AUTHOR INFORMATION

Section 1 of 12

Authored by James Li, MD, Assistant Professor, Division of Emergency Medicine, Harvard Medical School; Consulting Staff, Department of Emergency Medicine, Miles Memorial Hospital

Coauthored by Diana Brainard, MD, Consulting Staff, Department of Infectious Disease, Massachusetts General Hospital

James Li, MD, is a member of the following medical societies: American Academy of Emergency Medicine, and American College of Emergency Physicians

Edited by Theodore Gaeta, DO, MPH, Residency Director, Clinical Associate Professor of Emergency Medicine in Medicine, Department of Emergency Medicine, New York Methodist Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Eric L Weiss, MD, DTM&H, Director of Stanford Travel Medicine, Medical Director of Stanford Lifeflight, Assistant Professor, Departments of Emergency Medicine and Infectious Diseases, Stanford University School of Medicine; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Jonathan Adler, MD, Attending Physician, Department of Emergency Medicine, Massachusetts General Hospital; Division of Emergency Medicine, Harvard Medical School

Author's Email:	James Li, MD
Editor's Email:	Theodore Gaeta, DO, MPH

eMedicine Journal, March 13 2006, VOLUME 7, Number 3

INTRODUCTION

Section 2 of 12

Background: As with other scourges of the preantibiotic era, tuberculosis (TB) until recently was considered of passing historical significance to emergency physicians practicing in the developed world. In 1985, due primarily to the newly recognized HIV epidemic and to a growing indigent population, TB resurfaced in inner-city emergency departments. In 1991, highly virulent multi–drug-resistant (MDR) strains of Mycobacterium tuberculosis were reported by the Centers for Disease Control and Prevention (CDC). These strains not only produced fulminant and fatal disease among patients infected with HIV (TB exposure to death in 2-7 mo) but also proved highly infectious (conversion rates of up to 50% in exposed healthcare workers) (CDC MMWR, 1994). Recent recognition of the potential for catastrophic outbreaks resulting from MDR TB has led to national efforts for both surveillance and control.

Because of the prevalence of MDR strains, recommendations for pharmacologic management as well as exposure prophylaxis have evolved over the past decade. To avoid selecting drug-resistant organisms, treatment should begin with at least 4 medications until drug susceptibilities are known. (One in 106 tuberculous bacilli mutate and become isoniazid [INH] resistant.) In 1996, the CDC also provided recommendations for potential use of bacille Calmette-Guérin (BCG) vaccine in healthcare workers (see Special Concerns).

By virtue of the association between TB and poverty, the emergency physician may be a patient's only opportunity for recognition of mycobacterial infection. Note that drug treatment can and should be initiated in the emergency department (ED) for anyone suspected of having active TB infection and that these patients should be isolated and hospitalized.

Pathophysiology: A single cough can generate 3000 infective droplets. Fewer than 10 mycobacterial bacilli may initiate a pulmonary infection (Sherris, 1990). TB inoculation can result in latent infection or active disease. Depending on the population, 10-30% of inoculated individuals progress directly to active primary disease. More commonly, however, TB inoculation results in an asymptomatic latent infection. Skin test conversion and identification of a Ghon complex on chest radiography are the only means of identifying such cases.

Patients often remain healthy for years; however, some experience reactivation of their disease due to subsequent immunologic stressors. Such reactivation occurs at a rate of approximately 1% percent per year in immunocompetent hosts. The conversion rate is 10% in patients who are immunocompromised. While asymptomatic, patients with latent infection are not contagious. Most qualify for INH prophylaxis, which significantly decreases the risk of future reactivation of disease.

Roughly 80% of TB cases involve pulmonary disease, though TB can involve any organ system. In patients who are severely immunocompromised, extrapulmonary disease and atypical presentations are common.

Treatment markedly reduces infectivity. The first dose of medication reduces the bacillary load 10-fold. Therapy for 2 weeks reduces the bacillary load by a 100-fold factor (CDC, 1997). Patients require 3 negative sputum samples to be considered noninfectious, which usually necessitates treatment for 4 weeks.

Frequency:

• In the US: In 2004, the national active TB case rate was 4.9 cases per 100,000 persons, representing 14,511 reported cases and a decline of 3% from 2003. The majority of cases reported (60%) came from 7 states: California, Florida, Illinois, New York, New Jersey, Georgia, and Texas (CDC MMWR, 2004). In 1997, the CDC estimated that 1 in 17 persons has latent infection.

