 0.01% GI Symptoms Polyarthralgias: 1-2% at standard doses Pseudojaundice (HIV, with clarithromycin and EMB) Hepatotoxicity, flu-like syndrome
Pyrazinamide (PZA) Toxicity Hepatotoxicity: Less at 25 mg/kg than 50 mg/kg Gastrointestinal symptoms: nausea and vomiting mild at standard doses. Nongouty polyarthralgia: Up to 40% of patients: not an indication to stop therapy. Asymptomatic hyperuricemia: Expected Acute gouty arthritis: Unusual except in patients with pre-existing gout. Rash/dermatitis: usually self limited
Fluoroquinolone Toxicity Musculoskeletal Tendonitis/Tendon Rupture (Black box warning) If tendon inflammation is mild: Rest the joint/nsaid s Reduce dose of FQ if possible If symptoms progress, stop the FQ If tendon inflammation is moderate/severe Stop the FQ Rest the joint/nsaid s Risk/benefit evaluation of FQ continuation Tendon rupture (usually Achilles) is rare
Fluoroquinolone Toxicity Gastrointestinal disturbance: nausea/bloating 0.5-2% Neurologic effects: dizziness, insomnia, tremulousness, headache 0.5% Cutaneous reactions: rash, pruritis, photosensitivity 0.2-0.4% Arrhythmias: QT prolongation (congenital, medications, MI)
Second-Line TB Drugs Cycloserine Central Nervous System Effects: headaches, restlessness, suicidal ideation psychosis, seizures (3% at 500 mg/day). May exacerbate underlying seizure disorders or mental illness. Pyridoxine at 50-100 mg/day may help prevent neurotoxicity Administer with caution to alcoholics, patients with history of mental illness or seizures Peripheral neuropathy Rash Drug levels are necessary reduce dose if peak levels >35 even if no symptoms 20-35 mcg/ml)
Second-Line TB Drugs Ethionamide Gastrointestinal Effects: commonly causes profound GI side-effects. Symptoms may improve if taken with food or at bedtime Hepatotoxicity: 2% of patients Neurotoxicity: Peripheral neuritis, optic neuritis, depression, psychosis Endocrine Effects: blood glucose abnormalities hypothyroidism, gynecomastia, hair loss, Acne, metallic taste in mouth
Injectable TB Drugs Streptomycin, Kanamycin, Amikacin, Capreomycin Ototoxicity Nephrotoxicity Electrolyte disturbances: hypokalemia, hypomagnesemia, cardiac dysrhythmias Rash
Second-Line TB Drugs P-Aminosalicylic acid (PAS) Gastrointestinal Distress: less with lower doses, diarrhea may be debilitating Hepatotoxicity: 0.3% of patients (including jaundice) Malabsorption syndrome Hypothyroidism: common with prolonged administration or concomitant ethionamide Rash, lymphadenopathy, leukocytosis, arthralgia Fluid overload
Second-Line TB Drugs Linezolid Myelosuppression Peripheral Neuropathy Optic Neuritis Gastrointestinal Disturbance Rash Hepatitis (rare) Serotonin Syndrome Lactic acidosis Rhabdomyolysis
Linezolid for treatment of chronic extensively drug-resistant tuberculosis (Myungsun et al NEJM 2012, 367; 1508) 82% clinically significant adverse events (AE s) possibly or probably linezolid related 7 episodes of myelosuppression (anemia and leukopenia) 7 episodes optic neuropathy 21 episodes of peripheral neuropathy 1 episode rhabdomyolysis Only 3 patients permanently discontinued linezolid owing to drug toxicity 1 anemia, 2 optic neuropathy
References Agents,Tuberculosis 2008; 66: Treatment of Tuberculosis: Am J Respir Crit Care Med, 2003; 167: 603-662. Hepatotoxicity of Antituberculosis Therapy: Am J Respir Crit Care Med, 2006; 174: 935-95 Official ATS/CDC/IDSA Clinical Practice Guidelines: Treatment of Drug Susceptible Tuberculosis: Clin Infect Dis, 2016;63:853-867. Drug Resistant Tuberculosis: A Survival Guide for Clinicians, 3 rd edition Curry International Tuberculosis Center Seaworth BJ, Griffith DE. 2017. Therapy of multidrug-resistant and extensively drug-resistant tuberculosis. Microbiolspec. 2017 April; 5(2) Hearing loss in patients on treatment for drug-resistant tuberculosis Seddon J, et al ERJ Express June 14, 2012