![Page 1: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/1.jpg)
Drug Side Effects and ToxicityGwen A. Huitt, MD MS
Professor, Division of Mycobacterial and Respiratory Infections
National Jewish HealthPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 2: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/2.jpg)
Disclosures
• None
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 3: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/3.jpg)
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 4: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/4.jpg)
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 5: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/5.jpg)
Toxicity – Nausea and vomiting
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 6: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/6.jpg)
Any Drug Can Cause a Rash
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 7: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/7.jpg)
Isoniazid
• Role: primary drug, along with rifampin
• Action: inhibits cell wall synthesis
• Dosage: oral, IM, IV (in saline only)
• Dose: 300mg QD; 10-20mg/kg for peds
• Clearance: liver>>kidney
• Toxicity: Hepatitis, neuropathyPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 8: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/8.jpg)
INH Drug Interactions
• Increased concentrations of:• Anticonvulsants
• Phenytoin, Barbiturates
• Warfarin
• Decreases concentrations• Azole antifungals
• Inhibits histaminase and monoamine oxidase
• INH absorption inhibited by aluminum• Avoid antacids containing aluminum
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 9: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/9.jpg)
Rifampin
• Role: primary drug, along with INH
• Action: DNA – dependent RNA synthetase
• Dosage: oral, IV
• Dose: 600mg daily; 10-20mg/kg for peds• New treatment regimens are looking at 35mg/kg doses
• Cleared: liver >> kidneys
• Toxicity: hepatotoxicity, flu-like syndromeProp
erty o
f Pres
enter
Not for
Rep
roduc
tion
![Page 10: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/10.jpg)
Rifabutin
• Role: Used when concerned about drug-drug interactions
• Action: DNA-dependent RNA synthetase
• Dosage: Oral
• Dose: 300mg once daily
• Clearance: liver >> kidneys
• Toxicity: neutropenia, thrombocytopenia, uveitisPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 11: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/11.jpg)
Rifamycin Toxicity
• Hematologic
• Hepatotoxicity
• Nephrotoxicity
• Hypersensitivity
• “Influenza syndrome”
• “Lupus syndrome”• Fever, Rash, Leukopenia, thrombocytopenia, arthralgias
• Nausea and vomiting
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 12: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/12.jpg)
Rifabutin Toxicity
• Hepatitis
• Uveitis
• Arthritis
• Fever
• Thrombocytopenia, Leukopenia
• Drug induced lupus
• Nausea and vomiting
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 13: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/13.jpg)
Case
• 55 y/o female started on INH, ethambutol, moxifloxacin and rifampin for pulmonary M. tuberculosis infection
• 2 month f/u shows WBC of 4.0
• What are your thoughts about the WBC?
• What should you do?
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 14: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/14.jpg)
Case continued
• 3 month f/u shows WBC of 1.5 (ANC 0.5); Platelet ct. 128,000
• What would you do next?
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 15: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/15.jpg)
Case
• 66 y/o male with Interstitial Pulmonary Fibrosis and bronchoscopy specimen is culture positive for M. tuberculosis seen at NJH. AFB smear negative. Requiring 6 liters of supplemental oxygen in Denver. Seen by ILD service and started on 40 mg of prednisone with minimal response at 2 weeks. Patient had been started on rifampin, ethambutol, INH, and streptomycin by ID physician and had been started on prednisone by pulmonary docs.
• Why might he not be responding to the prednisone?Prop
erty o
f Pres
enter
Not for
Rep
roduc
tion
![Page 16: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/16.jpg)
Case continued
• Pt. with severe nausea, vomiting and weight loss 2 months into therapy with rifampin, ethambutol, INH, and SM.
LFT’s 5/23/11 6/27/11
AST 32 129AP 95 442TB 0.5 0.9ALT 20 121
What could be causing the LFT’s abnormalities?
Why might he not be responding to the prednisone with improved oxygenation?
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 17: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/17.jpg)
Case
• 66 y/o female with drug susceptible tuberculosis being treated with I/R in the 5th month of treatment.
• Develops severe joint aches, in knees and elbows and terrible fatigue and malaise
• What are your thoughts?