  Active TB cases decreased by about 6% per year from 1953-1979. From 1979-1981, immigration by Indochinese refugees caused a slight increase, but incidence again declined from 1982-1984. From 1985-1992, due to HIV infection and a sharp rise in homelessness, incidence increased by some 20%. From 1993-2004, due to national TB control measures, the rate of new cases fell from 9.8 to 4.9 per 100,000 persons, a relative decline of 50%.

• Internationally: TB still is on the top 10 list for all-cause, all-age worldwide mortality. It bears emphasis that 95% of all TB cases occur in developing countries. In 1988, TB was the ninth leading cause of death worldwide (Walsh, 1988).

  Worldwide, TB prevalence is about 2 billion persons. New cases number about 8 million yearly, and annual mortality worldwide is estimated at 3 million, accounting for 7% of total worldwide mortality.

  A 1998 international survey revealed that approximately 1 in 10 new cases of TB is a resistant strain, and 1 in 100 is MDR (Pablos-Mendez, 1998).

Mortality/Morbidity: Active TB was fatal for up to 50% of untreated patients, based on data collected prior to the advent of antibiotic therapy (Lindhardt, 1939). The US mortality rate from TB is currently 0.3 deaths per 100,000 persons—approximately 800 deaths per year. (The mortality rate in 1953 was 12.4 deaths per 100,000 persons.) This represents an annual mortality rate of approximately 6% of newly identified cases (CDC, 2004). MDR TB cases have a reported fatality rate of more than 70% (CDC MMWR, 1996).

Race: In the United States, two thirds of TB cases occur among minorities. The risk to people who are indigent is 300 times higher than the national risk (Slutkin, 1986); the risk for persons with HIV is 200-400 times greater. Other high-risk populations include hospital employees, inner-city residents, nursing home residents, persons with alcoholism, persons who use illicit drugs, and prisoners.

Sex: In the United States, overall incidence rates are twice as high for men as for women (CDC, 1994).

Age: Most TB cases are found in the 25- to 44-year-old age group. Two thirds of cases occur in minority populations, in which the median age at onset is 39 years. In nonminorities, the median age of onset is 62 years (Cantwell, 1994).

CLINICAL

Section 3 of 12

History: Inquire about historical features (eg, indigent, use of shelters, incarceration, HIV, travel to endemic area) that would increase a patient's risk of acquiring TB.

• Classic symptoms are often absent, particularly in patients who are immunocompromised or elderly. Up to 20% of patients with active TB may be asymptomatic. Classic features associated with active TB are as follows:

• Productive cough

• Hemoptysis

• Fever

• Night sweats

• Anorexia

• Weight loss

• Symptoms of extrapulmonary tuberculosis may be nonspecific.

Physical:

• Fever

• Cachexia

• Hypoxia

• Tachycardia

• Lymphadenopathy

• Abnormal lung sounds

• The absence of any significant physical findings does not exclude active disease. In the high-risk patient, respiratory isolation and sputum sampling are essential.

Causes: TB is caused primarily by direct inhalation of infective droplet nuclei. Transdermal and gastrointestinal (GI) transmission also have been reported. Infected patients living in crowded or closed environments pose a particular risk for noninfected persons.

DIFFERENTIALS

Section 4 of 12

Alcohol and Substance Abuse Evaluation
Asthma
Back Pain, Mechanical
Encephalitis
HIV Infection and AIDS
Meningitis
Neoplasms, Lung
Osteomyelitis
Panic Disorders
Pediatrics, Bacteremia and Sepsis
Pediatrics, Meningitis and Encephalitis
Pediatrics, Pneumonia
Pediatrics, Respiratory Distress Syndrome
Pericarditis and Cardiac Tamponade
Pleural Effusion
Pneumonia, Aspiration
Pneumonia, Bacterial
Pneumonia, Immunocompromised
Pneumonia, Mycoplasma
Pneumothorax, Iatrogenic, Spontaneous and Pneumomediastinum
Pneumothorax, Tension and Traumatic
Respiratory Distress Syndrome, Adult
Shock, Septic
Tuberculosis

WORKUP

Section 5 of 12

Lab Studies:

• In the ED setting, the two most important diagnostic tests are random sample sputum staining for acid-fast bacilli and chest radiography.

• Accept the diagnosis and initiate treatment if either of these tests indicates active disease.

• Ziehl-Neelsen staining of sputum is a simple 5-step process that takes approximately 10 minutes to accomplish (WHO, 1980).

• Do not delay the diagnosis until the following day for patients at high risk for active disease.

• Attempt several sputum collections or induce sputum production by respiratory physiotherapy.

• The absence of a positive smear result does not exclude active TB infection.

