Gail Itokazu, Pharm.D.
Spring 1998

Tuberculosis

  1. Pathogenesis and Natural History
  2. Diagnosis/Screening
  3. Treatment
  4. Case 1

Required Reading

1. Ebert CE. Tuberculosis. In Pharmacotherapy: A Pathophysiologic Approach. DiPiro JT, et al, eds. Elsevier, NY, 3rd Edition, 1997. Chapter 105, pp 2101-2118.

Optional Reading

The following readings are not required, but may enhance your understanding of the material in this section.

  1. Official Statement of the American Thoracic Society (ATS). Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149:1359-74.

GOAL

Be able to discuss treatment options and monitoring parameters to evaluate the efficacy and toxicity of drug therapies for patients infected with Mycobacterium tuberculosis.

HISTORY AND INCIDENCE IN THE UNITED STATES

  1. Discuss the patient populations in whom M. tuberculosis is most problematic.

PATHOGENESIS AND NATURAL HISTORY

Although the genus mycobacterium includes may species, we will be concerned only with M. tuberculosis, the most prevalent species found to be pathogenic to normal human hosts.

Transmission

  1. Discuss the mechanisms via which microsize droplet nuclei transmit M. tuberculosis.

Primary Infection

  1. Define primary infection.
  2. Discuss the factors that determine progression of infection to clinical disease. Be aware that the majority (90%) of patients who experience primary infection have no further clinical manifestations except a positive PPD skin test with or without evidence of stable granulomas on CXR.

Influence of HIV Infection on Pathogenesis

Be aware that impaired CD4 lymphocyte activity increases the rate and extent of tuberculous infection, thus increasing the risk that a patient will develop active tuberculous disease.

EPIDEMIOLOGY

Risk Factors for Infection

Individuals exposed to patients with active pulmonary tuberculosis in closed environments are at high risk for becoming infected with M. tuberculosis

1. Discuss the specific patient populations who are at high risk of becoming infected with M. tuberculosis.

Risk Factors for Disease

1. Understand the difference between infection and clinical disease (active infection) with M. tuberculosis.

2. Know the specific group of immunocompromised patients at high risk of developing active tuberculosis.

DRUG RESISTANCE

Mechanisms

  1. Know the most common mode for the development of drug-resistant M. tuberculosis.
  2. Discuss the significance of drug-resistant M. tuberculosis.

Epidemiology of Resistance

  1. Define multi-drug resistant M. tuberculosis (MDR-TB).
  2. Discuss the means via which MDR-TB occurs.

CLINICAL PRESENTATION

Non-HIV-Infected Patients

  1. Discuss the clinical presentation of active M. tuberculosis infection in non-HIV-infected patients.

HIV-Infected Patients

  1. Compare and contrast the clinical presentation of active M. tuberculosis infection in HIV-infected vs non-HIV infected patients.

DIAGNOSIS/SCREENING

Identification of Individuals with Asymptomatic Infection

  1. Understand how the induration associated with a PPD skin test is formed.
  2. Discuss how the induration, not erythema of a PPD skin test is used to determine the need for prophylaxis against the development of active tuberculous infection.
  3. Be aware that HIV-infected patients are frequently anergic, thus a negative PPD skin test cannot rule out infection with M. tuberculosis.

Symptomatic Disease

1. Discuss tests that may be performed to confirm a clinical suspicion of active tuberculosis infection.

TREATMENT

Factors to Consider When Selecting Therapy

The general principle to heed when treating tuberculosis is: the greater the number of organisms present, the more likely are drug-resistant organisms to be found

  1. Discuss factors to consider when selecting therapy for M. tuberculosis infection.
  2. Discuss 3 subpopulations of mycobacteria postulated to exist in the body and the specific antimycobacterial drugs that are particularly active against these subpopulations of mycobacteria.
  3. Discuss the antimycobacterial therapy that is generally sufficient to treat asymptomatic infection due to sensitive organisms.
  4. Discuss the situation in which combination antimycobacterial therapy is used.

PHARMACOLOGY OF ANTITUBERCULAR AGENTS

Isoniazid

  1. Discuss the situations in which isoniazid may be used.
  2. Discuss the important adverse effects of isoniazid.
  3. Discuss the role of pyridoxine (vitamin B6) in the prevention of some of the adverse effects of isoniazid.

Rifampin

  1. Discuss the importance of including rifampin in the treatment of active disease.
  2. Discuss the frequent adverse effects of rifampin.
  3. Be aware of the multiple drug interactions associated with rifampin therapy, particularly with warfarin, protease inhibitors (refer to HIV Handouts by Dr. Diaz-Linares, section on "Anti-retroviral Agents"), oral contraceptives.

Pyrazinamide

  1. Discuss the importance of using pyrazinamide in the management of active disease.
  2. Be aware of the dose-dependent nature of hepatotoxicity associated with pyrazinamide.

