Georgia tuberculosis reference guide

Dear Clinician,

September 2001

This booklet responds to clinicians questions about tuberculosis infection, disease, and control. The standards and guidelines are based on the work and experience of the American Thoracic Society, the Centers for Disease Control and Prevention, the Infectious Disease Society of America, the New York City Department of Health, and the Atlanta TB Prevention Coalition. This edition contains updated recommendations on the treatment of latent tuberculosis infection.

The treatment of a patient with TB always requires a clinician to exercise clinical and professional judgment. These guidelines provide a framework for the treatment of patients with TB infection or disease. Standardized treatment offers the greatest opportunity for controlling tuberculosis.

This is not an exhaustive treatment of the subjects covered. It is an accessible reference guide. Since guidelines for treating and controlling TB continue to evolve, it is appropriate for clinicians to check further for new treatment regimens.

Detailed information is available from: Your county public health department Georgia Division of Public Health: 404-657-2634 Atlanta TB Prevention Coalition: 404-616-6145

Sincerely,

Henry M. Blumberg, M.D.
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Grady Memorial Hospital, and The Atlanta TB Prevention Coalition

Naomi Bock, M.D., M.S.
Medical Consultant Georgia Department of Human Resources

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Acknowledgment
This booklet has been updated from the previous versions of the Georgia TB Reference Guide and was initially adapted from Tuberculosis at a Glance, A Reference Guide for Practitioners Covering the Basic Elements of Tuberculosis Care, designed and produced by the New York City Department of Health, Bureau of Tuberculosis Control. The Atlanta Tuberculosis Prevention Coalition gratefully acknowledges permission to draw on the content and design of the New York booklet and on the Treatment of Latent Tuberculosis Infection handout produced by the Charles P. Felton National Tuberculosis Center at Harlem Hospital. We also extend a special thanks to Jane Tapia, RN, for editorial assistance and to Rose Sales, MD, for epidemiology consultation.

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Atlanta Tuberculosis Prevention Coalition
American Lung Association of Georgia Centers for Disease Control and Prevention
DeKalb County Board of Health Emory University School of Medicine and Public Health
Fulton County Health and Wellness Center Georgia Department of Corrections
Georgia Department of Human Resources/Division of Public Health Georgia Infection Control Network Grady Health System Mercy Mobile Health Care Morehouse School of Medicine

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Table of Contents
I. Classification System for Tuberculosis ...................... 1
II. Epidemiology of Tuberculosis ................................. 2 Worldwide .............................................................. 2 United States .......................................................... 2 State of Georgia ...................................................... 4 City of Atlanta ........................................................ 4 Trends in TB, 1992-2000 ....................................... 5
III. Tuberculin Skin Testing .............................................. 6 A. Administering and Reading the Skin Test .............. 6 B. Criteria for Tuberculin Positivity ........................... 8 C. Chest Radiography ................................................. 9 D. Anergy Testing ..................................................... 10 E. Two Step Testing (Booster) .................................. 10
IV. Treatment of Latent TB Infection ............................ 11 A. Candidates for Treatment of LTBI ....................... 12 B. Recommended Drug Regimens for Treatment of LTBI in Adults ................................ 14 C. Monitoring of Patients on Treatment for LTBI .... 16 D. Contacts of MDR-TB Cases ................................. 18 Public Health Service Rating System ................... 20
V. Current TB Disease Therapy ................................... 22 A. Considerations ...................................................... 22 B. Standard Daily Therapy ....................................... 23 C. Drug Resistance or Drug Intolerance ................... 26 D. Dose Counting ...................................................... 30 E. Regiment Options ................................................. 31 Dosage in Renal Impairment ................................ 34

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F. Drug Resistance ................................................ 36 G. Drug Monitoring ............................................... 37 H. TB and HIV ...................................................... 39 I. Antiretroviral Therapy & Treatment of HIV .... 42 J. Paradoxical/Immune Reconstitution Reactions 47 K. Extrapulmonary TB .......................................... 49 L. Corticosteroid Therapy ..................................... 50
VI. Pregnancy ............................................................... 51 A. Preventive Therapy and Risk Factors ............... 51 B. Treatment of TB in Pregnancy .......................... 51
VII. Childhood Tuberculosis ......................................... 53
VIII. Tuberculosis and Nursing Homes ......................... 57
IX. BCG Vaccination .................................................... 58
X. TB Infection Control in Hospitals ........................ 60 A. Administrative Controls .................................... 60 B. Surveillance for Health Care Workers .............. 60 Grady Hospital TB Isolation Policy ................. 61 C. Engineering Controls ........................................ 62 D. Personal Respirator Protection ......................... 62
XI. Community Tuberculosis Control ........................ 62 A. Reporting Requirements ................................... 62 B. Role of the Health Department ......................... 62 C. Grady Hospital TB Discharge Policy ............... 64
XII. DHR Community Guidelines for Respiratory Isolation of TB Patients .................... 68
XIII. References ............................................................... 71

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ABBREVIATIONS

AFB: BCG: CAP: CBC: CNS: CXR: DOPT: DOT: DTH: EMB: HIV: IM: INH: IV: KM: LFT: LTBI: MDR: NRTI: NNRTI: PAS: PI: PO: PPD: PZA: RFB: RIF: SM: TU:

Acid-Fast Bacilli Bacillus Calmette-Guerin Capreomycin Complete Blood Count Central Nervous System Chest X-Ray Directly Observed Preventive Therapy Directly Observed Therapy Delayed-Type Hypersensitivity Ethambutol Human Immunodeficiency Virus Intramuscular Isoniazid Intravenous Kanamycin Liver Function Test Latent Tuberculosis Infection Multidrug Resistant Nucleoside Reverse Transcriptase Inhibitor Non-nucleoside Reverse Transcriptase Inhibitor Para-aminosalicylic Acid Protease Inhibitor Per os (Oral) Purified Protein Derivative Pyrazinamide Rifabutin Rifampin Streptomycin Tuberculin Unit

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I. Classification System for Tuberculosis

Class O: No TB Exposure--Not Infected No history of exposure. Negative reaction to the tuberculin skin test.

Class I: TB Exposure--No Evidence of Infection History of exposure (contact to a case of TB) and negative reaction to the tuberculin skin test.

Class II: TB Infection--No Disease Positive reaction to the tuberculin skin test, no clinical or radiographic evidence of TB, and/or negative bacteriologic studies (if done).

Class III: Current TB Disease M. tuberculosis cultured (if done), or both a positive reaction to tuberculin skin test and clinical or radiographic evidence of current disease.

Class IV: Previous TB Disease History of episode(s) of TB, or abnormal but stable radiographic findings, positive reaction to the tuberculin skin test, negative bacteriologic studies (if done) and no clinical or radiographic evidence of current disease.

Class V: TB Suspected Diagnosis pending. Patient should not remain in this category for more than three months.

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II. Epidemiology



Worldwide, TB is the second leading cause of death

due to an infectious disease. HIV is number one. TB

is also the main cause of death in persons with HIV/

AIDS worldwide (although not in the United States).



The World Health Organization (WHO) estimates that

there are more than 8 million new cases of TB disease

and more than 2 million deaths due to TB each year.



One-third of the world's population harbors Myco-

bacterium tuberculosis (i.e., TB infection) and

therefore is at risk for developing active disease.



The interaction between the TB epidemic and the

HIV/AIDS epidemic is lethal. TB adds to the burden

of illness of HIV-infected people and shortens their

life expectancy, while the HIV epidemic spurs the

spread of TB.



In the United States there was a resurgence of TB

from 1985 to 1992. The number of cases increased

20% during this time period, peaking in 1992 with

26,673 cases reported. The increased case numbers

have been attributed to the HIV epidemic, decreased

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funding for public health, immigration from countries where TB is endemic, and transmission of TB in congregate settings such as hospitals, correctional institutions and homeless shelters.



From 1992 until 2000, there has been a 39% decrease

in the number of cases in the U.S., as TB control was

strengthened nationally. In 2000, there were 16,377

cases reported, ( 5.8 per 100,000 population).



TB is not evenly distributed among the US popula-

tion. Cases occur disproportionately in urban areas,

in conditions of poverty and over-crowding, and

among racial and ethnic minorities. 46% of U.S. cases

in 2000 occurred among foreign-born persons(< 25%

in Georgia).



The average lifetime risk of developing active TB

following TB infection, if no treatment of latent TB

infection is received, is 10%: 5% in the first two years

after tuberculin skin test conversion (new infection)

and 5% in the remaining lifetime. UNAIDS estimates

that persons infected with both TB and HIV are 30 to

50 times more likely to develop TB disease than those

infected with TB but who do not have HIV infection

(10% per year risk in HIV+ patients with LTBI).

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The state of Georgia has had TB rates higher than the

US average for the last quarter of a century. In 2000,

Georgia had 703 cases, and was one of only three

US states that had an increase in cases.



The city of Atlanta has rates of TB more than

five (5) times the national average.



About one-half of TB cases in the state occurred in

the 8-county metropolitan Atlanta area, and about

one-half in the remainder of the state (see Figure).

Number of TB Cases City of Atlanta, Metro Atlanta*, Georgia,
1992-2000

*8 county metropolitan Atlanta

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III. Tuberculin Skin Testing Mantoux tuberculin skin testing is the standard
method of identifying persons infected with M. tuberculosis. Multiple puncture tests (Tine and Heaf) should not be used. Tuberculin skin tests should be administered and read by trained healthcare personnel.
A. Administering and Reading the Skin Test The skin test is administered by injecting 0.1 ml of 5
tuberculin units (TU) of PPD into the dorsal or volar surface of the forearm. The injection is made with a disposable tuberculin syringe, with the needle facing upward and placed just under the surface of the skin, so that a discrete, pale elevation of the skin (a wheal) 6 mm to 10 mm in diameter is produced.
Needles should not be recapped, purposely bent or broken, removed from disposable syringes, or otherwise manipulated by hand. Dispose of needles and syringes in puncture-resistant containers. Follow standard (universal) precautions for infection control.
Tests should be read 48 to 72 hours after administration. If test reading is delayed, a positive reaction may still be measurable up to one week after testing. A test cannot be read as negative if more than 72 hours have passed since it was placed.