• Approximately 35% of culture-positive specimens are associated with a negative smear result.

• Blood cultures using mycobacteria-specific, radioisotope-labeled systems help establish the diagnosis of active TB and are recommended in all patients infected with HIV (Bouza, 1993). Mycobacterial bacteremia (bacillemia) is detectable using blood cultures but only if specialized systems are used because the bacilli have specific nutrient growth requirements not met by routine culture systems. Such blood cultures should be used for all patients with HIV who are suspected of having TB, as bacillemia is particularly prevalent in this population. If available, such cultures may be used on any patient with a high suspicion for active TB.

• One study found an incidence of 88% mycobacterial infection (66% TB, 22% Mycobacterium avium complex [MAC]) detected by blood culture in stage IV HIV disease).

• Most patients had insidious and atypical symptoms (Grinsztejn, 1997).

• All patients who are diagnosed with active TB and who are not known to be HIV positive should be considered for HIV testing. This testing is not usually initiated in the ED.

Imaging Studies:

• Chest radiography consistent with TB indicates active disease in the symptomatic patient even in the absence of a diagnostic sputum smear result. Similarly, normal chest radiography in the symptomatic patient does not exclude TB, particularly in a patient who is immunosuppressed.

• In classic reactivation TB, pulmonary lesions are located in the posterior segment of the right upper lobe, apicoposterior segment of the left upper lobe, and apical segments of the lower lobes. In the presence of HIV or other immunosuppressant disease, lesions are often atypical (Korzeniewska-Kosela, 1992). Up to 20% of patients who are HIV positive with active disease have normal chest x-ray findings.

• Radiographic findings consistent with active primary TB are similar to those of lobar pneumonia with ipsilateral hilar adenopathy, often accompanied by atelectasis.

Other Tests:

• Tuberculin skin testing using 5 units (0.1 mL) of purified protein derivative (PPD) injected intradermally may be used for screening or to supplement other diagnostic testing.

• Positive criteria are population dependent, but any induration of 5 mm or more is now suspect.

• Induration, not erythema, is measured 48-72 hours following injection, although positive test results can be declared up to a week after placement.

• Approximately 20% of patients with active TB, particularly those with advanced disease, may have normal PPD test results.

• Testing is also unreliable in infants, patients with immunosuppressive conditions, and patients with serious illnesses (Canadian Thoracic Society, 1994).

• Population-based criteria for PPD positivity

• Patients who are HIV positive, have abnormal chest radiography, or have recent contact with active TB cases - 5-mm induration or more

• Patients who are IV drug users, residents of nursing homes, prisoners, impoverished, or members of minority groups - 10-mm induration or more

• Patients who are young and in good health - 15-mm induration or more

• Reactions in patients who have received the BCG vaccine are often difficult to interpret.
  • In adults who received BCG vaccination at birth, consider a 10-mm induration or more a positive result.

  • In persons receiving BCG vaccination as adults, consider a 30-mm induration (or larger) a positive result (King, 1990).

TREATMENT

Section 6 of 12

Prehospital Care:

• Prehospital providers should be equipped with respiratory masks meeting standards for prevention of TB transmission and should receive annual tuberculin skin testing.

• For high-risk cases, prehospital workers can assist in identifying household contacts who also may be infected or who may be at high risk of becoming infected. Prehospital workers should be aware that any case of active TB in a child indicates disease in 1 or more adults within the same household (CDC MMWR, 1996).

• A special regimen exists for patients with TB who are actively seizing or who have overdosed on antimycobacterial medication.

• In these patients, overdose with INH should be suspected.

• Diazepam can be attempted to control seizure activity, but IV pyridoxine is the drug of choice, in a gram-for-INH-ingested-gram dose. (If the ingested dose is unknown, 5 g of pyridoxine can be used empirically.)

• For patients who are awake and alert, an oral dose of activated charcoal (1 g/kg) with sorbitol can be administered.

Emergency Department Care: Isolate any patient with suspected TB infection in a private room (not cohorted, as in the past), ideally with negative pressure. Anyone entering should wear high-efficiency disposable masks sufficient to filter the TB bacillus. Continue isolation until sputum smears return negative results 3 consecutive times. Such sterilization usually requires 2-4 weeks of treatment and must be accompanied by clinical improvement (CDC MMWR, 1994).

• Initial 4-drug therapy is recommended in most areas. Intermittent treatment is as effective as daily treatment (~2% relapses) with the advantage of increased compliance (see below).