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 18: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/18.jpg)
Drug-Induced Lupus Syndrome Associated with Rifamycin Therapy• 5 pts on rifamycin (3 RFB, 2 RIF) developed malaise,
arthralgias/arthritis and edema 5-7 months after starting therapy• Rheum Hx: 1 prior drug induced lupus 4 yrs prior (INH Tx). 1 prior with
Raynaud’s
• All pts on Clari or other known hepatic enzyme inhibitors
• All improved 1-10 weeks after D/C rifamycin
Berning Se, Cook LJ, Iseman MD. Clin Infect Dis. 1995;21:746.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 19: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/19.jpg)
Pyrazinamide (PZA)
• Role: primary drug, first 2 months
• Action: affects fatty acid synthesis
• Dosage: oral
• Dose: 25-30mg/kg once daily (adults and peds)
• Cleared: liver, then metabolites via kidneys
• Toxicity: hepatotoxicity, elevated uric acidPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 20: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/20.jpg)
Pyrazinamide (PZA)
• Hepatotoxicity
• Hyperuricemia (arthralgias)
• Gastrointestinal
• Hypersensitivity
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 21: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/21.jpg)
Ethambutol (EMB)
• Role: Part of initial treatment regimen
• Action: inhibits cell wall synthesis
• Dosage: oral
• Dose: 15-25mg/kg once daily (adults and peds)
• Cleared: kidneys >> liver
• Toxicity: ocular toxicity, rashesPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 22: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/22.jpg)
Case presentation
• 76 year old female continuing on Rifampin, Ethambutol, and levofloxacin for M. tuberculosis (INH induced hepatitis)
• 2 months later reported visual changes to local MD, but no med changes were made. Told her this was likely secondary to cataracts (known)
• What would you do in this situation?Prop
erty o
f Pres
enter
Not for
Rep
roduc
tion
![Page 23: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/23.jpg)
Case presentation
• At 3 months, could not read newspaper; legally blind
• Vision returned to normal over 1 years, and doing fine 2 years later. Had cataracts removed later.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 24: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/24.jpg)
Ethambutol Optic Neuritis
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 25: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/25.jpg)
Ethambutol Optic Neuritis
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 26: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/26.jpg)
Ethambutol Optic Neuritis
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 27: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/27.jpg)
Ethambutol Toxicity
• Optic Neuritis
• Hyperuricemia
• Peripheral Neuropathy
• Hypersensitivity
• Hair loss
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 28: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/28.jpg)
Ethambutol Toxicity
• Different dosing regimens are used
• 25 mg/kg once daily x 2 months then decrease to 15 mg/kg daily to complete 18-24 months
• Griffith - Retrospective study of 229 patients Mean age 63.8; 55% women• 139 pts with daily therapy
• Mean duration of EMB tx 16.1 months
• EMB daily 25 mg/kg/d x 2 mos then 15 mg/kg day
• 6% developed ocular toxicity
Griffith DE, Am J Respir Crit Care Med 2005 Jul 15; 172:250-3
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 29: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/29.jpg)
Ethambutol Toxicity
• None of the cases were detected by routine ocular exam• Ishihara vs. visual acuity vs. visual field testing
• Visual acuity returned to normal after discontinuation of EMB
• 90 patients received Mon, Wed, Fri therapy with 25 mg/kg• None had ocular toxicity
• Cum dose of EMB in daily significantly higher (P=0.0001)
Griffith DE, Am J Respir Crit Care Med 2005 Jul 15; 172:250-3
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 30: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/30.jpg)
Ethambutol Monitoring
• Regular assessment of color and acuity
• ?Avoid use in children (NO!)