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The transverse diameter of palpable induration should be measured and recorded in millimeters. If no induration is present, record "0 mm". Do not measure erythema (redness).
Tuberculin skin testing is not contraindicated for persons who have been vaccinated with BCG, although no method can reliably distinguish tuberculin reactions caused by vaccination with BCG from those caused by natural mycobacterial infections. A positive test with BCG-vaccinated persons indicates infection with M. tuberculosis when the person tested is at increased risk for recent infection or has medical conditions that increase the risk for disease (Section IV, B).

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B. Criteria for Tuberculin Positivity, by Risk Group
Reaction > 5 mm of induration
Human immunodeficiency virus (HIV)- positive persons
Recent contacts of infectious TB case
Fibrous changes on chest radiograph consistant with prior
TB
Patients with organ transplants and other immunosupressed
patients (receiving the equivalent of > 15 mg/d of prednisone for 1 mo or more)

Reaction > 10 mm of induration
Recent immigrants (within the last 5 yrs) from high preva-
lence countries
Injecting drug users
Residents and employees of the following high-risk congre-
gate settings: prisons and jails, nursing homes, hospitals, residential facilities for persons with HIV/AIDS and homeless shelters
Mycobacterial laboratory personnel

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Persons with the following clinical conditions that place them
at risk of progression from, infection to disease: silicosis, diabetes, chronic renal failure, leukemias and lymphomas, carcinoma of the head, neck or lung, weight loss of > 10% of ideal body weight, gastrectomy, and jejunoilleal bypass
Children younger than 4 yrs of age or infants, children, and
adolescents exposed to adults at high-risk
Recent conversion ( increase of > 10 mm of induration
within the past 2 years)

Reaction of > 15 mm of induration
Persons with no risk factors for TB
Persons who are otherwise at low risk and are tested at
the start of employment, a reaction of > 15 mm is considered positive

C. Chest radiography Persons with a newly documented positive tuberculin
skin test should have a chest x-ray performed to assure that they do not have active tuberculosis disease. After an initial negative chest x-ray, no routine follow-up chest x-rays are necessary. Persons with a positive tuberculin skin test should be educated about the signs and symptoms of TB disease and instructed to consult with a physician if these symptoms occur.

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D. Anergy Testing Anergy testing is not recommended for routine use in
persons who are infected with HIV or otherwise immunocompromised. Factors limiting the usefulness of anergy skin testing include problems with the standardization and reproducibility, the low risk for TB disease associated with a diagnosis of anergy, and the lack of apparent benefit of treatment of LTBI for groups of anergic HIVinfected persons. Recommendations for treatment of LTBI in some persons with negative tuberculin skin tests, regardless of anergy test results, are outlined in Section IV.

E. Two Step Testing and the Booster Reaction In some people (especially individuals > 50 years) with
LTBI, delayed-type hypersensitivity reactions to tuberculin may wane over the years. When skin-tested years after infection occurred, these persons may have a negative reaction. However, this test may stimulate (boost) their ability to react to subsequent tuberculin testing, causing a positive reaction to subsequent tests. The boosted reaction represents a true positive result, but not a true conversion due to recent infection. Two-step testing is used to distinguish boosted reactions and reactions due to new infection.
Two step testing is recommended for employees or residents in high-risk congregate settings (such as some health care or correctional institution employees) who will undergo routine, serial tuberculin screening, and for whom it is important to distinguish between new infection and boosted reaction from past infection.

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Two Step Testing
1. Place the first test with 0.1 ml (5 TU) of tuberculin. 2. If the reaction to the first test is negative, give a
second test with the same dose and strength of tuberculin, 1-3 weeks later. (If the reaction to the first test is positive, consider the person infected and there is no need for a second test.) 3. If the second test is positive, consider the person infected. 4. If the second test is negative, consider the person uninfected. 5. Individuals who have a positive reaction to either test require a follow-up evaluation with chest x-ray. 6. For individuals who undergo annual or semi-annual tuberculin testing, two-step testing in required for only the first test, to establish a negative test. Subsequent tuberculin testing should be only one test.

IV. Treatment of Latent TB Infection (LTBI)
The purpose of targeted testing is to find and treat persons who have both LTBI and high risk for TB disease (e.g., recent exposure to an infectious case). Persons at low risk for developing TB and who have had a TST for other reasons, such as a baseline TST of health-care workers, are not necessarily candidates for treatment if found to be infected.

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A. Candidates for Treatment of LTBI

CATEGORY OF PERSON TESTED Child < 5 years and recent contact* HIV-infected and recent contact* Immunosuppressed and recent contact* HIV-infected Immunosuppressed persons Recent contact of TB case Fibrotic changes on chest X-ray Recent arrival from endemic country Injection drug user Resident/Employee institutional setting Mycobacteria lab personnel High-risk clinical conditions Child < 5 years Persons < 18 exposed to high-risk adults No risk factors (TST discouraged)

TST < 5 mm TREAT TREAT TREAT
Do Not Treat Do Not Treat Do Not Treat Do Not Treat Do Not Treat Do Not Treat Do Not Treat Do Not Treat Do Not Treat Do Not Treat Do Not Treat Do Not Treat

* Recent contacts of an active TB case who are initially TST-negative should have TST repeated 12 weeks after last exposure to TB Case. Treatment can be discontinued after second negative TST in children. Silicosis, diabetes mellitus, chronic renal failure, some hematologic disorders (e.g. leukemias and lymphomas), other specific malignancies (e.g. carcinoma of the head and neck or lung), weight loss of >10% ideal body weight, gastrectomy, jejunoileal bypass.

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NOTE: CXR MUST RULE OUT ACTIVE DISEASE BEFORE BEGINNING TREATMENT FOR LTBI

TST > 5 mm

TST > 10 mm

TST > 15 mm

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

TREAT

Do Not Treat

TREAT

TREAT

Do Not Treat

TREAT

TREAT

Do Not Treat

TREAT

TREAT

Do Not Treat

TREAT

TREAT

Do Not Treat

TREAT

TREAT

Do Not Treat

TREAT

TREAT

Do Not Treat

TREAT

TREAT

Do Not Treat

Do Not Treat Consider Treatment**

Pregnancy: Treat during pregnancy if either HIV-infected or recent M. tb infection. Contraindications to treatment of LTBI include: INH - history of INHinduced severe hepatitis, rash, neuropathy or presence of severe liver disease; RIF/PZA - presence of severe liver disease or history of prior INH hepatotoxicity. ** See section A, page 11.

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B. Recommended Drug Regimens for Treatment of LTBI in Adults

Drug Interval and Duration

Adult Dosage (maximum)

INH* Daily for 9 mos. 5 mg/kg (300 mg)

Twice-weekly for 15 mg/kg (900 mg) 9 mos.

INH* Daily for 6 mos. 5 mg/kg (300 mg)

Twice-weekly for 15 mg/kg (900 mg) 6 mos.

RIF plus PZA

Daily for 2 mos.

RIF 10 mg/kg (600 mg) PZA 15-20 mg/kg (2.0 gm)

RIF Daily for 4 mos. 10 mg/kg (600 mg)

Criteria for Completion

Comments

270 doses within 12 mos. 76 doses within 12 mos.

Preferred regimen for all persons. In HIV-infected patients, INH may be administered concurrently with NRTIs, protease inhibitors, or NNRTIs.
DOT must be used with twice-weekly dosing.

Offer if preferred or alternate regimens not feasible.
180 doses within 9 mos. Not indicated for persons with HIV infection or fibrotic
lesions. Not indicated for children.
52 doses within 9 mos. DOT must be used with twice-weekly dosing.

60 doses within 3 mos.

Alternate regimen for adults (not in children, pregnancy, renal failure) when completion of longer treatment courses is unlikely and when the patient can be monitored closely. Use caution, especially in patients concurrently taking other medications associated with liver injury and those with alcoholism, even if alcohol use is discontinued during treatment. Not recommended for persons with underlying liver disease or for those who have had INH-associated liver injury.

120 doses within 6 mos. For persons who cannot tolerate PZA. For persons who are contacts of patients with INH-resistant, RIF susceptible TB.

Abbreviations: INH=isoniazid, RIF=rifampin, PZA=pyrazinamide, NRTIs=nucleoside reverse transcriptase inhibitors, NNRTIs=non-nucleoside reverse transcriptase inhibitors, DOT=directly observed therapy, mos.=months Pregnancy: INH regimens preferred for pregnant woman. Some experts would use RIF plus PZA as alternate regimen in HIV-infected pregnant women. PZA should be avoided during first trimester.

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Children: The only recommended treatment regimen for LTBI in children is INH for 9 months, daily 10 mg/kg or twice-weekly 20-40 mg/kg by DOT. HIV-infected children, but not others, should have routine minitoring of liver enzymes and should receive pyridoxine (vitamin B6) supplementation. *Pyridoxine (vitamin B6) should be used (25 mg daily or 50 mg twice-weekly) with INH for adults.

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C. Monitoring of Patients on Treatment for LTBI For all patients: Initial clinical evaluation Follow-up clinical evaulations at least monthly if receiving INH or RIF alone; at 2, 4, 6, and 8 weeks if receiving RIF and PZA Include careful questioning about side effects and a brief physicial examination checking for evidence of hepatitis or other side effects Educate patients about side effects associated with LTBI treatment Advise to stop treatment and promptly seek medical evaluation if these occur If side effects occur, evaluate promptly and change treatment as indicated Laboratory monitoring for patients receiving RIF and PZA should include AST and biliru bin at baseline and 2, 4, and 6 weeks. CDC guidelines state routine monthly monitoring of liver function tests not generally indicated with INH or RIF-only treatment. Consider baseline and 4 week AST in adults. In the absence of liver disease, children on LTBI do not need AST monthly monitoring.