• Six-month course, daily therapy - The compliance rate is 61%.
  • Initial 2 months (all PO doses) - INH 300 mg qd (pediatric dose: 10-20 mg/kg/d, not to exceed 300 mg/d); rifampin (RIF) 600 mg qd (pediatric: 10 mg/kg/d, not to exceed 600 mg/d); pyrazinamide (PZA) 2 g qd (pediatric: 25 mg/kg/d, not to exceed 2 g/d); and ethambutol (ETB) 2 g qd (pediatric dose: 25 mg/kg/d, not to exceed 2 g/d)

  • ETB may be dropped if TB culture drug sensitivities return favorable results.

  • Final 4 months (if initial 2 months are successful by smear conversion and resolving symptoms) - INH 300 mg qd and RIF 600 mg qd or, alternatively, INH 900 mg and RIF 600 mg twice weekly.

• Six-month course, directly observed intermittent therapy (Denver protocol) - The compliance rate is 91%.
  • Initial 2 weeks (all PO doses except for streptomycin, which is administered IM) - INH 300 mg qd, RIF 600 mg qd, PZA 2 g qd, and streptomycin 1 g qd (pediatric dose: 20 mg/kg/d, not to exceed 1000 mg/d)

  • Next 6 weeks - Same drugs twice weekly

  • Final 18 weeks - INH and RIF only, twice weekly

  • Relapse rate - Comparable to daily 6-month protocol (1.6%) (CDC, 1997)

• Special cases

• Patients who are HIV positive - Extend the treatment protocol to a minimum of 9 months (final stage, 7 mo) with at least 6 months’ culture-negative sputum.

• Patients who are pregnant - A 9-month daily course of INH, RIF, and ETB is recommended in the doses above.
  • Breastfeeding is permitted.

  • PZA is contraindicated due to inadequate teratogenicity data.

  • Streptomycin is discouraged unless other drugs are contraindicated (16% fetal ototoxicity).

• Patients who have meningitis - Dexamethasone added to routine 4-drug therapy reduces complications.

• Multi–drug-resistant tuberculosis
  • Administer all of the following - An injectable anti-TB aminoglycoside (eg, amikacin, capreomycin, kanamycin), a fluoroquinolone (eg, ciprofloxacin, ofloxacin), ETB, PZA, INH, RIF, and cycloserine, ethionamide, or amino salicylic acid.

  • Consider rifabutin substitution for RIF, as approximately 30% of RIF-resistant strains are rifabutin sensitive.

  • Do not use intermittent therapy.

  • Clusters of MDR TB with 7-drug resistance have been reported and have a high infectivity rate.

  • The healthcare worker PPD conversion rate is 18-50% with exposure to MDR TB.

Consultations: Due to changing recommendations, particularly with regard to the treatment of drug-resistant TB, expert consultation for TB management is available from several national centers.

• For information on current national policies and recommendations, call the CDC Division of Tuberculosis Elimination at (404) 639-8140. The CDC Voice and Fax Information System is also available at 1-888-232-3228.

• For expert consultation on the management of drug-resistant TB, call one of the following national Model TB Centers:
  • San Francisco Model TB Center - (415) 502-4700

  • New York City Model TB Center - (212) 939-8254

MEDICATION

Section 7 of 12

Treatment of TB has 3 basic therapeutic principles. First, any regimen must use multiple drugs to which M tuberculosis is susceptible. Second, the therapy must be taken regularly. Third, the therapy must continue for a period sufficient to resolve the illness.

In the United States, anti-TB therapy is available to all patients at no cost through the Department of Health (see Emergency Department Care).

Drug Category: Anti-TB agents -- Patients thought to have pulmonary TB whose sputum smear returns positive for acid-fast bacillus can be presumptively diagnosed and treated with anti-TB therapy. TB therapy also may be appropriate in patients with a negative sputum smear who have clinical and radiographic findings consistent with pulmonary TB. Immediately treat severely ill patients with presumed TB because a few days on anti-TB agents does not interfere with bacteriologic diagnosis.

