Pulmonary tuberculosis pharmacology by Marc Imhotep Cray, M.D.

Marc Imhotep Cray, M.D.

Case Trigger 3 A 42-year-old HIV-positive man presents to the emergency department with hemoptysis. He states that he has lost 15 pounds over the last 2 months and has had an intermittent fever, cough, and chills. He has not been taking any of his HIV medications and his CD4 count is 130. A chest x-ray reveals a lesion in his apical right lung. He is able to cough up green mucous coated with blood. You send the sample off for staining and culture. The sample reveals acid-fast bacilli and you decide to admit this patient to an isolation room and begin him on a multidrug treatment regimen while drug susceptibility tests are run.

Marc Imhotep Cray, M.D.

Pulmonary Tuberculosis  Caused by Mycobacterium tuberculosis  Major global problem; Seen in pts with HIV, other immunocompromised states, developing countries, etc.  Contracted by inhalation

Diagnosis suggested by:  chronic cough  hemoptysis  weight loss  fevers  night sweats

Scanning electron micrograph of

Mycobacterium tuberculosis

M. tuberculosis bacterial colonies Marc Imhotep Cray, M.D.

Pulmonary Tuberculosis (2)

Marc Imhotep Cray, M.D.

Chandrasoma P, Taylor CR. Concise Pathology, 3rd ed. Stamford, CT: Appleton& Lange, 1998: 523

Pulmonary Tuberculosis (3)

Marc Imhotep Cray, M.D.

Pulmonary TB (4) Diagnosis: confirmed by CXR, PPD, sputum smears and culture

Mycobacterium tuberculosis Ziehl-Neelsen stain

 Treatment: 4 drug therapy • Rifampin • Isoniazid • Pyrazinamide • Ethambutol Marc Imhotep Cray, M.D.

Chest X-ray of a person with advanced tuberculosis http://upload.wikimedia.org/wikipedia/commons/ 9/9c/Tuberculosis-x-ray-1.jpg 6

Tuberculosis Map

Marc Imhotep Cray, M.D.

Modified from: Jones CH. Mind Maps for Medical Students, 2015

Key Points Presenting symptoms of reactivation TB include chronic cough, hemoptysis, intermittent fevers, night sweats, and weight loss Chest x-ray may show any variety of infiltrate although classically shows granulomatous or cavitary lesions in upper lobes Patients with pulmonary infiltrates suspicious for TB must be kept in isolation until three sputum samples are negative for acid-fast organisms Positive PPD suggests prior infection with M. tuberculosis, but does not necessarily imply active TB Marc Imhotep Cray, M.D.

Key Points (2) Any PPD reaction in immunocompromised persons is positive For individuals at high risk, 5 mm is positive For individuals with several risk factors, 10 mm is positive For individuals at low risk, 15 mm is positive Initial treatment of active TB consists of a four-drug regimen Duration of treatment is at least 6 months due to large number of inactive organisms and poor drug penetration into caseating granulomas and cavitary lesions Marc Imhotep Cray, M.D.

Pulmonary Tuberculosis Pharmacology

Marc Imhotep Cray, M.D.

“Tuberculosis Medication” Medication Summary “The treatment of tuberculosis (TB) must satisfy the following basic therapeutic principles: • Any regimen must use multiple drugs to which Mycobacterium tuberculosis is susceptible • The medications must be taken regularly • The therapy must continue for a period sufficient to resolve the illness New cases are initially treated with four drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. After 2 months, they are then treated with a continuation phase of 4 months with isoniazid and rifampin. Patients requiring retreatment should initially receive at least 5 drugs, including isoniazid, rifampin, pyrazinamide, and at east 2 (preferably 3) new drugs to which the patient has not been exposed.” Source: Herchline ET, Tuberculosis Medication. Medscape. Updated Oct 22, 2015 Available at: http://emedicine.medscape.com/article/230802-medication Accessed: Dec. 30, 2015 Marc Imhotep Cray, M.D.

Commonly used drug regimens for Tuberculosis (MTb Drug Combinations)  Active TB is Tx most often initially with four drugs in a long-term treatment (6–12 months) plan to avoid development of antibiotic resistance  

In general, 6-month regimens are used for patients with culture-positive TB Regimen consists of INH, rifampin, pyrazinamide, and ethambutol o All four agents are used for initial 2 months continuation phase is 4 months and consists of first two agents (INH, rifampin) only o Continuation phase is extended for an additional 3-6 months in patients who had cavitary lesions at presentation or on a follow-up chest x-ray, or are culture positive at 2-month point o Second-line agents (e.g., fluoroquinolones, cycloserine, and amikacin) can be used when there is resistance to first-line agents

 Due to rapid development of resistance, single-drug therapy is only useful for prophylaxis Marc Imhotep Cray, M.D.

