# Presentation: 619686

## TUBERCULOSIS TREATMENT

-    Prompt and efficient treatment of active tuberculosis is a key element in the prevention of spread of TB infection.

**Notes:**
This is the prompt slide for the TB Therapy section.

This presentation will be presented at the local level by an Infectious Disease Practitioner or Pulmonary TB Control Officer.  The Objectives of this presentation are to provide the attendees an understanding of the therapies used to treat TB and adverse events.  The presentation is scheduled to be 30 minutes to include time for questions to be asked.  Answers to some questions during the sessions may not be possible (time limitations or technical clarification needed).  In such cases the speaker should request that the attendees write the question down and provide their FAX number, so that an answer to their question can be provided later.
The opening statement should emphasize that prompt and efficient treatment of active tuberculosis is a key element in the prevention of spread of TB infection.

## TB TREATMENT PLANACET (CDC, ATS)

- For + culture do susceptibilities and
-      report results to Health Department
- Initial trtmt. = 4 drugs; at least 2 mon.
-      INH, RIF, PZA, EMB or SM (unless
-      likelihood of INH resistance almost
-      non-existent)
- Adjust Rx when susceptibilities known
- DOT

**Notes:**
This defines initial treatment. 
The abbreviations are as follows: CDC = Centers for Disease Control and Prevention, ACET = Advisory Council for the Elimination of Tuberculosis, ATS = American Thoracic Society, INH = isoniazid, RIF = rifampin, PZA = pyrazinamide, EMB = ethambutol, SM = streptomycin, and DOT = directly observed therapy.
A study by Burman et al published in Chest July, 1997 addressed the cost of DOT versus self-administered therapy by pointing out that “despite a greater initial cost, DOT is a more cost-effective strategy because it achieves a higher cure rate after initial therapy, and thereby decreases treatment costs associated with failure of therapy and acquired drug resistance”.

## TREATMENT OPTION 1

-    _Initial Phase_:
- Daily INH, RIF, PZA & either EMB or
-      SM X 8 wks
- May D/C EMB or SM if _M_. _tb_ is
-      susceptible to INH & RIF
- EMB or SM may not be necessary in
-       areas with documented INH
-       resistance <4%

**Notes:**
The potential for isoniazid or rifampin resistance in an individual patient is related to the location where the patient likely acquired the disease.  For instance, a patient seen in the upper Midwest who lives in New York City for most of the year has a greater potential for antitubercular drug resistance than a person who has not left the Midwest.

## TREATMENT OPTION 1(Continued)

-   _Continuation Phase_:
- INH & RIF X 16 wks QD, 2 X wkly
-     or 3 X wkly
- All regimens given 2 X wkly or 3 X
-     wkly should be given by DOT

**Notes:**
(No provided text)

## TREATMENT OPTION 2

- _Initial Phase_:
- 	  INH, RIF, PZA & either EMB or SM
-      QD X 2 wks, then 2 X wkly X 6
-      wks
- _Continuation Phase_:
- 	  INH & RIF 2 X wkly for 16 wks

**Notes:**
This regimen decreases the time for daily dosing, but again should then be given by directly observed therapy. 

## TREATMENT OPTION 3

- Treat with DOT 3 X wkly with INH, RIF, PZA, EMB or SM X 6 months
- Strong evidence from clinical trials to be effective
- Weaker evidence to D/C SM after 4 months if isolate drugs susceptible to all drugs
- D/C PZA before 6 months is equivocal for 3 X wk regimen
- No evidence of effectiveness of this regimen with EMB <6 months

**Notes:**
This regimen eliminates any daily dosing but requires long term streptomycin and ethambutol both of which have substantial toxicity.
Note: the issue of treatment of TB in the setting of HIV infection is discussed by Dr. Benator.

## ISONIAZIDAdverse Reactions

-  Hepatitis
-  Peripheral neuropathy
-  Lupus

**Notes:**
Hepatitis is a particular problem if doing mass PPD skin test screening and preventive therapy in low risk groups since there would be the probability of risking hepatitis in people with false positive PPD skin tests.