Drug Name	Isoniazid (Laniazid, Nydrazid) -- Best combination of effectiveness, low cost, and minor adverse effects. First-line drug unless known resistance or another contraindication exists. Therapeutic regimens of <6 mo demonstrate unacceptably high relapse rates. Coadministration of pyridoxine is recommended if peripheral neuropathies secondary to INH therapy develop. Prophylactic doses of 6-50 mg of pyridoxine daily are recommended.
Adult Dose	5 mg/kg PO qd (usually 300 mg/d); not to exceed 300 mg/d
Pediatric Dose	10-20 mg/kg PO qd; not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; previous INH-associated hepatic injury or other severe adverse reactions
Interactions	Higher incidence of INH-related hepatitis can occur with daily alcohol ingestion; aluminum salts may decrease INH serum levels (administer 1-2 h before taking aluminum salts); may increase anticoagulants effects with coadministration; may inhibit metabolic clearance of benzodiazepines; carbamazepine toxicity or INH hepatotoxicity may result from concurrent use (monitor carbamazepine concentrations and liver function); coadministration with cycloserine may increase CNS adverse effects (eg, dizziness); acute behavioral and coordination changes may occur with coadministration of disulfiram; coadministration with RIF after halothane anesthesia may result in hepatotoxicity and hepatic encephalopathy; may inhibit hepatic microsomal enzymes and increase toxicity of hydantoin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor patients with active chronic liver disease or severe renal dysfunction; periodic ophthalmologic examinations during INH therapy are recommended even when visual symptoms do not occur

Drug Name	Rifampin (Rifadin, Rifadin IV, Rimactane) -- For use in combination with at least 1 other anti-TB drug; inhibits DNA-dependent bacterial polymerase but not mammalian RNA polymerase. Cross-resistance may occur. Treat for 6-9 mo or until 6 mo have elapsed from conversion to sputum culture negativity.
Adult Dose	600 mg PO/IV qd
Pediatric Dose	10-20 mg/kg PO/IV; not to exceed 600 mg/d
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with INH may result in higher rate of hepatotoxicity than with either agent alone (discontinue 1 or both agents if alterations in LFTs occur)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Obtain CBCs and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Drug Name	Pyrazinamide -- Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis, depending on concentration of drug attained at site of infection; mechanism of action is unknown. Administer for initial 2 mo of a 6-mo (or longer) treatment regimen for drug-susceptible patients. Treat drug-resistant patients with individualized regimens.
Adult Dose	15-30 mg/kg PO qd; not to exceed 2 g/d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severe hepatic damage, acute gout
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use only in combination with other effective anti-TB agents; inhibits renal excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline serum uric acid determinations; discontinue drug if signs of hyperuricemia with acute gouty arthritis manifest; perform baseline LFTs (closely monitor in liver disease); discontinue if signs of hepatocellular damage appear; caution in history of diabetes mellitus

Drug Name	Ethambutol (Myambutol) -- Diffuses into actively growing Mycobacterium cells such as tubercle bacilli. Inhibition in the synthesis of 1 or more metabolites impairs cell metabolism, which in turn inhibits bacterial multiplication and causes cell death. No cross-resistance with other agents has been demonstrated. Mycobacterial resistance to drugs used in initial therapy is frequent in patients who have received previous therapy. Useful in treatment of these groups of patients when administered with at least 1 of the second-line drugs that have not previously been administered to the patient and to which bacterial susceptibility has been shown. Administer this medication once every 24 h only, and continue therapy until bacteriological conversion has become permanent and maximal clinical improvement has occurred. Absorption is not significantly altered by administration with food.
Adult Dose	No previous anti-TB therapy: 15 mg/kg (7 mg/lb) PO qd Previous anti-TB therapy: 25 mg/kg (11 mg/lb) PO qd
Pediatric Dose	<13 years: Not recommended >13 years: Administer as in adults
Contraindications	Documented hypersensitivity; optic neuritis (unless clinically indicated)
Interactions	Aluminum salts may delay and reduce absorption (administer several hours before or after ETB dose)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Reduce dose in impaired renal function; may have reversible visual adverse effects if promptly discontinued

Drug Name	Streptomycin sulfate -- For treatment of susceptible mycobacterial infections. Use in combination with other anti-TB drugs (eg, INH, ETB, RIF). Total period of treatment for TB is a minimum of 1 y; however, indications for terminating streptomycin therapy may occur at any time. Recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.
Adult Dose	1 g IM qd
Pediatric Dose	20-40 mg/kg/d IM; not to exceed 1 g/d
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Narrow therapeutic index; not intended for long-term therapy; caution in renal failure not on dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission

Drug Name	Capreomycin (Capastat) -- Obtained from Streptomyces capreolus for coadministration with other anti-TB agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. For use only when first-line agents (eg, INH, RIF) have been ineffective or cannot be used because of toxicity or presence of resistant tubercle bacilli.
Adult Dose	1 g IM qd for 60-120 d; followed by 1 g IM 2-3 times weekly; not to exceed 20 mg/kg/d
Pediatric Dose	15 mg/kg/d IM; not to exceed 1 g/d
Contraindications	Documented hypersensitivity
Interactions	Coadministration with aminoglycosides may increase risk of respiratory paralysis and renal dysfunction; with nondepolarizing neuromuscular blocking agents has synergistic effects on myoneural function
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Assess vestibular auditory function prior to therapy and regularly while treating; monitor renal function throughout treatment (reduce dose in renal impairment); monitor serum potassium levels