TB Treatment  M. tuberculosis is slow growing and requires treatment for months to years  LTBI can be treated for 9 months with isoniazid (INH) monotherapy or with 12 once-weekly doses of INH (900 mg) and rifapentine (900 mg)  In contrast, active TB disease must be treated with several drugs as indicated in previous slide  Treatment for drug-susceptible TB lasts for at least 6 months and can be as long as 12 months  Treatment of multidrug-resistant TB (MDR-TB) typically starts with 6 drugs, administered by a specialist and lasts for about 2 years Marc Imhotep Cray, M.D.

Drugs Used To Treat Tuberculosis 1st

Line Drugs Ethambutol MYAMBUTOL Isoniazid Pyrazinamide Rifabutin MYCOBUTIN Rifampin RIFADIN Rifapentine PRIFTIN

2nd Line Drugs Aminoglycosides Aminosalicylic acid Capreomycin Cycloserine Ethionamide Fluoroquinolones Macrolides

 Active TB treatment generally includes four first-line drugs  isoniazid, rifampin, pyrazinamide, and ethambutol  Second-line drugs are typically less effective, more toxic, and less extensively studied used for patients who cannot tolerate first-line drugs or who are infected with resistant TB Marc Imhotep Cray, M.D.

Mechanism of action for each of following firstline antituberculosis medications  Rifampin Inhibition of DNA-dependent RNA polymerase  Isoniazid Inhibition of mycolic acid synthesis  Pyrazinamide Unknown; activated by susceptible bacterial strains which in turn lowers pH of surrounding environment  Ethambutol Inhibition of RNA synthesis Marc Imhotep Cray, M.D.

1st line Anti-TB Drugs Ethambutol Isoniazid (INH) Pyrazinamide Rifamycins Rifabutin Rifampin Rifapentine

Isoniazid (INH) MOA:  Isoniazid decreases synthesis of mycolic acid, which is a long chain fatty acid cell wall component in Mycobacterium  INH is a synthetic derivative of pyroxidine  It is bactericidal in rapidly dividing cells; however, resistance develops rapidly by mutation due to the large population of bacteria in an active infection  Mutation leads to enzyme modification or overexpression

ROA:  Oral administration of isoniazid is effective drug is distributed to all body fluids and sites of infection, including tubercles in lungs Marc Imhotep Cray, M.D.

Isoniazid Pharmacokinetics-metabolism:  Isoniazid is acetylated in liver rate of acetylation varies in a bimodal distribution due to genetic polymorphisms  Fast acetylators will have lower blood concentrations o This is dominant trait  Slow acetylators are more likely to develop toxicity

Adverse Effects:  Side effects from isoniazid are rare, are usually dose dependent, include:  Hepatitis increases in incidence with age and use of alcohol  Peripheral neuritis (INH interferes with peripheral metabolic activation of vitamin B6) o Note: Isoniazid can achieve levels in breast milk high enough to cause a pyridoxine deficiency in infant unless mother is supplemented with vitamin

This can be avoided by giving pyridoxine Marc Imhotep Cray, M.D.

Rifampin MOA:  Rifampin inhibits the β-subunit of DNA-dependent RNA Polymerase selectively reduces RNA synthesis in bacteria  Bactericidal for Mycobacterium and has good penetration into tissues and tuberculous lesions

Other Uses:  It is also used prophylactically for patients exposed to:  Neisseria meningitidis  Haemophilus influenzae, type b

Marc Imhotep Cray, M.D.

Rifampin Pharmacokinetics-metabolism:  Metabolism occurs in liver activates MFOs (enzyme inducer)  Rifampin self-induces its own metabolism (cytochrome P450 system)  It also enhances metabolism of several other drugs (enzyme inducer) o oral contraceptives, anticoagulants, ketoconazole, cyclosporine, and chloramphenicol are examples

o Rifabutin can be substituted for rifampin to avoid this problem=less potent inducer of cytochrome P450 enzymes  Rifampin is not used in TB Tx as a single agent due to emergence of resistance

Mechanisms of resistance:  Resistance can be caused by alteration of β-subunit of RNA polymerase, or decreased permeability to drug Marc Imhotep Cray, M.D.