• Use with caution in renal failure
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 31: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/31.jpg)
Ethambutol Induced Rash
• After a rash occurs, it is best to let things quiet down for 4 weeks
• Then you can consider desensitization to either/both ethambutol and rifampin
• Consider starting H1/H2 blocker (cetirizine/ranitidine) as soon as possible and you may need to use prednisone as well to help rash resolve
Matz J, et al ; Am J Resp Crit Care Med; 1994;149:815-7
Kim JH, et al; Allergy; 2003 June; 58(6):540-1.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 32: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/32.jpg)
Streptomycin
• Role: “Fourth drug” in case of resistance
• Action: inhibits protein synthesis
• Dosage: IM, IV
• Dose: 12-15mg/kg once daily (adults and peds)
• Cleared: kidneys
• Toxicity: ototoxicity, nephrotoxicity, cation lossPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 33: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/33.jpg)
Amikacin, Capreomycin, Kanamycin
• Role: Drug resistant TB
• Action: same as streptomycin
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 34: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/34.jpg)
Side Effects/Toxicity
• Nephrotoxicity →
• Ototoxicity →
• Vestibular toxicity →
• Electrolyte abnormality →
• Eosinophilia →
• Local soreness →
Management
• Electrolyte panel
• Audiogram
• Vestibular testing
• Replacement therapy
• Not significant
• Ultrasound, hot packs, lidocaine
Aminoglycosides
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 35: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/35.jpg)
Hearing Loss Monitoring
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 36: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/36.jpg)
Other Aminoglycoside Effects
• Hypersensitivity
• Neurotoxicity• Circumoral paresthesias
• Decreased mental concentration
• Post operative respiratory depression
• Drug induced myasthenia gravis
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 37: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/37.jpg)
Other Aminoglycoside Effects
• Hematologic• Aplastic anemia
• Agranulocytosis
• Drug Interactions• Heparin breaks down aminoglycosides in vitro
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 38: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/38.jpg)
Levofloxacin
• Role: drug resistant TB
• Action: inhibits DNA gyrase
• Dosage: oral, IV
• Dose: 750-1000mg once daily
• Cleared: kidneys
• Toxicity: caffeine like effects, GI, tendonitisPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 39: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/39.jpg)
Moxifloxacin
• Action: inhibits DNA gyrase
• Dosage: oral, IV
• Dose: 400mg once daily
• Cleared: kidneys
• Toxicity: caffeine-like effects, GI, tendonitis, hypoglycemia
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 40: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/40.jpg)
Case
• 65 y/o physician with MDRTB contracted while serving as a medical missionary in the Ukraine.
• Avid runner
• On Ethambutol, Amikacin, PAS, and Moxifloxacin
• 6 months into therapy begins to experience calf tightness after running
• What are your thoughts?Prop
erty o
f Pres
enter
Not for
Rep
roduc
tion
![Page 41: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/41.jpg)
Ruptured Achilles Tendon
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 42: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/42.jpg)
Prolonged QT interval – Quinolones, macrolides, clofazimine, bedaquiline
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 43: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/43.jpg)
Quinolone Pearls
• Things to watch for with moxifloxacin• Best on empty stomach
• Don’t take within 2 hours of calcium/magnesium/iron containing supplements or foods
• Take in AM because of caffeine-like effects
• Use with caution in the elderly because of CNS side effects, hypoglycemia, and tendonitis
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 44: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/44.jpg)
Ethionamide
• Role: drug resistant TB
• Action: inhibits cell wall synthesis
• Dosage: oral
• Dose: 250-500mg BID; 10-20mg/kg divided BID for peds
• Cleared: liver
• Toxicity: GI upset, decreased thyroid function, decreased libido, and hyperglycemia
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 45: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/45.jpg)
P-aminosalicylic Acid (PAS)
• Role: drug resistant Tb
• Action: not known
• Dosage: oral
• Dose: 4gm BID-TID
• Cleared: liver >> kidneys
• Toxicity: GI upset, increased flatulence, hypothyroidismPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 46: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/46.jpg)
Case
• 26 year old female with MDRTB tx’d for 2 years with ethambutol, PAS, ethionamide, levofloxacin, and cycloserine.
• 4 weeks after completing therapy she has tachycardia, weight loss, “feels like she is going to die”
• What is going on?