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Indications for regular monitoring of LFTs: All patients receiving RIF and PZA Abnormal AST at baseline HIV infection Pregnancy First three months postpartum Chronic liver disease Regular alcohol use
Medication should be withheld and patients evaluated if:
Transaminase levels > 3 times upper limit of test in presence of symptoms of adverse events
Transaminase levels > 5 times upper limit of test in asymptomatic patient

Pyridoxine (Vitamin B6) should be used (25-50 mg/day) with INH for persons with conditions in which neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition) as well as pregnant women and persons with a seizure disorder to prevent isoniazid-associated neuropathy. For healthy individuals on a normal diet, pyridoxine is optional. However, we prefer to give pyridoxine to all
patients on INH.

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D. Contacts of MDR-TB Cases (i.e., cases resistant to at least isoniazid and rifampin) In deciding how to treat persons with latent TB infec-
tion which may be due to an MDR-TB strain, the following four questions should be considered. A TB specialist should be consulted in the management of contacts to MDR-TB cases.
How likely is it that a patient is newly TB in
fected? A patient with a documented positive prior PPD skin test is much less likely to be newly infected.
How likely is it that the patient is infected with
an MDR-TB strain? A PPD-positive infant of a parent with active MDR-TB is highly likely to be infected with MDR-TB. In contrast, a health care worker with a positive PPD and no known source case may have a low probability of being MDR-TB infected.
How likely is the patient to develop active TB?
Those at highest risk include infants and persons who are HIV infected or otherwise immunocompromised.
What is the drug-susceptibility pattern of the
source patient's isolate? Treatment of LTBI must be tailored to the susceptibility pattern of the source patient's isolate. In some cases, no preventive therapy regimen is available.

NOTES

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ADAPTED PUBLIC HEALTH SERVICE RATING SYSTEM FOR THE STRENGTH OF TREATMENT
RECOMMENDATIONS AND QUALITY OF EVIDENCE
Strength of the recommendation
A. Preferred; should generally be offered B. Alternate; acceptable to offer C. Offer when preferred or alternative regimens
cannot be given D. Should generally not be offered E. Should never be given
Quality of evidence supporting the recommendations
I. At least one randomized trial with clinical end points
II. Clinical trials that either are not randomized or were conducted in other populations
III. Expert opinion

SUMMARY OF LTBI TREATMENT GUIDELINES

Drugs Isoniazid

Duration (mo) Interval

Rating (Evidence) HIV- HIV+

9 Daily

A (II) A (II)

Twice weekly B (II) B (II)

Isoniazid

6 Daily

B (I) C (I)

Twice weekly B (II) C (I)

Rifampinpyrazinamide

2 Daily

B (II) A (I)

2 - 3 Twice weekly C (II) C (I)

Rifampin

4 Daily

B (II) B (III)

MMWR 2000 49 (RR-6): 1-51

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V. Treatment of Current (Active) Disease Therapy
(Classes III & IV)

A. Considerations 1) It is strongly recommended that TB treatment be undertaken in consultation with a physician who is well-versed and experienced in its management.

2) In general, initiate therapy with a fourdrug regimen (INH, RIF, PZA, EMB) as described on pp. 23-25) is recommended. DIRECTLY OBSERVED THERAPY SHOULD BE CONSIDERED FOR ALL PATIENTS WITH ACTIVE DISEASE, because it is difficult to predict a patient's adherence to therapy. DOT can be given by the county public health department.

3) For all patients, do drug susceptibility testing on initial M. tuberculosis isolates. Drug susceptibility testing and AFB cultures are performed by the Georgia Public Health Laboratory (Phone: (404) 327-7945 or 3277946). Repeat susceptibility testing for patients who do not respond to therapy or who have positive cultures after two months of therapy.

4) The best way to measure the effectiveness

of therapy for pulmonary TB is to monitor

patients bacteriologically through sputum ex-

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amination at least monthly until conversion to negative culture. We recommend obtaining monthly sputum examinations throughout the course of therapy. Patients being treated for uncomplicated pulmonary TB do not require frequent chest x-rays; bacteriologic examination is far more important than monitoring chest films.
5) If a patient's sputum cultures remain positive beyond two months of therapy, the possibility of drug-resistant disease, malabsorption or patient failure to take medications as prescribed should be considered. Drug susceptibility studies should be repeated, and if not already on directly observed therapy (DOT), such patients should be placed on DOT.
6) Adjust weight-based doses as weight changes.

B. Standard Daily Therapy for Current (Active) Disease
All patients should initially be started on a 4-drug regimen (INH, RIF, PZA, EMB) unless there are contraindications to any of the drugs or the patient is pregnant. See Table 1 on the following pages for maximum doses for children and adults.

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Recommended four drug therapy for the initial treatment of TB in children (C) and adults (A), with maximum [MAX] doses:
Table 1: First-Line Medications

Drug

Daily Dose [MAX]

Twice Weekly Dose* [MAX]

Isoniazid (INH) PO, IM or IV

C:10mg/kg A:300mg [300mg]

C:20-40mg/kg A:15mg/kg [900mg]

Rifampin (RIF) PO or IV

C:10-20mg/kg A:10mg/kg [600mg]

C:10-20mg/kg A:10mg/kg [600mg]

Pyranizamide (PZA) PO
Ethambutol (EMB) PO

C:20-30mg/kg A:25 mg/kg [2gm]

C:50-70mg/kg A:50-70mg/kg [4 gm]

C:15-25mg/kg C:50mg/kg A**:15-25mg/kg A**:50mg/kg

*These regimens should be given by DOT only.

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Table 1: First-Line Medications

Thrice Weely Dose* [MAX]

Adverse Reactions

C:20-40 mg/kg [900] A:15 mg/kg [900]

Hepatic enzyme elevation; hepatitis; peripheral neuropathy; CNS effects: rash

C:10-20 mg/kg A:10 mg/kg [600]

Orange discoloration of secretions and urine (occurs in all patients); GI upset; hepatitis; immune mediated toxicity (e.g., thrombocytopenia, renal failure); flu-like symptoms; many drug interactions; rash

C: 50-70 mg/kg A: 50-70 mg/kg [3 gm]

GI upset; hepatitis; hyperuricemia; arthralgias

C&A**: 25-30mg/kg

Optic neuritis (decreased red-green color discrimination; decreased visual acuity)

** EMB dosing should be based on ideal body weight. The formula to determine ideal body weight is: males: 50 kg + 2.3 (height in inches - 60) females: 45 kg + 2.3 (height in inches - 60)

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C. Therapy for Patients with Drug Resistance or Drug Intolerance: The following medications should only be used in consultation with a physician with expertise in the management of drug-resistant TB.

Table 2: Second-Line Medications

Drug

Daily Dose

*Streptomycin (SM): IM
Levofloxin: PO Ofloxacin: PO Ciprofloxacin: PO

C:20-40mg/kg
A:15mg/kg A:750mg A:600-800mg A:750-1500mg

[MAX] [1gm]

Amikacin IV, IM

C:15-30 mg/kg/d A: 15 mg/kg/d

Kanamycin (KM), Capreomycin (CM): IM/IV
Ethionamide: PO

C:15-30mg/kg A:15mg/kg
C:15-20mg/kg A:500-1000mg

[1gm] [1gm]

Cycloserine (CS): PO

C:15-20mg/kg A:250-1000mg

[1gm]

Para-amino-salicylic acid (PAS): PO

C:150mg/kg A:150mg/kg

[12 gm]

Clofazimine: PO

C:50-200mg;

A:100-300mg

* First line medication; can be substituted for EMB in intitial regimen.

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Note: Always use at least 2-3 drugs to which the organism is likely to be susceptible. Never add a single drug to a failing regimen. Intermittent dosing of second-line medications is not recommended.

Adverse Reaction
Ototoxicity (hearing loss, vestibular dysfunction); renal toxicity
GI upset; dizziness; hypersensitivity; headaches Contraindicated in children

Auditory, vestibular & renal toxicity

Auditory, vestibular & renal toxicity; hypokolemia; hypomagnesemia; eosinophilia
GI upset; hepatotoxicity; hypothyroidism; metallic taste; bloating Psychosis; seizures; headache; depression; other CNS effects (give 50 mg Vitamin B6/250mg of CS)
GI upset; hypersensitivity; hepatotoxicity; sodium load; drug interactions
Orange/brown skin discoloration; GI complaints

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Table 3: Use of Anti-TB Medications in Special Situations: Pregnancy, Tuberculous Meningitis and Renal Failure

Drug

Safety in Pregnancy (1)

Central Nervous System Penetration (2)

Dosage in Renal Insufficiency (3)

Isoniazid

Safe (4)

Good (20-100%) No change

Rifampin

Safe (isolated reports of maformation)

Fair, Inflamed

No change

meninges (10-20%)

Pyrazinamide

Caution (1)

Good (75-100%) Decrease dose/ Increase interval

Ethambutol

Safe

Inflamed meninges Decrease dose/

only (4-64%)

Increase interval

Aminoglycosides (Streptomycin, Kanamycin, Amikacin)

Avoid

Poor (5)

Decrease dose/ Increase interval (6)

Capreomycin

Avoid

Poor

Decrease dose/ Increase interval (6)

Levofloxacin, Ciprofloxacin, Ofloxacin

Do not use

Fair (5-10%)

Decrease dose/

Inflamed meninges Increase interval (7)

(50-90%)

Ethionamide

Do not use

Good (100%)

No change

Cycloserine

Avoid

Good (50-100%) Decrease dose/ Increase interval

Para-amino-sili- Safe cylic acid

Inflamed meninges Incomplete data only (50-100%)

Clofazimine

Avoid

Unknown

Probably no change

Safe: Avoid:
Do Not Use:

Drug has not been demonstrated to have teratogenic effects. Limited data on safety or for aminoglycosides asssociated with hearing impairment and/or other toxicity. Associated with premature labor, congenital malformations or teratogenicity.