## INH ASSOCIATED HEPATITISNew York 1991 - 1993

- Ten cases for liver biopsy
- Eight on INH alone
- Six (75%) female
- Median age 33
- Three people _<_ 20 years

**Notes:**
This was presented by Halpern in JAMA 1993 and was also in a 1993 MMWR.  The data are from a New York transplant registry.  There were seven (7) cases from center A, two (2) from center B, and one (1) from Center C.  The ages ranged from 5 to 58 years of age.  Five (5) had liver transplantation (four (4) were alive and well), three (3) died awaiting transplantation.  Of the ten, six were females (three black and three Hispanic) raising the question as to whether women of color are more at risk than others.

The Food and Drug Administration has noted the following: Special Precautions for Isoniazid Therapy in Minority Women: The product labeling for all isoniazid formulations is being revised to strengthen precautionary language regarding the risk of isoniazid-associated fatal hepatitis in minority women.  The new language in the warning box for these products states that “a recent report suggests an increased risk of fatal hepatitis associated with isoniazid among women particularly black and Hispanic women.  The risk also may be increased during the postpartum period.  More careful monitoring should be considered in these groups, possibly including more frequent laboratory monitoring.”   The labeling revision was prompted by information in a joint statement on treatment of tuberculosis and tuberculosis infection in adults in children by the American Thoracic Society and the Centers for Disease Control and Prevention (Am J Respir Crit Care Med. 1994;149:1359) and by a review of relevant reports to FDA’s MEDWATCH spontaneous reporting system.  A total of 101 cases of isoniazid-associated fatal hepatitis have been reported through FDA’s reporting system during the period 1969 to 1996.  In 1995 and 1996, there were 3 reported cases of fatal hepatitis in minority women of childbearing age receiving isoniazid for preventive therapy; 1 of the women was stated to be postpartum.  Reports of serious and unexpected adverse events should be made to FDA’s MEDWATCH program at (800) FDA-1088.  MEDWATCH forms may also be faxed to (800) FDA-1078.

The U.S. Food and Drug Administration recently published a brief notice in the Journal of the American Medical Association (JAMA 1997;277[21]:1664) about a change in product labeling for isoniazid to strengthen the warning about isoniazid-associated hepatitis mortality.

## ISONIAZIDMonitoring

-  Liver function tests
-  Clinical signs of hepatic
-       toxicity
-  CBC
-  Numbness/tingling of
-       extremities

**Notes:**
(No provided text)

## ISONIAZIDDrug Interactions

-    Alcohol, Phenytoin, Disulfiram, Aluminum Salts, Carbamazepine, Benzodiazepines, Anticoagulants, and Ketoconazole

**Notes:**
It is necessary to take a thorough medication history before initiating isoniazid therapy.

## RIFAMPINAdverse Reactions

-  Hepatitis
-  Orange discoloration of
-      secretions
-  Drug interactions
-  Immunologic mediated
-      illness

**Notes:**
Be sure patient understands the orange coloration of secretions as this can be quite alarming to patients if they have not been forewarned.  Immunologic mediated illness is a flu-like syndrome most prominent in people on twice a week dosing. 

## RIFAMPINMonitoring

-  Liver function tests
-  Clinical signs of hepatic
-      toxicity
-  CBC, platelets, serum
-      creatinine, bilirubin
-  Bleeding abnormalities

**Notes:**
(No provided text)

## RIFAMPINDrug Interactions

-    Warfarin, Digoxin, Beta-blockers, Ketoconazole, Verapamil, Quinidine, Methadone, Phenytoin, Corticosteroids, Oral Contraceptives, Dapsone, Theophylline, Sulfonylureas, Cyclosporine, Protease Inhibitors

**Notes:**
It is necessary to take a thorough medication history before initiating rifampin therapy.
Note: The issue of protease inhibitors is discussed by Dr. Benator.

## ETHAMBUTOLAdverse Reactions

-  Gout
-  Rash
-  Peripheral neuritis

**Notes:**
(No provided text)

## ETHAMBUTOLAdverse Reactions

- Optic neuritis
-  Central fibers of optic nerve decreased
-       visual acuity central scotoma
- 		 green/red vision loss
-  Peripheral fibers of optic nerve decreased
-       peripheral vision no loss of visual acuity
-       rare

**Notes:**
Usually the patient notices a change in visual acuity or a “hole” in the central visual field.

Onset of symptoms may be sudden, such as overnight, though usually over days to weeks.