Rifampin Adverse Effects:  flu-like syndrome  hepatotoxicity [(hepatitis; elevated liver function tests (LFTs)]  drug-drug interactions (cytochrome P-450 inducer)  proteinuria  thrombocytopenia  red-orange discoloration of tears, sweat, urine and stool o Contact lenses can be permanently stained with this orange discoloration o This side effect can be a source of great concern to individuals who are not warned of its possibility

Marc Imhotep Cray, M.D.

Rifabutin A derivative of rifampin, is preferred drug for use in patients with tuberculosis and human immunodeficiency virus (HIV) disease who are concomitantly treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors  because it is a less potent inducer of cytochrome P450 enzymes MOA:  Same as rifampin=inhibits the β-subunit of DNA-dependent RNA Polymerase selectively reduces RNA synthesis in bacteria Adverse Effects:  Has adverse effects similar to those of rifampin but can also cause  uveitis,  skin hyperpigmentation, and  neutropenia Marc Imhotep Cray, M.D.

Pyrazinamide MOA:  Pyrazinamide is bactericidal by an unknown mechanism  It is effective when given orally, including good CSF penetration  Pyrazinamide is a prodrug that must be hydrolyzed to active form  Loss of hydrolase leads to resistance

Adverse Effects:      

Phototoxicity increased porphyrin synthesis hepatitis arthralgias myalgias hyperuricemia

Marc Imhotep Cray, M.D.

Ethambutol MOA: Ethambutol inhibits mycolic acid synthesis but is only bacteriostatic

Adverse Effects:  optic (retrobulbar) neuritis  decreased visual acuity  red-green color blindness (impaired ability to discriminate colors)  hyperuricemia

Marc Imhotep Cray, M.D.

Second-line Drugs Used in Tx of Tuberculosis Second- line agents can be used when there is resistance to first-line agents. The aminoglycoside streptomycin is bactericidal, but it:  Must be administered parenterally  Only kills extracellular organisms and does not penetrate into cells  Does not distribute as widely in body as other drugs  Although total period of Tx for TB is a minimum of 6 months, streptomycin therapy is not commonly used for full duration of therapy, because of toxicity concerns o Streptomycin is arguably most ototoxic aminoglycoside o recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated

Fluoroquinolones and macrolides also have antimycobacterial activity Marc Imhotep Cray, M.D.

Second-line Drugs Used in Tx of MTb cont.  Aminosalicylic acid (PAS) MOA Aminosalicylic acid is an analog of PABA; it works similar to sulfonamides but only penetrates mycobacteria Adverse effect GI disturbances  Ethionamide MOA Ethionamide, like isoniazid, blocks the synthesis of mycolic acids Resistance develops rapidly, but there is no cross-resistance to INH. Adverse effect poorly tolerated; it commonly produces severe GI disturbances Without concomitant pyridoxine peripheral, neuropathies may occur Hepatotoxicity is not uncommon  Cycloserine MOA Cycloserine is an analog of d-alanine that inhibits cell wall biosynthesis Adverse effect causes CNS toxicity, including seizures and peripheral neuropathy; alcohol increases the possibility of seizures Pyridoxine administered with cycloserine reduces incidence of neuropathies Marc Imhotep Cray, M.D.

ANTIMYCOBACTERIAL AGENTS MOA SUMMARY

Marc Imhotep Cray, M.D.

Johannsen EC. & Sabatine MS. PharmCards, 4th ed. Lippincott Williams & Wilkins, 2010

Question 1 As part of a multidrug attack on patientâ&#x20AC;&#x2122;s infection with Mycobacterium tuberculosis, a physician plans to use an aminoglycoside antibiotic. Which drug is most active against the tubercle bacillus and seems to be associated with the fewest problems with resistance or typical aminoglycosideinduced adverse effects? (A) Amikacin (B) Kanamycin (C) Neomycin (D) Streptomycin (E) Tobramycin

Marc Imhotep Cray, M.D.

Answer 1 D. Streptomycin is bactericidal for the tubercle bacillus organism. Other aminoglycosides (eg, gentamicin, tobramycin, neomycin, amikacin, and kanamycin) have activity against this organism but are seldom used clinically because of toxicity or development of resistance. Streptomycin is arguably the most ototoxic aminoglycoside Refs. Brunton, pp 1505-1509, 1514-1515 Katzung, pp 822f, 824-825, 828, 840t.

Marc Imhotep Cray, M.D.