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ATLANTA TB PREVENTION COALITION

NOTES: Table 3: Special Situations

(1) As with all medications given during pregnancy, anti-TB drugs should be used with caution. The risk of TB to the fetus far outweighs the risk of medications. Pregnant patients with active TB should be treated. Data are limited on the safety of some anti-TB drugs during pregnancy. Table 3 presents a consensus of published data and recommendations. PZA is not routinely recommended as initial therapy for pregnant patients by ATS/ CDC, except in HIV seropositive patients or if drug resistant TB is suspected. Concentrations of anti-TB drugs in breast milk are low; treatment with these medications is not a contraindication to breastfeeding. (Conversely, medication present in breast milk is not sufficient to prevent or treat TB in the newborn.) Consult a medical expert when treating a pregnant patient who has TB. For treatment of LTBI, most authorities recommend beginning INH several months after delivery, unless the woman is at high risk for progression to active TB (e.g., recent PPD conversion, HIV-infected).
(2) Steroid treatment appears to improve outcome in TB meningitis, particularly in patients with altered mental status.
(3) If possible, monitor serum drug levels of patients with renal insufficiency. See pages 34-35 for dosage.
(4) Supplement with pyridoxine (Vitamin B6) during pregnancy.
(5) Has been used intrathecally; efficacy not documented. (6) Avoid aminoglycosides and capreomycin in patients with
reversible renal damage, if possible. (7) Fluoroquinolones may accumulate in renal failure and
are poorly removed by dialysis.

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29

D. Dose Counting Although TB treatment regimens are generally
described in terms of "months" of treatment, it is important that each patient receives an adequate number of doses. For example, for Option 2 below, the patient should receive 15 daily doses of INH, RIF, PZA and EMB, followed by 12 twice-weekly doses of the same four drugs, followed by 38 twice-weekly doses of INH and RIF.

Option 1 (Daily)

Administer daily INH, RIF, PZA and EMB for 2 months followed by 4 months of INH and RIF daily or 2-3 times a week (only by directly observed therapy ) for susceptible isolates.
EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and
RIF.

Option 2 (Twice weekly)
Option 3 (Thrice weekly)

Administer daily INH, RIF, PZA and EMB for 2 weeks followed by 2 times a week administration of the same drugs for 6 weeks (only by DOT), and subsequently, with 2 times a week administration of INH and RIF for 4 months (only by DOT) for susceptible isolates. See dose counting above.
Treat only by directly observed therapy 3 times a week with INH, RIF, PZA, and EMB or SM for 6 months.

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ATLANTA TB PREVENTION COALITION

E. Regimen Options for the Preferred Initial Treatment of Children and Adults
1) Initiate therapy with a 4-drug regimen as shown left. For each of the options shown, a TB medical expert should be consulted if the patient is symptomatic or is AFB smearor culture-positive after two months.
2) Routine follow-up is not needed after completion of therapy for patients who have had a satisfactory and prompt bacteriologic response and who have completed a 6 or 9 month of an INH- and RIF-containing regimen. Patients should be informed to seek prompt medical evaluation if symptoms reappear. Many authorities would continue to follow patients who are HIV-infected or who had drug resistant isolates.
Precautions Daily intake of alcohol increases the risk of hepatitis for patients taking
INH. The reliability of oral contraceptives may be affected in patients being
treated with RIF. Alternate contraceptive measures should be recommended. RIF will decrease the activity of methadone and a number of other drugs (e.g., coumadin, anticonvulsants, fluconazole, protease inhibitors). A larger dose of methadone (often of 50% more) is needed to prevent drug withdrawal. Dosage adjustment of the interacting drugs is recommended. Carefully monitor renal function in patients receiving SM, KM or capreomycin. In persons >60 years of age, the daily dose of SM should be limited to 10 mg/kg (max dose = 750 mg). Never add a single drug to a failing regimen. Dispense only a 1-month supply of medicine at a time for patients on self-administered therapy (consider DOT for all patients).

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Table 4: Therapy Timeline for Previously Untreated Tuberculosis Patients with Active Disease1

Month of Treatment

0

Category by Immune Status

Medications4

Isoniazid (INH)5

Rifampin (RIF)

Pyrazinamide (PZA)6

Ethambutol (EMB)6,7

1

2

3

4

ALL PATIENTS2



5

6

7

8

9

* SELECTED PATIENTS3



(INH)



(RIF)

(PZA)

(EMB)

4 Ideally every TB patient should receive every dose of anti-TB medication on a program of directly observed therapy (DOT). Call your local Health Department for help in arranging DOT for your patient. 5 Pyridoxine (Vitamin B6), 25-50 mg with each dose of INH can be given to prevent INH-induced peripheral neuropathy. Pyridoxine should be given to all patients who are pregnant, malnourished or who use alcohol. 6 Continue PZA until a) at least eight weeks of therapy have been given, and b)

HIV Counseling and

G

G

Voluntary Testing3

laboratory results document susceptibility to INH and RIF. Many authorities would continue PZA until sputum is AFB-smear

negative. EMB should be continued until

susceptibility to INH and RIF is

Regular Monitoring

documented.

M.D. Assessment

G

G

G

G

G

G

G

G

(M.D.)
G

G 7 During treatment with EMB, monitor

Sputum Smear and Culture8 G

G

G

G

G

G

G

Chest X-ray9

G



G

G

(Sputum) visual acuity and color vision monthly.

G
(X-Ray)

G G

8 Regular monitoring of sputum AFB smears and mycobacteriology cultures is

Complete Blood Cell Count G with Platelets

essential. Examine sputum at least monthly until conversion to negative culture; some prefer to obtain monthly

Hepatic Enzymes10

G













sputum exminations throughout the course of therapy. If drug resistance is

1 All initial isolates of M. tuberculosis should have drug-susceptibility testing performed. This chart applies only to patients whose isolates are found to be drug susceptible. If drug resistance is documented, consult a physician expert in its management. 2 Pending the results of susceptibility testing, begin all patients on all four of the anti-TB medications listed, unless there are absolute contraindications. 3 HIV counseling and testing should be encouraged for all TB patients, ideally at the first or second clinical visit. Patients known or suspected to be HIV+ with drug susceptible disease should be treated for a minimum of 6 months. Patients who are sslow to respond to therapy or culture positive at 2 months should be treated for a total of 9 months.

documented, seek expert consultation. 9 Obtain chest x-ray after three months to document response to treatment if initial cultures are negative. 10 Monitor hepatic enzymes monthly if baseline levels elevated or history of alcoholism or liver disease. At least 20% of patients will have elevated hepatic enzymes: asymptomatic elevation less than five times the upper limit of normal is not an indication to stop treatment. If patients have jaundice or symptomatic liver disease, discontinue medications immediately and consult a specialist. * Extend therapy for 3 additional months (total 9 months) in patients who are still culture positive at 2 months because of high risk of relapse regardless of HIV status.

32

ATLANTA TB PREVENTION COALITION

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33

ANTITUBERCULOSIS ANTIBIOTICS IN Note: Drug adjustments are based on the patient's creatinine clearance
(140-age) (Ideal body weight in kg) for men (x 0.85 for women) (72) (serum creatinine, mg/dL)

DRUG INH

USUAL DOSE (UD) NORMAL RENAL FUNCTION
300 mg/d

CrCl 25-50 UD

Rifampin

600 mg/d

UD

Ethambutol

15-25 mg/kg/d

15mg/kg/d

Pyrazinamide

25 mg/kg/d (max 2.0 gm/d)

UD

Levofloxacin

750 mg/d

500 mg/d

Ciprofloxacin

750 mg BID

750 mg/d

Ofloxacin

400 mg BID

400 mg/d

UD = usual dose HD = hemodialysis PD = peritoneal dialysis CrCl = creatinine clearance (ml/min) d = day *All four first-line drugs (INH, RIF, PZA, EMB) may be adminstered thrice

34

ATLANTA TB PREVENTION COALITION

ADULT PATIENTS WITH RENAL IMPAIRMENT which can be estimated as follows: Ideal body weight for men: 50 kg + 2.3 kg per inch over 5 feet Ideal body weight for women: 45.5 kg + 2.3 kg per inch over 5 feet

CrCl 10-25 UD

CrCl <10 UD

Hemodialysis* UD

Peritoneal Dialysis
UD

UD

UD

UD

UD

15 mg/kg q 36 20 mg/kg/d 250 mg/d

15 mg/kg q 48
25 mg/kg thrice weekly 250 mg/d

15-25 mg/kg thrice weekly

15-25 mg/kg thrice weekly

25-30 mg/kg thrice 25 mg/kg

weekly after HD

thrice weekly

250 mg/d

250 mg/d

750 mg/d

500 mg/d

500 mg/d

500 mg/d

400 mg/d

300 mg/d

200mg BID

200mg/d

weekly after HD to facilitate DOT.

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F. Drug Resistance (See Table 2, pp. 26 and 27) For treatment of suspected or confirmed drug resis-
tance, select at least two drugs, and preferably at least three, to which the patient has never been exposed and to which the organism is known or likely to be susceptible. A single drug should never be added to a failing regimen or to one that failed in the past. Seek expert consultation for all patients with drug-resistant TB. Directly observed therapy is recommended for all patients with drug-resistant TB.
For patients with only INH resistance, treat with RIF, PZA, EMB for a minimum of 6 mo .
For patients with only RIF resistance, treat with INH, EMB, PZA for a minimum of 12 months.
MDR-TB (i.e., resistance to at least INH and RIF) presents difficult treatment problems. Treatment must be individualized and prolonged, based on medication history and drug susceptibility results; seek expert consultation. Regimens are often 24 months in duration (at least 12 mo after culture conversion is documented). Surgery may be beneficial in selected patients and improve cure rates for MDR-TB patients if the bulk of the disease can be resected.

36

ATLANTA TB PREVENTION COALITION

G. Drug Monitoring 1) Response to Treatment
a. For pulmonary TB patients, monitor patients bacteriologically at least monthly until cultures convert to negative. Some authorities prefer to obtain monthly AFB sputum smear and cultures throughout the course of therapy.
b. After two months of therapy, if cultures remain or convert to positive or if symptoms do not resolve, obtain new specimens for culture and drug susceptibility testing. Such patients should be reviewed for drug resistant disease and failure to adhere to the prescribed treatment regimen. For patients receiving self-administered therapy, if cultures do not convert to negative after two months of therapy, DOT should be initiated. Patients with drug susceptable disease who are culture positive at 2 months should receive a total of 9 months of therapy.
c. All pulmonary TB patients should have a sputum smear and culture performed at the completion of therapy as well as a CXR.