Ethambutol

  1. Discuss the role of ethambutol in the management of active disease.
  2. Be aware of the major adverse effect of ethambutol, in particular, how this adverse effect is manifested and what the risk factors for this toxicity are.

Streptomycin

  1. Know that streptomycin (like ethambutol) is primarily used in situations when drug-resistance is suspected.
  2. Discuss the major side effects associated with streptomycin.

Quinolones

  1. Discuss the role of quinolones (ciprofloxacin, ofloxacin) in the management of active disease.
  2. Which quinolone is generally preferred?

Penicillin-beta-lactamase Inhibitors

  1. Be aware that this class of drugs is a therapeutic option.

Rifabutin

  1. Be aware of the similarity between rifabutin (primarily used in HIV-infected patients with Mycobacterium avium intracellularae infection) and rifampin; specifically the greater likelihood of developing rifampin-resistant M. tuberculosis in patients who have received rifabutin.
  2. Data are available regarding the efficacy of rifabutin as part of a combination regimen in patients with pulmonary tuberculosis (Am J Respir Crit Care Med 1996; 154:1462-67).

Prognosis

  1. List the factors that are important for the successful treatment of tuberculosis.

DRUG REGIMENS/FOLLOW-UP

Asymptomatic Infection

  1. Discuss the goal of therapy for patients with asymptomatic infection.
  2. Discuss the patient populations with asymptomatic infection in whom prophylaxis should be initiated.
  3. Discuss the rationale for use of the following chemoprophylactic regimens: isoniazid alone, rifampin alone, rifampin plus pyrazinamide or ethambutol, pyrazinamide plus ofloxacin.
  4. How should patients given chemoprophylaxis be monitored?

Symptomatic Disease, Culture-Positive, Resistance Unlikely

  1. Discuss the goals of therapy for patients with clinically active disease.
  2. Discuss the advantages of short course (6 months) chemotherapy with multiple drugs.
  3. Discuss the difference between drugs with "early bactericidal activity" and those that are referred to as "sterilizing."
  4. Discuss the situation in which ethambutol may be prescribed.
  5. Know what is meant by the "induction" and "continuation" phases of chemotherapy, including the goals of these two phases for short-course therapy and which drugs are commonly used during these phases.
  6. Be able to discuss the various drug regimens for patients with clinically active disease, including the advantages/disadvantages of one regimen over another.
  7. Discuss the therapeutic endpoints for patients treated with a short-course regimen.

Monitoring

The ATS (optional reading #1) recommends the following baseline tests: hepatic enzymes, bilirubin, serum creatinine, complete blood count; serum uric acid (if pyrazinamide is used), and examination of visual acuity and red-green color perception (if ethambutol is used). Patients should be seen at least monthly by a health care provider and specifically asked about symptoms related to efficacy of therapy, and possible side effects of drugs. Consideration should be given to discontinuing isoniazid if transaminases are 3-5 times above normal.

OTHER THERAPEUTIC ISSUES/SITUATIONS

Drug Resistance Likely or Suspected

  1. Discuss the likely difference in drug-susceptibility patterns of M. tuberculosis in patients in who have a relapse of their disease vs patients who fail during therapy.
  2. Discuss the patient populations in whom drug-resistance should be suspected.

"Unreliable Patient"

  1. Discuss the advantages of DOT (directly observed therapy).

HIV Infected

  1. Discuss the therapeutic regimens generally used in HIV-infected patients.
  2. Be aware that HIV-infected patients frequently are on medications that interact with rifampin, e.g., protease inhibitors, itraconazole (refer to HIV handouts by Dr. Diaz-Linares).

Case 1.

CC: shortness of breath, coughing up blood, weight loss, decreased appetite, fatigue, night sweats, on and off fevers; all symptoms present for 3 months.

HPI: AB is a 26 year old female with no significant past medical history who presents with the above complaints. She has not sought medical attention for these problems. Instead, she has intermittently taken over the counter cough suppressants, vitamins, and acetaminophen to alleviate the various symptoms. She attributes her weight loss of 20 pounds over the last 3 months to a decrease in appetite. She has taken much time off from her work as a volunteer at a shelter for the homeless; a job she has had for the past year.

PMH: None.

SH: married with no children. Her husband is well and without similar symptoms.

MEDICATIONS: oral contraceptives, over the counter medications as above.

ALLERGIES: None.

PE: temp 101 degrees Fahrenheit; pulse 90; B/P 120/85; RR 30; weight 60kg; height 5 feet, 6 inches

Heent: pale conjunctiva

Chest: dullness to chest percussion

Extremities: clubbing of digits

CXR: patchy infiltrates of the apices of the lungs

Labs: arterial blood gas PO2 = reduced; serum electrolytes, creatinine are normal; CBC with differential is normal except for a hemoglobin of 10gm/dl.