## ETHAMBUTOLOptic Neuritis

-  May be time & dose dependent
-  Rate reported at 0.8 - 6% at
-      accepted doses
-  At 30-40 mg/kg/d - rate may be
-      up to 33%
-  Visual loss may be irreversible

**Notes:**
(No provided text)

## ETHAMBUTOLOptic Neuritis (Continued)

-  May occur despite proper dose &
-       visual monitoring
-  May be delayed (months) or rapid
-       onset (days) after start of EMB
-  Role of zinc debated
-  May increase risk of optic neuritis if
-       zinc levels <0.7 mg/l

**Notes:**
(No provided text)

## GUIDELINES BY THE JOINT TUBERCULOSIS COMMITTEE FOR PATIENTS ON EMB THERAPY

- Determine pretreatment renal function
- Recommended dose and duration should not be exceeded
- Record any history of eye disease
- Pretreatment record of Snellen visual acuity should be made.  Avoid EMB in patients with significantly reduced vision who may not notice further deterioration of vision

**Notes:**
Guidelines by the Joint Tuberculosis Committee for patients on ethambutol therapy were cited by Russo PA, Chaglasian MA. Toxic Optic Neuropathy Associated with Ethambutol: Implications for Current Therapy. J. Amer. Optometric Assoc., May 1994; 65;5, 332-38.

## GUIDELINES BY THE JOINT TUBERCULOSIS COMMITTEE FOR PATIENTS ON EMB THERAPY (Continued)

- The patient should be told that EMB may affect vision and the drug should be stopped immediately if vision is further impaired.  To guard against noncompliance, explain the small risk of this happening
- Document that the patient has been informed about the risk of ocular toxicity with EMB

**Notes:**
(No provided text)

## GUIDELINES BY THE JOINT TUBERCULOSIS COMMITTEE FOR PATIENTS ON EMB THERAPY (Continued)

- Patients complaining of ocular disturbances during therapy should be referred for a detailed ocular examination.  EMB should be discontinued pending this examination
- Routine visual acuity testing during treatment generally is not helpful in screening for ocular toxicity
- Avoid EMB in patients with language or communication problems

**Notes:**
Be certain that patient knows to stop the drug immediately if change in vision occurs since access to care may be delayed. 
The patient’s desire for compliance with the drug regime could be a problem here.

## ETHAMBUTOLMonitoring

-  Visual acuity
-  Uric acid levels

**Notes:**
Monitoring of visual acuity may best be accomplished thought education of the patient concerning ocular toxicity and to have the patient monitor their vision and report to the physician immediately any visual changes and stop the medication until they are reevaluated by the physician. 

## ETHAMBUTOLDrug Interaction

- Aluminum salts

**Notes:**
(No provided text)

## PYRAZINAMIDEAdverse Reactions

-  Hepatitis
-  Gout

**Notes:**
(No provided text)

## PYRAZINAMIDEMonitoring

-  Liver function tests
-  Clinical signs of hepatic
-     toxicity
-  Uric acid levels

**Notes:**
(No provided text)

## STREPTOMYCINAdverse Reactions

-  Auditory
-  Vestibular
-  Nephrotoxicity
-  Hypersensitivity

**Notes:**
(No provided text)

## STREPTOMYCINMonitoring

- Signs of Ototoxicity
-  Vertigo
-  Ataxia
-  Hearing Loss

**Notes:**
(No provided text)

## STREPTOMYCINDrug Interactions

-  Loop diuretics
-  Neuromuscular blockers

**Notes:**
Loop diuretics may enhanse the nephrotoxicity of streptomycin.
Streptomycin may escalate the effects of neuromuscular blockers and worsen the the condition of patients with certain neuromuscular diseases.

## ON THE LOCAL LEVEL

-  Who treats TB here?
-  Who interacts with Health Dept.
-      here?
-  Who officially reports TB to Health
-      Dept.?
-  How is DOT arranged here?
-  Who has follow-up responsibility for
-      TB patients locally?

**Notes:**
The local presenter should answer these questions using the methods available at the local facility to address or handle each issue.