Question 2 A patient with tuberculosis is being treated with isoniazid. She develops paresthesias, muscle aches, and unsteadiness. Which vitamin needs to be given in supplemental doses in order to reverse these symptomsâ&#x20AC;&#x201D;or used from the outset to prevent them in high-risk patients? (A) Vitamin A (B) Vitamin B1 (C) Vitamin B6 (D) Vitamin C (E) Vitamin K

Marc Imhotep Cray, M.D.

Answer 2 C. Pyridoxine deficiencies arise often during isoniazid therapy because the antimycobacterial drug interferes with metabolic activation of the vitamin. The treatment or prophylaxis for at-risk patients is to administer relatively large doses of B6 (pyridoxine) Refs. Brunton, pp 639, 780, 1086, 1555-1558 Katzung, pp 840-841.

Marc Imhotep Cray, M.D.

Question 3 A 59-year-old woman is diagnosed with tuberculosis (TB). Before prescribing a multidrug regimen, you take a careful medication history because one of the drugs commonly used to treat TB induces some of the microsomal cytochrome P450 enzymes in the liver, and is a common cause of drug窶電rug interactions. What is the most likely drug? (A)Ethambutol (B)Isoniazid (C)Pyrazinamide (D)Rifampin (E)Streptomycin

Marc Imhotep Cray, M.D.

Answer 3 D. Rifampin induces cytochrome P450 enzymes, which causes a significant increase in elimination rates of many interacting drugs, such as oral contraceptives, anticoagulants, ketoconazole, cyclosporine, and chloramphenicol. It also promotes urinary excretion of methadone, which may precipitate withdrawal. Ethambutol (a), isoniazid (b), pyrazinamide (c), and vitamin B6 (e) are not P450 inducers, although the metabolism of some of these drugs can be induced by rifampin. Refs. Brunton, pp 1012-1013, 1524-1525; Katzung, pp 840-842, 848, 1160t.

Marc Imhotep Cray, M.D.

Question 4 A patient with active tuberculosis is being treated with isoniazid (INH) and ethambutol as part of the overall regimen. What is the main effect expected of the ethambutol? (A)Facilitated entry of the INH into the mycobacteria (B)Facilitated penetration of the blood-brain barrier (C)Retarded absorption after intramuscular injection (D)Retarded development of organism resistance (E)Slowed renal excretion of INH to help maintain effective blood levels

Marc Imhotep Cray, M.D.

Answer 4 D. An important problem in the chemotherapy of TB is bacterial drug resistance. For this reason, concurrent administration of two or more drugs should be employed to delay the development of resistance. Ethambutol is often given along with INH for this purpose. Streptomycin or rifampin may also be added to the regimen to delay even further the development of drug resistance Refs. Brunton, pp 1533, 1558-1559 Katzung, pp 840t, 842

Marc Imhotep Cray, M.D.

Question 5 A 34-year-old man with a history of recurrent tuberculosis on a multidrug regimen, including isoniazid. He presents to his primary care physician complaining of paresthesias of his hands and feet. What is the most likely explanation for this finding? (A) Diabetes mellitus (B) Lumbar disc disease (C) Peripheral neuritis (D) Spinal cord compression (E) Urinary tract infection

Marc Imhotep Cray, M.D.

Answer 5 C. Isoniazid is associated with development of peripheral neuritis (manifesting as paresthesias of the hands and feet), which is the most common adverse effect and appears to be caused by a relative pyridoxine deficiency. Most of the toxic reactions are corrected by supplementation of 25 to 50 mg/d of pyridoxine (vitamin B6). (A) Although diabetes mellitus can cause peripheral neuropathy, it is unlikely in this patient because there is no indication that blood sugar levels are abnormal. (B) History in this question gives no indication of lumbar disc abnormality. No evidence of imaging study to suggest this finding is provided. (D)No history of trauma is provided in this question to suggest spinal cord compression. (E) This patient does not have any urinary symptoms; thus, urinary tract infection is unlikely.

Marc Imhotep Cray, M.D.

Question 6 A 34-year-old Ethiopian with HIV disease complains of a productive cough with hemoptysis and night sweats. A sputum smear is positive for acid-fast bacilli. He is placed in isolation and started on isoniazid, rifampin, pyrazinamide, and ethambutol. A few months later, he complains of a loss of his ability to discriminate certain colors. What is causing his vision impairment? (A) Ethambutol (B) Isoniazid (C) Miliary TB (D) Pyrazinamide (E) Rifampin

Marc Imhotep Cray, M.D.