1. What is your assessment (problem list and possible cause(s) for each problem). Providing subjective and objective data to support each problem is helpful when preparing your assessment of the patient.

This is a previously healthy female whose main subjective complaints are related to the respiratory tract (see chief complaints). Objective data supporting on her physical exam supporting a problem in the respiratory tract include dullness to chest percussion and clubbing of the fingers; the latter is suggestive of impaired oxygenation (see DiPiro’s text ). Hemoptysis is consistent with lung pathology. Objective lab data also confirm problems related to the respiratory tract -- decreased oxygenation, abnormal CXR. Fever should prompt a search for an infectious etiology for her respiratory complaints. Fatigue and shortness of breath are likely related to her low hemoglobin and chronic illness affecting the respiratory tract; the low hemoglobin is consistent with pale conjunctiva.

2. Discuss the possible microbiologic etiologies for this patient’s respiratory complaints. Be able to support your answer using the available data from the patient’s history and clinical data.

The complaints related to the respiratory tract could be related to a community-acquired pneumonia caused by bacterial, viral, fungal, or mycobacterial causes. The prolonged course of symptoms would suggest fungal or mycobacterial etiologies. She has no prior medical history but her contact with homeless individuals at the shelter puts her at risk for infection with M. tuberculosis (review risk factors for infection with M. tuberculosis).

3. Based on the above discussion, what would you do for the patient?

Since active tuberculosis is highly suspected, routine management should include respiratory isolation, obtain 3 sputa for analysis of acid-fast bacilli (other potential pathogens such as bacterial and fungal organisms are also usually tested for), place a PPD skin test, and initiate therapy for active pulmonary infection with M. tuberculosis. If significant pathogens are isolated, susceptibility testing should also be performed as necessary.

4. Discuss a therapeutic regimen you would initiate in this patient.

Selection of drugs should include a consideration of the likelihood of drug-resistant tuberculosis and potential for drug toxicities.

Information that would influence the selection of a drug regimen include the prevalence of isoniazid-resistance, if >4% in the community, a four drug regimen including ethambutol or streptomycin is recommended (ATS guidelines, optional reading #1). A reasonable empiric regimen would be rifampin, isoniazid, pyrazinamide, vitamin B6 (pyridoxine) + ethambutol or streptomycin, if isoniazid resistance is >4% (see DiPiro’s text for doses of drugs).

It would be prudent to investigate if there has been an outbreak of tuberculosis at the shelter, and if there was an outbreak, obtain information on the susceptibility of the isolate involved. Until susceptibility data are available, it is possible that this patient could be infected with the same isolate involved in the shelter outbreak.

5. Are there additional lab data you would order for this patient?

Baseline lab tests not previously obtained as discussed in handout (see section in handout on "Symptomatic disease, Culture-Positive, Resistance Unlikely").

6. Are there any contraindications or precautions that you would discuss with the physician/patient if the patient is initiated on the four drug regimen of rifampin, isoniazid with pyridoxine, pyrazinamide, and ethambutol?

Rifampin is well known to be involved in many significant drug-interactions. Anytime you recommend use of this agent, you should look up possible drug interactions in appropriate references. In this case, the efficacy of oral contraceptives can be compromised, and the patient should be advised to use other methods of contraception.

7. What is the purpose of basing the doses of antituberculous drugs on the patient’s body weight?

In general, to minimize the risk of drug toxicities (review text for details on dose-dependent drug toxicities).

8. What are the goals of your therapy?

Review section on "Symptomatic Disease, Culture Positive, Resistance Unlikely."

9. What is the purpose of initiating a multidrug regimen?

The patient has active infection (review section on "Factors to consider When Selecting Therapy").

10. Culture and susceptibility data reveal that this patient’s isolate is susceptible to all anti-tubercular drugs including rifampin, isoniazid, pyrazinamide, and ethambutol. Do these results alter your initial antituberculous recommendations?

Assuming a good response to her current regimen, any of the regimens listed in Table 105.8 of DiPiro’s would be acceptable. If the patient is compliant, the patient is likely to be prescribed a short-course regimen (6 months total). Since her isolate does not demonstrate resistance, ethambutol can be discontinued, she should complete 2 months of isoniazid, rifampin, and pyrazinamide; followed by 4 months of isoniazid and rifampin.

If she is non-compliant, she should be enrolled in a DOT program.

11. Could this case of active tuberculosis have been prevented?

Yes. Because she is exposed to people at risk for having tuberculosis, screening for tuberculous infection with a PPD skin test could have detected her infection during the asymptomatic phase, at which point she could have received preventive therapy with isoniazid alone (review indications for preventive therapy in patients with asymtomatic infection).

 

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