Drug Name	Clofazimine (Lamprene) -- Inhibits mycobacterial growth, binds preferentially to mycobacterial DNA. Has antimicrobial properties, but mechanism of action is unknown. Always use with other anti-TB agents.
Adult Dose	100 mg/d PO
Pediatric Dose	1 mg/kg/d PO
Contraindications	Documented hypersensitivity
Interactions	Dapsone may inhibit anti-inflammatory activity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Severe abdominal symptoms may require exploratory laparotomies; caution in patients with GI problems (eg, abdominal pain, diarrhea); skin discoloration due to drug may result in depression or suicide; apply oil to skin for dryness and ichthyosis

Drug Name	Cycloserine (Seromycin) -- Inhibits cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in M tuberculosis. Structural analogue of D-alanine, which antagonizes role of D-alanine in bacterial cell wall synthesis, thus inhibiting their growth.
Adult Dose	500 mg to 1 g PO qd in divided doses monitored by blood levels Alternatively, 250-500 mg PO bid for first 2 wk; not to exceed 1 g/d Pyridoxine administered at 200-300 mg/d may prevent neurotoxic effects
Pediatric Dose	10-20 mg/kg/d PO; not to exceed 0.75-1 g/d
Contraindications	Documented hypersensitivity; severe anxiety or psychosis, epilepsy, depression; severe renal insufficiency; alcoholism; patients with severe neurological impairments should not receive the drug
Interactions	Incompatible with alcohol consumption because may increase possibility and risk of epileptic episodes; INH in combination with cycloserine may result in increased CNS adverse effects such as dizziness
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue drug or reduce dosage if allergic dermatitis or symptoms of CNS toxicity, such as convulsions, headache, tremor, depression, confusion, psychosis, somnolence, hyperreflexia, vertigo, paresis or dysarthria, develop; risk of convulsions is increased in persons with chronic alcoholism; administration has been associated with vitamin B-12 and folic acid deficiency, megaloblastic anemia, and sideroblastic anemia; monitor blood levels weekly in reduced renal function, patients receiving more than 500 mg/d, and those with symptoms of toxicity

Drug Name	Ethionamide (Trecator) -- Bacteriostatic against M tuberculosis. Recommended when treatment with first-line drugs (INH, RIF) has failed. Treats any form of active TB. Use only with other effective anti-TB agents
Adult Dose	0.5-1 g/d PO divided qid; concomitant administration of pyridoxine recommended
Pediatric Dose	15-20 mg/kg/d PO divided tid/qid; not to exceed 1 g/d; concomitant administration of pyridoxine recommended
Contraindications	Documented hypersensitivity; severe hepatic damage
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Make determinations of serum transaminase (AST, ALT) prior to therapy and q2-4wk thereafter; perform in vitro susceptibility tests of recent cultures of M tuberculosis from patient with ethionamide and usual first-line anti-TB drugs; management of diabetes mellitus may be more difficult, and hepatitis may occur more frequently

Drug Name	Dapsone (Avlosulfon) -- Bactericidal as well as bacteriostatic against Mycobacterium strains. The mechanism of action is similar to that of sulfonamides, in which competitive antagonists of PABA prevent the formation of folic acid, causing bacterial growth inhibition. Use in the treatment of TB is largely experimental.
Adult Dose	50-300 mg/d PO
Pediatric Dose	1-2 mg/kg/d PO; not to exceed 100 mg/d
Contraindications	Documented hypersensitivity; known G-6-PD deficiency
Interactions	May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during the second and third months of therapy); probenecid increases toxicity; trimethoprim with dapsone may increase toxicity of both drugs; due to increased in renal clearance, dapsone levels may significantly decrease when administered concurrently with RIF
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Perform weekly blood counts (first month); then perform WBC counts monthly (6 mo); then semiannually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is seen; caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M due to high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light

Drug Name	Ciprofloxacin (Cipro) -- Useful in the treatment TB in combination with RIF and other anti-TB agents.
Adult Dose	750 mg PO bid
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Levofloxacin (Levaquin) -- Inhibit growth of susceptible organisms by inhibiting DNA gyrase and promoting breakage of DNA strands.
Adult Dose	750 mg PO q24h for 7-14 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Arrange for identification and prophylactic treatment of all contacts.