2) Monitoring for Adverse Reactions

a. Obtain the following baseline measurements to detect any abnormality that would complicate the regimen or necessitate its modification:

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37

Hepatic enzyme (e.g. AST) level, bilirubin, serum creatinine, complete blood count, platelet count
and uric acid level (if PZA is used). Baseline visual acuity (if EMB is used) Baseline audiometry (if SM is used).

e. Hyperuricemia may occur in patients on PZA but acute gout is uncommon. Asymptomatic hyperuricemia is not an indication for discontinuing the drug.
f. Drug Interactions:

b. All patients should be seen at least monthly and questioned about potential adverse reactions. If symptoms suggesting drug toxicity occur, appropriate laboratory testing should be performed to confirm or exclude such toxicity. Patients should be instructed to report symptoms of hepatitis (which can be induced by INH, RIF and/or PZA) immediately. Such symptoms include nausea, loss of appetite, vomiting, jaundice (dark urine, yellow skin), malaise, unexplained fever for > 3 days, or abdominal tenderness. If patients have jaundice or symptoms of liver disease, discontinue medications immediately and consult a specialist.

INH and phenytoin (Dilantin) increase the serum concentrations of both drugs. Follow phenytoin levels closely.
RIF may accelerate clearance of drugs metabolized by the liver including methadone, coumadin, glucocorticoids, estrogens, oral hypoglycemic agents, digitalis, anticonvulsants, ketoconazole, fluconazole, cyclosporin, and protease inhibitors.
Women taking RIF should use a birth control method other than oral contraceptives or contraceptive implant
(e.g., Norplant).

c. Routine monthly laboratory monitoring is generally not required for those with normal baseline. Some obtain transaminase levels periodically for patients >35 years. Monitor hepatic enzymes monthly if baseline levels are elevated, and for those with HIV infection, history of alcoholism, chronic liver disease and pregnancy. At least 20% of patients will have elevated hepatic enzymes; asymptomatic elevation less than five times the upper limit of normal is not an indication to stop treatment. If patients have jaundice or symptomatic liver disease, discontinue medications immediately and consult a specialist
d. Pyridoxine will usually prevent INH-induced neurotoxicity (peripheral neuropathy). The indications and use of pyridoxine are described on p. 17.

H. TB and HIV
If a patient is infected with M. tuberculosis, HIV infection is a very important risk factor for development of active TB disease. TB is one of the few diseases occurring in HIV-infected persons that is transmissible, curable and preventable.
Persons with HIV infection may have diminished tuberculin skin test reactions because of immunosuppression. Therefore, tuberculin reactions of > 5 mm of induration are considered indicative of TB infection in an HIV-infected individual (see p. 8).

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ATLANTA TB PREVENTION COALITION

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39

Anergy among persons with HIV infection is common, especially among those with very low CD4 counts.
Because HIV status is a critical factor in the treatment of TB, HIV counseling and testing should be offered to all patients with active TB disease.
The clinical presentation of TB in an HIV-infected person may differ from that in persons with relatively normal cellular immunity who develop reactivation TB. Apical pulmonary disease with cavitation, a classic finding in immunologically competent persons, is less common among HIV+ persons, especially among those with low CD4 counts. HIVinfected patients may present with infiltrates in any lung zone and/or with mediastinal or hilar lymphadenopathy. Extrapulmonary and disseminated TB is common among HIVinfected TB patients.
1) Treatment for Individuals with TB & HIV
HIV-infected patients with active TB disease should be initiated on a 4-drug treatment regimen (INH, RIF, PZA and EMB) and pyridoxine as outlined on p. 24 unless contraindications to medication exist or the patient is on or will be started on certain antiretroviral therapy which includes protease inhibitors. The use of antiretroviral therapy and TB meds is discussed on p.42. HIV-infected patients with drug-susceptible TB disease respond well to standard anti-TB drugs. Antituberculosis therapy should be started whenever AFB are seen in a specimen from the respiratory tract.

40

ATLANTA TB PREVENTION COALITION

2) Patients with HIV co-infection who have drugsusceptible TB disease should be treated for a minimum of 6 months of therapy. Duration of therapy should be prolonged for patients with delayed or slow response to therapy. HIV infected patients with TB disease should be monitored closely for clinical and bacteriological response. Prolonged treatment beyond 6 months (e.g., to 9 months) is recommended for patients who are slow to respond to therapy including patients who remain culture positive after two months of therapy. Because patient adherence to therapy is crucial for good outcomes, DOT is strongly recommended.
3) HIV-infected patients should be monitored very closely during therapy as they appear to have a greater frequency of adverse reactions to anti-TB drugs. (Obtain monthly AST.)
4) For patients with drug-resistant isolates, if both INH and RIF are not included in the regimen, treatment should be continued for at least 18 months and at least 12 months after culture conversion. Directly observed therapy is essential for all patients with MDR-TB. Seek expert medical advice for all patients with MDR-TB.

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5) After treatment is completed, patients should be reminded that if symptoms reappear, they should seek prompt medical evaluation.

I. Antiretroviral Therapy and Treatment of HIV Seropositive Patients with Active Tuberculosis Disease.
Treatment of HIV-infected patients with active TB disease who are on antiretroviral therapy or for whom this is planned, should be carried out in consultation with a physician who has experience in the use of rifamycin drugs and antiretroviral agents. Recommendations on the treatment of TB in combination with antiretroviral therapy continues to evolve and therefore it is important to check for new updated guidelines.

The introduction of highly active antiretroviral therapy (HAART) has dramatically improved outcomes for HIVinfected patients and decreased HIV related mortality. Patients in the United States with tuberculosis disease who are HIV-infected commonly have advanced HIV/AIDS with low CD4 counts and high plasma HIV RNA levels, and thus could potentially benefit from antiretroviral therapy. However, adherence to antiretroviral agents must be extremely high for there to be virologic response; the use of antiretroviral therapy among HIV-infected patients with tuberculosis is complicated by overlapping toxicity profiles of some antituberculosis and antiretroviral drugs; complex drug-drug in-

42

ATLANTA TB PREVENTION COALITION

teractions; and the occurrence of paradoxical or immune reconstitution reactions.

In order to prevent the occurrence of paradoxical or immune reconstitution reactions (see section below on page 47), especially among patients with low CD4 counts, and because of potentially overlapping toxicities, it is generally recommended not to start HAART until the tuberculosis disease is substantially improved (e.g., after two months of antituberculosis treatment). The use of antiretrovirals among HIV-infected patients with tuberculosis requires close and frequent communication between tuberculosis and HIV care providers. The use of rifampin or other rifamycin drugs in combination with HAART is outlined below. For additional information refer to updated CDC recommendations (MMWR 2000;49:185-9) and a recent article by Burman and Jones (Am J Resp Crit Care Med 2001;164:7-12).

There are clinically important drug-drug interactions between the rifamycins (e.g., rifampin, rifabutin) and some of the antiretroviral drugs, especially protease inhibitors. The rifamycins are inducers of the cytochrome P450-3A (CYP3A) system in the liver and thereby decrease serum concentrations of drugs metabolized by this system including protease inhibitors. Rifampin is a potent inducer of the CYP3A while rifabutin is a less potent inducer. Rifampin cannot be given with most protease inhibitors because it results in low serum levels of these drugs. Rifabutin has less of an effect

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TB Therapy in the HAART Era

Option 1- Rifabutin substituted for rifampin
PI (e.g., indinavir, nelfinavir or amprenavir) plus 2
NRTIs Substitute rifabutin at lower dose (150 mg/day or 300 mg 2x/week) with PI (indinavir 1000 mg tid or nelfinavir 1250 mg bid)
NNRTI (efavirenz) plus 2 NRTIs
Increase dose of rifabutin to 450-600 mg/d or 2x/week
Option 2 - Rifampin based regimen plus HAART (no PI) -limited data
Efavirenz (increase dose to 800 mg/day) plus 2 NRTIs
(e.g., zidovudine {AZT}/ lamivudine {3TC})
Option 3 - Rifampin as part of standard regimen, no HAART
patient not candidate for HAART
Option 4 TB regimen without rifampin/rifamycin drug
ContinuewithHAARTnorifamycin[Notrecommended]
Short course therapy (e.g., 6 months) not possible; potentially worse outcome without rifamycin drug.
PI - protease inhibitor NNRTI - non-nucleoside reverse transcriptase inhibitor NRTI - nucleoside reverse transcriptase inhibitor Adapted from MMWR 2000;49:185 and Am J Resp Crit Care Med 2001;164:7

44

ATLANTA TB PREVENTION COALITION

and therefore can be used with certain protease inhibitors as described below. The protease inhibitors also effect rifamycin metabolism and because the rifamycin metabolism is retarded by these drugs, the dose of rifabutin needs to be reduced when the drug is given daily in order to avoid rifabutin related toxicity. Most of the clinical experience to date involves the use of rifabutin given with antiretroviral agents. There is less clinical experience with the use of rifampin and as noted above, rifampin cannot be given with most protease inhibitors.
Rifabutin can be substituted for rifampin in the antituberculosis regimen as follows:
The protease inhibitors indinavir, nelfinavir, or amprenavir are used (TB Therapy in the HAART Era Figure, Option 1). The greatest clinical experience has been with the use of rifabutin in combination with the protease inhibitors nelfinavir or indinavir. If rifabutin is substituted for rifampin in combination with either of these protease inhibitors, the dose of rifabutin needs to be reduced by half (to 150 mg per day) when the drug is given daily. When given in a twice or thrice weekly regimen, a dose of 300 mg is recommended.
Nucleoside reverse transcriptase inhibitors (e.g., zidovudine, stavudine, lamivudine, etc) are used. There are no significant drug interactions between

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the NRTIs and rifamycins. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) efavirenz or nevirapine are used. The dose of rifabutin should be increased to 450 to 600 mg when administered with efavirenz.