• Heart rate is 130, diaphoretic, “panic” look
• TSH is 0.0
• She is HYPERTHRYROID b/c physician forgot to d/c the synthroid that was started during treatment for HYPOTHYROIDISM caused by ethionamide and PAS.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 47: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/47.jpg)
Cycloserine
• Role: drug resistant TB
• Action: inhibits cell wall synthesis
• Dosage: oral
• Dose: 250-500mg BID; 10-20 mg/kg divided BID for peds
• Cleared: kidneys
• Toxicity: lack of concentration, altered behaviorPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 48: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/48.jpg)
“Psychoserine”
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 49: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/49.jpg)
Therapeutic Drug Monitoring
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 50: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/50.jpg)
• INH 300mg daily
900mg BIW
• Rifampin 600mg daily
• Rifabutin 300mg daily
• Rifapentine 600mg daily
• PZA 35mg/kd daily
50mg/kg BIW
3 - 6 mcg/ml
9 – 18 mcg/ml
8 – 24 mcg/ml
0.3 – 0.9 mcg/ml
8 – 30 mg/ml
20— 50 mcg/ml
40 – 100 mcg/ml
Therapeutic Drug Monitoring
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 51: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/51.jpg)
• Ethambutol 25mg/kg daily
50mg/kg BIW
• Aminoglycoside 15mg/kg daily
(BIW) 22-25mg/kg
2 – 6 mcg/ml
4 – 12 mcg/ml
35 – 45 mcg/ml
65 – 80 mcg/ml
Therapeutic Drug Monitoring
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 52: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/52.jpg)
• Cycloserine
• Ethionamide
• PAS
• Ciprofloxacin
• Levofloxacin
• Clofazamine
20 – 35 mcg/ml
1 – 5 mcg/ml
20 – 60 mcg/ml
4 – 6 mcg/ml
8 – 12 mcg/ml
0.5 – 2 mcg/ml
Therapeutic Drug Monitoring
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 53: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/53.jpg)
Bedaquiline
• CDC Recommendations – Dosing administration• 400mg dose once daily for 2 weeks then lower to 200mg three times a week
for an additional 22 weeks (DOT is mandatory!)
• This antibiotic should only be used in combination with at least 3-4 other antibiotics to which laboratory tests indicate that the bacteria is susceptible
Mase S et al; MMWR;Oct. 25, 2013;1-12
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 54: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/54.jpg)
• CDC Monitoring Recommendations• Once a week, assess pt. for sxs of nausea, hemoptysis, chest pain, joint pain,
and rash• Do an ECG PRIOR TO and again at 2, 12, and 24 weeks after treatment is
started.• Monitor pts. For liver-related adverse drug reactions with serum
transaminases• TDM should be considered in patients with severe renal impairment, or if it is
being co-administered with other drugs that induce or suppress the cytochrome P450 system
• May be used on case-by-case basis in children, HIV-infected persons, pregnant women, extrapulmonary MDR TB.
Bedaquiline
Mase S et al; MMWR;Oct. 25, 2013;1-12
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 55: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/55.jpg)
What drug caused this?
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 56: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/56.jpg)
Treatment in Renal Failure
• INH - Decrease dose if severe, monitor drug concentrations
• Rifampin - No change
• Ethambutol - Reduce dose or increase intervals
• Pyrazinamide - Use with caution
• Streptomycin - Adjust dose according to concentrations
• Cycloserine - Monitor concentrations and CNS effectsPropert
y of P
resen
ter
Not for
Rep
roduc
tion
![Page 57: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/57.jpg)
Treatment in Pregnancy
• INH - Safe, give with pyridoxine
• Rifampin - Manufacturers caution, may be used safely
• Ethambutol - Safe
• Pyrazinamide - Little known
• Aminoglycosides - May cause CN 8 nerve toxicity, but may be necessary to use
• Fluoroquinolones - Avoid may cause fetal joint abnormalitiesProp
erty o
f Pres
enter
Not for
Rep
roduc
tion
![Page 58: Drug Side Effects and Toxicity - National Jewish Health•Thrombocytopenia, Leukopenia •Drug induced lupus •Nausea and vomiting Property of Presenter Not for Reproduction. Case](https://reader031.vdocuments.site/reader031/viewer/2022013008/5e4f01d06b2e5e107573da83/html5/thumbnails/58.jpg)
Great Sand Dunes National Park
Propert
y of P
resen
ter
Not for
Rep
roduc
tion