• Baseline labs for patients undergoing treatment for active TB include liver transaminases, bilirubin, blood count, platelet count, urea nitrogen, creatinine, and, if therapy includes PZA, uric acid. On discharge, conduct monthly follow-up appointments with sputum mycobacterial culture and sensitivity.

• Directly observed therapy (DOT) has proved successful in ensuring ongoing compliance with TB therapy, particularly in areas with high rates of multidrug resistance.

• Consider HIV testing.

Complications:

• Cavitary lesions

• Spread to susceptible persons

• Drug resistance

Prognosis:

• Generally, few complications ensue, and full resolution is expected if the drug regimen is completed.

Patient Education:

• For excellent patient education resources, visit eMedicine’s Bacterial and Viral Infections Center. Also, see eMedicine’s patient education article Tuberculosis.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Patients with active TB who are persistently nonadherent with treatment present a public health hazard. Accordingly, legal measures have been initiated in several states allowing for civil or criminal detention of such patients for DOT (Oscherwitz, 1997).

• At this writing, such measures have been enacted in the following locations:
  • New York City (New York City Health Code 1994;11.47 and 11.55)

  • Louisiana

  • California (Calif Health and Safety Code 1996;120175-121400)

  • Massachusetts (Mass Gen Laws 1996;94(A)-94(H))

  • Florida (Fla Pub Health Code 1996;309.02-392.69)

• In 1997, federal legislation established a cooperative agreement between Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont on the legal detention of patients with TB who refuse treatment (Senate Bill S97-0388, passed Senate and House June 11, 1997).

Special Concerns:

• Among immunocompetent adults who have latent TB, the risk of reactivation is approximately 0.5-1% per year or 15% during the course of a lifetime (Stead, 1987).

• The risk of reactivation is greatest in the first 2 years following initial infection.

• In patients with HIV and TB infection, the risk of reactivation is 10% per year.

• Patients who have HIV without latent disease have a 5% per year risk of developing active primary disease (Hyman, 1995).

• Consider INH prophylaxis in anyone (regardless of age) who has a positive PPD test result in the last 2 years due to the significant likelihood of reactivation disease later in life.
  • In addition, prophylaxis is recommended for those patients (regardless of age) who have distant conversions (>2 y prior), who are HIV positive, who use IV drugs, or who have comorbid medical conditions. Prophylaxis also is recommended for known contacts of patients with active TB.

  • Additionally, prophylaxis is recommended for patients younger than 35 years with distant conversions who are foreign-born, impoverished, employed as healthcare workers, or living in long-term institutions.

  • Pregnant women with recent skin conversions can begin INH following the first trimester. Those with distant conversions can wait until after delivery.

• Protocols vary as follows:
  • Three common protocols include INH 300 mg PO qd for 12 months (75% risk reduction), INH 300 mg PO qd for 6 months (65% risk reduction), and INH 900 mg PO twice weekly for 12 months (unknown risk reduction but likely efficacious).

  • The dose for children is INH 10-20 mg/kg/d. Recently, INH 300 mg PO qd and RIF 600 PO qd for 3 months was demonstrated to provide a 60% risk reduction in patients who are HIV positive.

  • Alternatives currently being studied include RIF 600 mg PO qd for 4 months and RIF 600 mg PO qd plus PZA 1 g PO qd for 2 months. The latter course recently was demonstrated to provide identical risk reduction when compared to 12 months of daily INH (Gordin, 2000).

• A common concern relating to INH prophylaxis is the rate of INH-associated hepatitis. Such rates are age-dependent and are greatly increased with significant ethanol consumption.
  • Instruct patients on INH prophylaxis to refrain from ethanol use.

  • For patients younger than 35 years, the relative risk of death from reactivation TB (>6%) outweighs the risk of death from INH-related hepatitis ( <1%).

  • Halt INH therapy if liver transaminase levels rise to 3 times or more above pretreatment levels.

• The rate of INH toxicity is probably much lower than has been reported. Recent analysis of data from a longitudinal survey of 11,141 consecutive patients treated with preventive INH therapy yielded a total rate for hepatotoxic reactions of 0.10% (n=11) and no mortality. This compares to previously reported rates of 0.5-2.0%. Such data should give clinicians greater confidence in the safety of INH preventive therapy.

• In 1996, due to increased rates of MDR TB, the CDC released updated recommendations for use of the BCG vaccine within the United States.
  • Published data evaluating the efficacy of BCG vaccination in preventing pulmonary TB, particularly when used in adulthood, has been disappointing.