Rifabutin should NOT be used in combination with the following antiretrovirals:
Saquinavir hard-gel capsules NNRTI drug delavirdine

Rifampin can be given with the following antiretrovirals (although there is less clinical experience compared to rifabutin in combination with antiretrovirals):
Nucleoside reverse transcriptase inhibitors (e.g., zidovudine, stavudine, lamivudine, etc). There are no significant drug interactions between the NRTIs and rifamycins.
NNRTI efavirenz (TB Therapy in the HAART Era Figure, Option 1). The dose of efavirenz should be increased to 800 mg/day when used with rifampin.

Rifampin cannot be used with the following: Protease inhibitors including indinavir, nelfinavir, amprenavir, lopinavir. Rifampin can be used with ritonavir (600 mg twice daily) when it is used as a single PI as part of a HAART regimen but this approach is limited by the poor tolerability of full dose ritonavir.

46

ATLANTA TB PREVENTION COALITION

Low dose ritonavir (100 mg twice daily) is used a pharmacokinetic booster of other protease inhibitors. Rifampin should NOT be used in combination with low dose ritonavir (100 mg twice daily) and a second PI. The NNRTI drug delavirdine.
Rifapentene, a long acting rifamycin, which is given once a week should NOT be used in patients with HIV co-infection because of the development of rifamycin resistant M. tuberculosis which occurred among HIV-infected patients with tuberculosis on rifapentene.
A summary of treatment options for patients with tuberculosis disease who are HIV-infected are shown in the table on page 44. Option 3 (standard therapy with rifampin) should be used in patients who are not candidates for or who cannot tolerate antiretroviral therapy. For HIV-seropositive patients on HAART, there is the most clinical experience for Option 1.

J. Paradoxical or Immune Reconstitution Reactions Associated with Initiation of Antiretroviral Therapy During the Course of TB Therapy

The temporary exacerbation of TB symptoms and lesions after initiation of anti-tuberculosis therapy - known as a paradoxical reaction - has been described as a rare occurrence in HIV-negative patients after the initiation of anti-

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tuberculosis therapy. These "paradoxical reactions" are thought to be due to immune reconstitution and are not uncommon among HIV-infected patients who are started on highly active antiretroviral therapy (HAART) early during antituberculosis therapy. After initial clinical improvement, paradoxical worsening of disease developed in up to 36% of HIV infected TB patients on HAART compared with 7% of HIV co-infected patients treated for TB but who did not receive HAART [Narita et al].

Paradoxical or immune reconstitution reactions are characterized by fever, worsening chest infiltrates on chest radiograph and peripheral and mediastinal adenopathy. The paradoxical reactions are associated with increase reactivity on tuberculin skin testing and a significant reduction in HIV viral load. Patients with clinical findings that are compatible with an immune reconstitution reaction should have other diagnoses ruled out. These paradoxical or immune reconstitution reactions are usually self-limited and can last 10 to 40 days. Mild to moderate reactions can be managed by reassurance and non-steroidal anti-inflammatory drugs. Severe reactions included those characterized by marked increase in adenopathy causing an anatomic problem (e.g., compromised breathing, swallowing or movement of the neck; or expanding central nervous system lesions) can be managed with corticosteroids (with continuation of the antituberculosis therapy and HAART) or temporary discontinuation of the antiretroviral agents.

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ATLANTA TB PREVENTION COALITION

In order to prevent the development of immune reconstitution reactions, it may be prudent to delay the initiation of antiretroviral agents until the patient has received two months of antituberculosis therapy and the disease is under better control.

K.

Treatment of Extrapulmonary TB

The basic principles that underly the treatment of pulmonary TB also apply to extrapulmonary forms of the disease. As a general rule, regimens that are adequate for the treatment of pulmonary TB in adults and children will also be effective in extrapulmonary disease. However, infants and children with miliary TB, and TB meningitis in infants and children should receive 12 months of therapy.

Lymphatic and hematogenous TB are especially common among persons with HIV infection. Central nervous system (CNS) involvement has been reported and may be difficult to diagnose when it occurs in conjunction with other opportunistic CNS infections.

To establish the diagnosis of extrapulmonary TB, a variety of specimens including pleural fluid, peritoneal fluid, pleural and peritoneal biopsy specimens, lymph node tissue, bone marrow, bone, blood, urine, brain or cerebrospinal fluid may need to be obtained for mycobacterial culture. Specimens must be examined microscopically, but the inability to demonstrate AFB and the absence of granuloma formation does not exclude the diagnosis of TB. Surgery

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may be necessary to obtain specimens for diagnosis and to treat such processes as constrictive pericarditis or spinal cord compression from Pott's disease.
Corticosteroids may be beneficial in decreasing the neurologic sequelae of TB meningitis and in improving outcomes in patients with tuberculosis pericarditis.
L. Adjunct Use of Corticosteriod Therapy
Adjunct corticosteroid therapy is indicated in the treatment of tuberculous meningitis and pericarditis as its use along with appropriate antituberculosis drugs is associated with a lower mortality. Corticosteroids are recommended as adjunctive therapy for tuberculous pericarditis during the first 11 weeks of antituberculosis therapy. Corticosteroids do not reduce the risk of development of constrictive pericarditis, however. For the treatment of adults with tuberculous pericarditis, 60 mg of prednisone should be given for 4 weeks, followed by 30 mg for 4 weeks, 15 mg for 2 weeks, and finally 5 mg for the 11th and final week. For patients with tuberculous meningitis, dexamethasone is recommended for a total of 6 weeks. An initial dose of 8 mg per day of dexamethasone for children <25 kg and 12 mg per day for children >25 kg and adults can be used. The initial dose is given for 3 weeks and then the dose should be tapered during the following 3 weeks.

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ATLANTA TB PREVENTION COALITION

VI. Pregnancy
A. Treatment for LTBI and Risk Factors A pregnant woman with a positive skin test and negative
chest x-ray (a lead apron should cover the entire abdomen during x-ray) should be started on treatment for LTBI with INH (300 mg daily) immediately if they have one or more of the following risk factors:
Documented recent tuberculin skin test conversion; HIV infection or those with HIV risk factors who refuse
HIV testing; Close contact of patient with AFB smear-positive pulmo-
nary TB, at physician's discretion.
Pyridoxine (25-50 mg/d) is recommended for all pregnant or nursing mothers who receive INH. All pregnant and immediate postpartum patients should have a baseline and monthly AST performed. Treatment of other positive reactors can be deferred until several months after the completion of pregnancy.

B. Treatment of Active TB in Pregnancy TB disease discovered during pregnancy should be treated
without delay. A pregnant woman with a positive skin test and abnormal x-ray findings compatible with TB who has not been treated, should be started on treatment. Three sputum samples should be submitted for examination. The outcome of the cultures and susceptibility test results will determine the regimen for continuation of treatment.

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1) Drug Treatment in Pregnancy (See Table 3, p. 28) a) The initial treatment regimen usually consists of INH, RIF and EMB.
b) PZA should be included in the initial regiment for HIV seropostive women and for HIV seronegative women who are thought to be at high risk for drug resistant TB.
c) Pyridoxine (Vitamin B6) is recommended for all pregnant women taking INH.
d) PAS has been used safely in pregnancy but is poorly tolerated.
e) Avoid: Aminoglycosides (e.g., streptomycin, kanamycin, amikacin) and capreomycin are contraindicated for all pregnant women because of potential adverse effects on the fetus. Do not use: quinolones (e.g.,levofloxacin, ofloxacin and ciprofloxacin), and ethionamide.
2) Breast Feeding The small concentrations of TB drugs in breast milk
do not have a toxic effect on nursing newborns and breast feeding should not be discouraged. Conversely, drugs in breast milk should not be considered to serve as effective treatment for disease or as treatment of LTBI in a nursing infant.

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VII. Childhood Tuberculosis
The basic principles for treatment of TB in children and adolescents are essentially the same as adults. For children who receive LTBI therapy, a nine-month course is required. Dosage adjustments of medications are made based on weight.

Management Considerations

1) TB in infants and children younger than 4 years of age is much more likely to disseminate; therefore, prompt and vigorous treatment should be started when the diagnosis is suspected.

2) Primary intrathoracic TB (parenchymal infiltration, hilar adenopathy, or both, in a child with a significant tuberculin skin test reaction) should be treated in the same manner as pulmonary TB.

3) Because sputum specimens are less likely to be helpful in children, it may be necessary to rely on the results of cultures and susceptibility tests of specimens from the adult source case to "confirm" the diagnosis in the child and to guide the choice of drugs. In cases of suspected drug-resistant TB or where adult isolates are not available, the aggressive pursuit of early morning gastric aspirates, bronchoalvelar lavage, or tissue diagnosis should be considered.

4) For the same reason, bacteriologic examinations are less useful in evaluating the response to treatment; thus, clinical and radiographic examinations are of relatively

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greater importance in children. However, CXRs of children with hilar adenopathy may not become normal for two to three years after treatment. In this instance, a normal CXR is not a necessary criterion for discontinuing antiTB drugs.
5) Because it is difficult to monitor for ocular toxicity from EMB, this agent is less useful in very young children. Streptomycin is an alternative.
6) In general, extrapulmonary TB, including cervical adenopathy, can be treated with the same regimens as pulmonary TB (e.g., 6 months for drug-susceptible disease). Exceptions include disseminated (milary) disease, and meningitis for which 12 months of therapy is currently recommended.

7) Directly observed therapy is recommended for all children.