Answer 6 A. This patient’s presentation is consistent with an active tuberculosis infection. Because of his HIV status, he is started on quadruple therapy. Ethambutol is notable for its ability to cause optic neuritis, which may manifest as impaired ability to discriminate colors as in this patient’s case. Vision usually returns to normal after a few weeks of discontinuation of ethambutol. (B) Isoniazid can cause optic neuritis but much less commonly than ethambutol. Isoniazid’s major adverse reaction is hepatitis. C) Miliary tuberculosis is extremely unlikely in this case because the patient is taking four antituberculosis drugs. This patient’s presentation and history point to ethambutol toxicity. (D) Pyrazinamide is not known to cause optic neuritis.

Marc Imhotep Cray, M.D.

Question 7 A 39-year-old man with HIV disease and active tuberculosis is hospitalized for therapy. He currently takes a protease inhibitor. He complains of cough, dyspnea, and chest pressure. Which of the following is the best treatment adjunct for this patient? (A) Prednisone (B) Rifabutin (C) Rifampin (D) Ribavirin (E) Testosterone

Marc Imhotep Cray, M.D.

Answer 7 B. Rifabutin, a derivative of rifampin, is the preferred drug for use in patients with tuberculosis and human immunodeficiency virus (HIV) disease who are concomitantly treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors because it is a less potent inducer of cytochrome P450 enzymes. (A)This patient would benefit from an antituberculosis agent that will have limited hepatic side effects. (C) Rifampin is not the preferred treatment for this patient with HIV disease. (D) Ribavirin would not likely be of benefit to this patient with tuberculosis. (E)Testosterone is not helpful because this patient has HIV disease and tuberculosis.

Marc Imhotep Cray, M.D.

The next two questions are linked.

Questions 8 A 42-year-old man who recently immigrated to California from Cambodia presents with a 2-week history of fever, night sweats, a 15-pound weight loss, and cough productive of bloody sputum. Granulomatous lesions can be visualized on a chest radiograph. What is the most likely organism causing this infection? (A) Histoplasma capsulatum (B) Echinococcus granulosus (C) Mycobacterium tuberculosis (D) Streptococcus pneumoniae (E) Salmonella typhi

Marc Imhotep Cray, M.D.

Linked to previous question.

Question 9 Sputum from the patient in the above case showed acid-fast bacilli. A nucleic acid amplification test confirmed the diagnosis. What is the appropriate initial therapy for this patient? (A) Isoniazid (B) Drug combination of isoniazid and rifampin (C) Drug combination of isoniazid, ciprofloxacin, and amikacin (D) Drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (E) Drug combination of isoniazid, streptomycin, pyrazinamide, ciprofloxacin, and amikacin

Marc Imhotep Cray, M.D.

Answer 8 C. Mycobacterium tuberculosis. The history, signs, and symptoms of this case are consistent with tuberculosis. This infection is more common among immigrants from Southeast Asia. California is one of several states from which most of the diagnoses of TB are reported. None of the other infections present in the manner described in this case. Although a cause of lung granulomas, H. capsulatum is not endemic to California, or to Southeast Asia. Pulmonary infections due to S. pneumoniae typically have an abrupt onset. Rust-colored sputum may be produced; however, granulomas are not found. S. typhi presents with fever and abdominal complaints

Marc Imhotep Cray, M.D.

Answer 9 D. Drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Current treatment guidelines recommend these four drugs for the first 2 months of therapy for TB. A reduction in the number of drugs after 2 months is dependent on finding no cavitation of chest radiographs and no acid-fast bacilli on sputum stain. The rationale for a four drug combination is to cover for drug-resistant organisms as well as to prevent the development of drug resistance.

Marc Imhotep Cray, M.D.

Question 10 Which of the following side effects occurs commonly with the administration of rifampin? (A) Liver failure (B) Renal failure (C) Orange discoloration of secretions (D) Anemia (E) Leukopenia

Marc Imhotep Cray, M.D.

Answer 10 Rifampin will turn all of an individualâ&#x20AC;&#x2122;s secretions, such as urine, sweat, tears, and stool, an orange color. Contact lenses can be permanently stained with this orange discoloration. This side effect is a source of great concern to individuals who are not warned of its possibility.

Marc Imhotep Cray, M.D.

Further study: eLearning (IVMS Cloud Folders)  Pharmacology  Infectious Disease  Microbial biology & Immune System Textbooks:  Batchelder A. et al. Rapid Clinical Pharmacology- A Student Formulary. 1st ed. John Wiley & Sons, 2011  Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York: McGraw-Hill, 2016  Gallagher JC, MacDougall C. Antibiotics simplified. 2nd Ed. Jones & Bartlett Learning, 2012  Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010 Marc Imhotep Cray, M.D.