  • BCG vaccination’s greatest utility appears to be in the prevention of meningeal and miliary TB in children, for whom it has demonstrated efficacy rates of 65-95%.

• The CDC recommends BCG vaccination for the following 2 populations (CDC MMWR, 1996).
  • Healthcare workers employed in settings with a high likelihood of transmission of TB resistant to both INH and RIF, provided other TB control precautions have failed to prevent transmission

  • Children or infants living in settings where the risk of TB (drug resistant or not) transmission is high, when removal of such children from such settings is not possible

TEST QUESTIONS

Section 10 of 12

CME Question 1: A single cough has been estimated to produce 3000 droplet nuclei. Assuming that 1 in 10 droplets contains a tuberculosis (TB) bacilli, exposure to how many coughs from a patient with active TB is required to initiate an infection in an immunocompetent healthcare worker?

A: Two
B: Three
C: Four
D: Seven
E: None of the above

The correct answer is E: Fewer than 10 mycobacterial bacilli are required to initiate a pulmonary infection. Thus, 0.03 coughs may start an infection in the exposed healthcare worker. Infectivity in cases of multi–drug resistant TB is even higher, with up to 50% of healthcare workers reporting skin conversion in some series. This underscores the necessity of measures to prevent transmission in the ED setting.

CME Question 2: Guidelines published by the Centers for Disease Control and Prevention (CDC) recommend isoniazid prophylaxis for healthcare workers who have purified protein derivative (PPD) skin test conversions and meet which of the following additional criteria?

A: Recent skin test conversion and age younger than 35 years
B: Any history of skin test conversion and age younger than 35 years
C: Recent skin test conversion and age older than 35 years
D: Recent skin test conversion and any age
E: All of the above

The correct answer is E: The CDC recommends isoniazid prophylaxis for anyone with recent PPD skin conversion, regardless of age or employment status. For persons who have a history of skin conversion for more than 2 years (considered distant conversions), other, more confusing, criteria apply. In such cases, the CDC recommends prophylaxis for healthcare workers younger than 35 years and suggests consideration of prophylaxis in workers who are older. This is often a point of confusion, leading to poor compliance with national recommendations and a high potential for reactivation disease.

Pearl Question 1 (T/F): An emergency physician has worked in the field for 5 years, at which time her annual purified protein derivative (PPD) skin test turned positive. Without isoniazid prophylaxis, her chance of developing reactivation tuberculosis in the future is more than 10%.

The correct answer is True: The chance of developing active disease is 0.5-1.0% per year or roughly 15% over the remainder of her lifetime. If she had HIV, the rate would jump to 10% per year.

Pearl Question 2 (T/F): Patients with active tuberculosis should be started on combination drug therapy in the ED. Four drugs are used in the initial treatment of these cases. For suspected multi–drug-resistant tuberculosis, 7 drugs should be used initially.

The correct answer is True: For routine cases, initiate treatment with 4 drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. For cases of multi–drug-resistant tuberculosis, initiate treatment with 7 drugs by adding amikacin, ciprofloxacin, and cycloserine. Consider changing rifampin to rifabutin. Consult a national expert center for possible changes to this regimen.

Pearl Question 3 (T/F): A patient with AIDS (known to be undergoing 4-drug treatment for active pulmonary tuberculosis) overdosed on one of his anti-mycobacterial medications and is in seizure. (The treatment of choice for this seizure is a benzodiazepine, often in high doses.) An overdose of rifampin probably caused his seizure.

The correct answer is False: He probably ingested an overdose of isoniazid. Treat with intravenous pyridoxine in a gram-for-ingested-INH-gram dose. Benzodiazepines, intubation, and possible intravenous bicarbonate also may be beneficial.

Pearl Question 4 (T/F): Tuberculosis is not detectable by blood cultures.

The correct answer is False: Mycobacterial bacteremia (bacillemia) is detectable using blood cultures but only if the mycobacteria-specific, radioisotope-labeled BACTEC 13A system is used because the bacilli have specific nutrient growth requirements not met by routine culture systems. The BACTEC 13A system should be used for all patients with HIV who are suspected of having tuberculosis, as bacillemia is particularly prevalent in this population. If available, the system may be used on any patient with a high suspicion for active tuberculosis.

PICTURES

Section 11 of 12

Caption: Picture 1. Anteroposterior chest radiograph in a young ED patient presenting with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. (Image courtesy of Remote Medicine, remotemedicine.org)
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Caption: Picture 2. Lateral chest radiograph in the patient above. (Image courtesy of Remote Medicine, remotemedicine.org)
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BIBLIOGRAPHY

Section 12 of 12

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