8) Management of the newborn infant whose mother or other household contact is suspected of having TB is based on individual considerations. Separation of the mother (or contact) and infant should be minimized, if possible. Differing circumstances and resulting recommendations are as follows:

i. Mother or other household contact who has a positive tuberculin skin test reaction and no evidence of current disease. If, after investigation,

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no evidence of active disease is found in the mother or extended family to whom the infant is exposed, the infant should be tested with a Mantoux test (5 TU PPD) at 4-6 wk of age and at 3-4 mo of age. Separation of mother and infant is not indicated. If the family cannot be tested promptly, consider administration of INH (10 mg/kg/d) to the infant until skin testing of family has excluded contact with a case of active TB.

ii. Mother who has current disease and is judged to be noncontagious at delivery. Investigation of household members and extended family is mandatory. A CXR and Mantoux test at 4-6 wk of age should be performed on the infant; if negative, test again at 3-4 mo and at 6 mo. Separation of mother and infant is not necessary if mother is adherent with therapy.

The infant should receive INH even if the tuberculin skin test and CXR do not suggest TB disease, since cell-mediated immunity of a degree sufficient to mount a significant reaction to tuberculin skin testing can only develop as late as 6 mo of age in an infant infected at birth. INH can be discontinued if skin test is negative at 6 mo of age and no active disease exists in family members. Examine infant carefully at monthly intervals.

iii. Mother who has active disease and is suspected of being infectious at the time of delivery. The

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mother and infant should be separated until the mother is judged to be noninfectious. Otherwise, manage the same as when the disease is judged to be noninfectious to the infant at delivery (see p. 55).
iv. Mother who has hematogenous spread of tuberculosis (e.g., meningitis, miliary disease, or bone involvement). If mother has hematogenous spread of TB, congenital TB in the infant is possible. If the infant is suspected of having congenital TB, a PPD Mantoux skin test and CXR should be performed promptly and treatment of the infant for TB disease should begin at once. If clinical or x-ray findings do not support the diagnosis of congenital TB, the infant should be separated from the mother until she is judged to be noninfectious. The infant should be given INH until 6 months of age at which time the skin test should be repeated. If the skin test is positive, INH should be continued for a total of 9 months.

VIII. Tuberculosis and Nursing Homes
TB remains a problem in older individuals who were infected many years ago and did not develop active disease at the time. Also, there is increasing documentation of outbreaks of TB occurring in nursing home residents when a patient with TB disease infects a population of older people who are newly exposed to that case.
TB control in nursing homes must begin with a careful assessment of TB status upon admission, including tuberculin skin testing and chest x-rays for individuals who are tuberculin skin-test positive.
Since older people (>55 years old) may have diminished skin test reactivity, the two-step technique (see p. 10) of tuberculin skin testing is recommended at admission. A "booster effect" has been noted in persons in whom DTH reaction to tuberculin may have waned over the years. In these situations, an initial tuberculin skin test may demonstrate a negative or only weakly positive reaction but it boosts the immune system so that subsequent tuberculin skin tests may be increased in size and may be interpreted as positive. This "boosted" response is considered as the valid baseline for the individual.

Residents of nursing homes whose two-step skin tests are negative on admission should have repeat tuberculin testing when an exposure to a case of potentially infectious TB has occurred.
Any person who converts the PPD test from negative to positive should be considered for treatment of LTBI after active TB is ruled out (by chest x-ray at least and
sputum specimens if indicated).

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Any resident with symptoms of TB regardless of PPD test results should have a chest x-ray to evaluate for active TB.
Treatment of active TB disease (Class III) is the same as that used for younger adults.
Employees of nursing homes should have two-step tuberculin testing when they start to work in the nursing home, and annual single-step testing thereafter. Employees who are PPD+ at baseline should be evaluated for treatment for LTBI (see pages 11-14). Those with recent conversion should be strongly encouraged to take treatment for LTBI. Routine annual CXR for previously PPD+ employees is not recommended.
IX. BCG Vaccination
Bacille Calmette-Guerin (BCG) is a vaccine for TB disease that is used in many countries. Because of variable effectiveness, BCG is not generally recommended in the U.S. All individuals who need to be screened, including those who have ever had BCG vaccination, should have a Mantoux tuberculin skin test with 5TU of PPD as part of TB screening and evaluation.
Interpretation of a tuberculin skin test reaction is not changed for patients who have received BCG. A reaction of >10 mm of induration should be considered infection with M. tuberculosis because:
Conversion rates after BCG vaccination are not 100%;

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The mean reaction size among BCG vaccinees is often less than 10 mm (a large reaction is more likely to be due to infection with M. tuberculosis than BCG vaccination);
Tuberculin sensitivity tends to wane considerably after BCG vaccination; and,
BCG is often given where TB is endemic, so assume that the reaction is from infection, not vaccination.
Since many BCG-vaccinated persons come from areas of high TB prevalence, it is important that persons with significant reactions to the tuberculin skin test be evaluated for presence of disease and managed accordingly. Appropriate follow-up includes a careful medical history, CXR to rule out disease, and evaluation for treatment of LTBI.
Individuals with a history of BCG vaccination should have a tuberculin skin test performed when required for pre-employment, admission or periodic testing unless there is a documented recent history of a positive Mantoux skin test reaction.

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X. TB Infection Control: Hospital Isolation Procedures
Effective infection control efforts are essential in preventing nosocomial transmission of TB. A hierarchy of control measures is recommended to prevent TB transmission in health care facilities.

A. Administrative Controls Administrative controls are most important and in-
clude measures to reduce the risk of exposure to persons with infectious TB; this includes careful screening, early identification and treatment of patients with TB. A high index of suspicion is critical. Patients with or at risk for TB need to be isolated upon admission. Unsuspected patients with TB and misdiagnosis (especially among HIV-infected patients who may have "atypical" or non-classical presentations) have led to nosocomial transmission at a number of hospitals (as well as at correctional institutions and other health care facilities).
Grady Memorial Hospital in Atlanta, which has cared for approximately 200 patients with lab-confirmed disease each year over the past decade, has prevented nosocomial transmission in large part by the effective use of administrative controls. Careful screening of patients and isolation of those at risk for TB have been accomplished by the introduction of an expanded respiratory isolation policy.
B. Surveillance for Health Care Workers All health care workers should have a tuberculin skin
test upon employment (unless documented to be previously PPD positive) and at intervals determined by their risk of exposure (minimum of yearly). Any worker who develops symptoms of

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Grady Hospital TB Isolation Policy

Criteria for Isolation

Length of Isolation

1. Active Pulmonary TB

Duration of hospitalization if less than 4 weeks; if >4 weeks must have clinical response, drug susceptibility data and 3 negative AFB sputum smears

2. "Rule Out" TB Any patient who has sputum for AFB collected or pulmonary TB is in the differential diagnosis.

Until 3 sputum AFB smears are negative

3. HIV+ patient admitted Until 3 sputum AFB smears are

with abnormal CXR

negative

TB or whose skin test result converts to positive should be evaluated promptly. Health care workers with a recent PPD conversion (regardless of age) and no evidence of active disease should be encouraged to take treatment for LTBI (see pp. 11-20). Health care workers should be educated about the basic concepts of TB transmission and pathogenesis, infection control practices, and the signs and symptoms of TB.

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C. Engineering Controls Patients admitted to health care facilities with suspected
or confirmed TB should be placed in respiratory isolation in negative pressure rooms with > 6 air changes per hour (> 12 for new construction); air from isolation rooms should be exhausted directly to the outside or through a HEPA filter before being recirculated.
D. Personal Respirator Protection Appropriate respirator masks should be worn by health
care workers when entering isolation rooms or performing high risk procedures such as cough inductions and bronchoscopy. Use of the N-95 respirator mask is required by OSHA.

XI. Community Tuberculosis Control

A. Reporting Requirements
In Georgia all TB cases must, by law, be reported to the local county public health department. This is the responsibility of the physician. At Grady Memorial Hospital, the TB Control Coordinator in the Epidemiology Department (404-6165323) reports all patients with active disease to the local health departments for the physician. Any health care provider who is managing TB patients in non-health department settings must update the health department on the progress of each patient, including sputum results.

B. Role of the Health Department
Health department staff are trained and experienced in contact investigation, provision of directly observed preventive

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therapy (DOPT) and directly observed therapy (DOT) and the treatment of patients with TB infection and disease. DOT is the standard of care for all TB patients in Georgia.
Early reporting of suspected or confirmed TB cases is important for control of TB and it gives the clinician access to the resources of the public health department for assistance in case management and contact investigation. Contact investigations are indicated to determine those who have been exposed to infectious TB patients so tuberculin skin testing can be per-
Role of the Health Department
Identify and treat all persons with TB disease; ensure that patients complete appropriate therapy
Provide Directly Observed Therapy (DOT)
Provide laboratory services
Identify and evaluate contacts to persons with infectious TB; offer therapy as appropriate
Screen high-risk groups for TB infection; offer therapy as appropriate
Collect and analyze data
Provide training, education, and consultation

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formed on close contacts and preventive therapy can be initiated for those who have been infected. Social service and county health liaison have documented stable/appropriate home environment.
Tuberculosis services (radiology, medical consultations, DOT, etc.) are available in every health district. All TB medications are provided by the state pharmacy free of charge.
C. Grady Hospital TB Discharge Policy For TB control efforts, it is important that there be a
smooth transition from the in-patient to the out-patient setting and close cooperation and coordination of activities among the wide variety of organizations involved in TB patient care, education and TB control.
To improve TB control efforts in Atlanta and protect the community from TB, a TB Discharge Policy has been developed for Grady Memorial Hospital. The standard requires that:
Patients be discharged on an appropriate anti-TB regimen (e.g., 4 drug regimen)
All TB patients have their discharge endorsed in the chart prior to discharge by the Hospital's TB social worker and the local health department liaison;
All TB patients meet appropriate criteria for dischargeaccording to the following policy:

Summary: Grady Hospital TB Discharge Policy

Site & Patient Characteristics

Criteria

I. Another Acute Care Hospital

Transfer anytime when stable

II. Prison with Appropriate Transfer when medically ready

Isolation

for discharge unless MDR-TB

suspected

III. Alternative Housing Program (GA DHR/ALAG)

Transfer when medically ready for discharge

IV. Home

When medically ready for discharge AND the criteria shown in the chart on the following page are met:

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Patient Characteristics
Known or suspected MDR-TB
Cavitary or moderate infiltrate an/or/ posittive initial respiratory AFB smear
Minimal or no infiltrate & initial AFB respiratory smears (>3) were negative
Non-respiratory TB closed site of infection (Pleural, etc.)
Non-respiratory TB open site of infection (skin, etc)
Positive smear now; previous pos. culture for non-TB Myco-bacteria collected within 60 days
Situations Other Than Those Above

Discharge Destination Stable Home Unstable Home or Prison Stable Home Unstable Home
Stable Home Unstable Home

Criteria (See Below)
Need A, B, C, D, H
Cannot discharge to these sites
Need A, B, C, H
Need C, E, F, I or C, E, F, G
Need A, B, & C
Need C, E, & F

Stable Home Unstable Home Stable Home Unstable Home Stable Home

Need A, B, & C Need C, E, & F Need, A, B, C, D Need C, D, E, & F Need A, B, C, D, H

Unstable Home

Need C, D, E, & F

Stable Home Unstable Home

Need A, B, C, & D Need C, D, E, & F

Keys to Letters Defining Criteria:
A. Social service and county health liaison have documented stable/appropriate home environment.
B. Arrangement is made and documented in the chart for followup visit by appropriate county health dept, clinic or other appropriate health care provider, as soon as possible and no longer than 10 week days after discharge. Patient (and/or family and/or significant other) are informed of arrangement.
C. Patient (and/or family and/or significant other) has received discharge teaching about the disease and about isolation, if appropriate.
D. Pulmonary or infectious disease consult or hospital epidemiologist endorses in chart that disposition if appropriate.
E. Social service and the county health liaison document unstable home environment.
F. Patient has arrangement made and documented in chart for follow-up visit by county health dept, clinic or other appropriate health care provider, as soon as possible (no longer than 5 week days after discharge). Patient, family and/or significant other are informed of arrangement.
G. After 3 negative AFB smears. H. With good clinical response to initial anti-TB therapy of at least
5 days; there will be no new persons exposed to the patient in the home who have not been in long-term contact with patient prior to the hospitalization; patient and others agree to and are assessed as likely to comply with isolation of the patient at home until the patient is seen by the health department. I. Patient accepted into Alternative Housing Program.

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XII. DHR Community Guidelines for Respiratory Isolation of Patients with Active TB in the Community

In setting guidelines, the GA Department of Human Resources, Division of Public Health, follows CDC recommendations that a stepwise approach be used to seek the least intrusive policy that is consistent with maintaining the health of the community.
These guidelines provide a framework for clinical management of TB patients. The management of each patient must be customized to the individual's circumstances, living environment, and compliance with TB therapy. The guidelines classify active TB cases into three grades of infectiousness and two grades of organism resistance. They recommend appropriate levels of housing options and degrees of respiratory isolation for each grade of infectiousness and resistance.
Infectiousness is graded by AFB smear, TB culture results, clinical improvement in response to medical therapy, and evidence of adherence with therapy.
Grades of Infectiousness: Grade I: smear positive, culture positive Grade II: smear negative, culture positive or unknown Grade III: smear negative, culture negative Smear negative = three consecutive negative sputum AFB smears on separate days. Culture negative = three consecutive negative AFB cultures one week apart.
Drug sensitivity or drug resistance is based on the drug sensitivity of the patient's TB isolate. Sensitive isolates are those sensitive to all anti-TB drugs. Resistant strains are those resistant to one or more drugs.

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Housing options include home for patients who can return to a stable home and three levels of facilities for those without a stable home.

Levels of housing: Level 1: Acute care hospital Alternative Housing Program (smear positive, medically stable and clinical improving) Level 2: Shelters that require negative smears; trained staff provide DOT Alternative Housing Program (smear positive, medically stable and clinical improving) Level 3: Shelters that require negative cultures; trained staff for DOT available (e.g., Madison House in Atlanta or some church shelters)

These categories of respiratory isolation, based on guidelines from the National Jewish Center for Immunology and Respiratory Disease, regulate patient activities and use of masks based on grade of infectiousness:

A) Activity defined by the Level 1 institution; B) Home permitted provided that no new persons will be exposed
in the home; C) Wear mask to medical appointments, otherwise stay home; D) Wear mask only when indoors around groups of unexposed
people.
Per CDC guidelines, use simple surgical masks for patients.

Isolation categories apply to patients with clinical improvement in response to medical therapy (e.g., resolution of fever, diminished cough, reduced number of organisms on AFB smear) and evidence of adherence with therapy. DOT is the standard of care for all TB patients in Georgia.

Patients must cover all coughs or sneezes with double tissues and dispose of the tissues directly into the toilet or into a paper or plastic bag before putting them in the trash.

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All high risk contacts (i.e., immunocompromised individuals, inmates of correctional facilities, residents of long term care facilities, IVDUs, close contacts, children < 5 years of age) should be placed on treatment for latent TB infection for three months, unless otherwise contraindicated, regardless of results of skin testing and x-ray. If initial PPD is negative, PPD should be re-evaluated in three months.
NOTE: If patient is high risk for MDR-TB, manage as drug-resistant until susceptibilities are available and isolate is known to be sensitive. If at low risk for MDR-TB and clinically improving, patient can be managed with restrictions as for drug sensitive disease.

Infectiousness

Isolation Category

Organism Grade Smear Culture Resistance

No Stable Stable

Home

Home

Drug Resistant Level I (A) Home (BC) I Positive Positive
Drug Sensitive Level I (A) Home (BC)

II

Negative Positive or Drug Resistant Unknown Drug Sensitive

Level I (A) Level 2 (D)

Home (BC) Home (BD)

Drug Resistant Level 2,3 III Negative Negative
Drug Sensitive Level 2,3

Home Home

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XIII. References
American Thoracic Society and Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberclosis infection. Am J Respir Crit Care Med 2000; 161 (Pt2): S1-S27.
American Thoracic Society/Centers for Disease Control and Prevention. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149:1359-1374.
Blumberg HM, Watkins DL, Berschling JD, et al. Preventing the nosocomial transmission of tuberculosis. Ann Intern Med 1995; 122: 658-663.
Bock NN, Metzger BS, Tapia JR, Blumberg HM. A tuberculin screening and isoniazid preventive therapy program in an inner-city population. Am J Respir Crit Care Med 1999; 159:295-300.
Burman WJ, Jones BE. Treatment of HIV-related Tuberculosis in the Era of Effective Antiretroviral Therapy. Am J Resp Crit Care Med 2001;164:7-12.
Camins BC, Bock N, Watkins DL, Blumberg HM. Acceptance of isoniazid preventative therapy by health care workers after tuberculin skin test conversion. JAMA 1996; 275:1013-1015.
Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2000. June 2001 p. 1-73.
Centers for Disease Control and Prevention. Core Curriculum on Tuberculosis, 2000.
Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. MMWR 1994; 43 (RR-13): 1-132.

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Centers for Disease Control and Prevention. Updated guidelines for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors orninnucleoside reverse transcriptase inhibitors. MMWR 2000;49:185-189.

Centers for Disease Control and Prevention. Prevention and Treatment of Tuberculosis Among Patients Infected with Human Immunodeficiency Virus: Principles of Therapy and
Revised Recommendations. MMWR 1998;47(RR20):1-51.

Centers for Disease Control and Prevention. Anergy skin testing and preventive therapy for HIV-infected persons:revised recommendations. MMWR 1997; 46 (No.RR-15); 1-10.

Centers for Disease Control and Prevention. Update: Fatal and Severe Liver Injuries Associated With Rifampin and Pyrazinamide for Latent Tuberculosis Infection, and Revisions in American Thoracic Society/CDC Recommendations. MMWR
2001;50:733-735.

Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis: consensus statement of the Public Heath Tuberculosis Guidelines Panel. JAMA 1998; 279:943-8.

Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the litera-
ture. Clin Infect Dis 1997;25:872-877.

Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999; 282:677-86.

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Ellard GA. Chemotherapy of tuberculosis for patients with renal impairment. Nephron 1993; 64: 169-181.
Geiseler PJ, Manis RD, Maddux MS. Dosage of Antituberculous Drugs in Obese Patients. Am Rev Resp Dis 1985;131:944946.
Gordin F, Chaisson R, Matts J et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in hiv-infected persons. JAMA. 2000;283:1445-1450
Havlir DV, Barnes PF. Tuberculosis in patients with Human Immunodeficiency Virus infection, N Eng J Med 1999; 340:367-73.
Heyman SJ, Brewer TF, Wilson ME, Fineberg HV. The need for global action against multidrug-resistant tuberculosis. JAMA
Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329:784-791 . Malone RS, Fish DN, Spiegel DM, et al., The effects of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol. Am J Respir Crit Care Med 1999;159:1580-1584.
Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999; 281:10141018.
Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med 1998;158:157-61.

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Small PM, Fujiwara PI. Management of Tuberculosis in the United States. NEJM 2001;345:189-200
Starke JR, Correa AG. Management of mycobacterial infection and disease in children. Pediatric Infect Dis J 1995;14:455-470.
Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIVrelatedtuberclosis treated with once-weekly rifapentine and isoniazid. Lancet 1999; 353:1843-7.
Weis SE, Slocum PC, Blais FX, et al., The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994; 330:1179-1184.

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Division of Public Health, District Health Offices

District 1-1, Rome 706-295-6704
District 1-2, Dalton 706-272-2342
District 2, Gainesville 770-535-5743
District 3-1, Cobb 770-514-2362
District 3-2, Fulton 404-730-1450
District 3-3, Forest Park 770-471-8635
District 3-4, Lawrenceville 770-339-4260
District 3-5, DeKalb 404-294-3730
District 4, LaGrange 706-845-4035
District 5-1, Dublin 912-275-6545

District 5-2, Macon 912-751-6303
District 6, Augusta 706-721-5846
District 7, Columbus 706-321-6300
District 8-1, Valdosta 912-245-8711
District 8-2, Albany 912-430-2918
District 9-1, Savannah 912-356-2155
District 9-2, Waycross 912-389-4586
District 9-3, Brunswick 912-264-3961
District 10, Athens 912-542-9027
State TB Program, Atlanta 404-657-2634