New recommendations for the treatment of tuberculosisJoseph P. Myers The aim of this article is to give practicing physicians a While the incidence of active tuberculosis in the United practical approach to the treatment of latent and active States continues to decrease, it is estimated that there are tuberculosis and to review newer recommendations and eight million new cases per year worldwide as well as common problems encountered in the treatment of patients approximately two million deaths per year More than one third of the world’s population is infected with Mycobacterium tubercThe continued immigration Recently published literature documents the increased of high-risk persons to the United States and the world- incidence of multidrug resistant strains of Mycobacterium wide pandemic of HIV infection with its attendant tuberculosis, the importance of antituberculosis drug increased risk of tuberculosis infection make continued toxicities and drug–drug interactions, persistent problems vigilance for active and latent tuberculosis mandatory for in the correct interpretation of the tuberculin skin test and any practicing physician. I will review the latest recom- ongoing problems with treatment compliance and treatment mendations for treatment of latent and active tubercu- losis in the United States with special attention given to recently updated recommendations including the bene- This article provides a practical approach to the fits of directly observed therapy; the importance of interpretation of the tuberculin skin test, the proper sputum cultures at the completion of the ‘initial phase’ approach to the treatment of latent tuberculosis infection, of therapy in determining the remaining course of treat- and a structured approach to the treatment of presumed or ment; the appropriate use of extended treatment regi- documented active tuberculosis infection. Questions about mens; the roles of new antimycobacterial agents in tuberculosis that are often asked of infectious disease and treatment; the definition of ‘treatment completion’ based pulmonary specialists are addressed in a very practical upon numbers of doses taken; the treatment of tubercu- losis in special situations such as in HIV-infected persons;and the management of drug-resistant tuberculosis. I will also try to address questions often asked of infectious active tuberculosis, isoniazid, latent tuberculosis, rifampin, disease and pulmonary disease specialists about the tuberculin skin test (TST), the definition of latent tuber-culosis infection (LTBI) and the influence of Bacille Curr Opin Infect Dis 18:133–140. # 2005 Lippincott Williams & Wilkins.
Calmette-Guerin (BCG) vaccination on recommendationsfor treatment of LTBI. Excellent discussions regarding Department of Internal Medicine, Northeastern Ohio Universities College of non-treatment issues such as epidemiology, pathophy- siology, pathology and diagnosis can be found in text- Correspondence to Joseph P. Myers, MD, Summa Health System, 75 Arch Street,Suite 105, Akron, OH 44304, USA books and in the joint recommendations of the American Tel: +1 330 375 3894; fax: +1 330 375 3161; e-mail: Thoracic Society (ATS)/Centers for Disease Control Current Opinion in Infectious Diseases 2005, 18:133–140 and Prevention (CDC)/Infectious Diseases Society ofAmerica (IDSA) published in 2003 Centers for Disease Control and Prevention In the year 2000, the CDC published new guidelines for the TST that included major changes from longstanding recommendations regarding who should undergo TSTscreening, how the TST should be interpreted, what treatment should be provided, and which patients require initial and follow-up laboratory monitoring during the Reprinted from Current Opinion in Infectious Diseases 2005, 18:133–140 treatment for LTBI The changes presented in thatCDC document caused considerable confusion to noviceand experienced physicians alike. I will address thechanges recommended by this document and try tosimplify the approach to both TST interpretation andresultant approaches to the treatment of LTBI Who should be tested with the tuberculin skin test? chest radiograph consistent with previous tuberculosis The new recommendations stress the administration of (defined as fibrotic opacities occupying more than 2 cm2 the TST to those persons who have a high risk of of the upper lobe only), and immunosuppressed patients developing active tuberculosis and who would benefit receiving the equivalent of !15 mg or greater of predni- from treatment of latent tuberculosis infection In the sone per day for more than 1 month .
United States today the incidence and epidemiology oftuberculosis do not mandate or support large population Induration of 10 mm or greater is considered a positive screenings as was the case in the mid-20th century. The TST for foreign-born persons recently arrived (<5 years new tuberculin skin testing strategies target those groups earlier) from a country with a high prevalence of tuber- at high risk and discourage testing in population groups at culosis; for persons with a medical condition that low risk of acquiring tuberculosis Those persons who increases the risk of tuberculosis (see prior section); for should be tested include those with an increased risk of injection drug-users; for medically underserved, low- exposure to infectious cases, those with an increased risk income populations especially homeless persons; for of tuberculosis infection, and those with an increased risk residents and staff of long-term care facilities including of progression to active tuberculosis once infection has nursing homes, correctional institutions and homeless occurPersons with an increased risk of exposure to shelters; for health care workers; for children <4 years infectious cases include recent close contacts of persons of age, and for persons with recent conversion of a with known active tuberculosis and health care workers at tuberculin skin test defined as an increase in induration facilities where patients with active tuberculosis are of the TST of 10 mm or greater within a 2-year period treated Persons with an increased risk of tuberculosis infection include foreign-born persons from countrieswith a high prevalence of tuberculosis, homeless persons, Induration of 15 mm or greater is considered a positive and persons living or working in facilities providing long- TST for all others at increased risk of tuberculosis term care Those with an increased risk of active infection. People should not undergo routine TST tuberculosis once infection has occurred include HIV- screening in the absence of an indication for increased infected persons, injection drug-users, persons receiving risk of tuberculosis infection. Those who do not meet the immunosuppressive therapy, and patients with end-stage criteria for receiving a TST (see section ‘Who should be renal disease, silicosis, diabetes mellitus, hematologic tested?’) and who inadvertently undergo TST and are malignancies, prior gastrectomy, prior jejunoileal bypass, found to have induration of 15 mm or greater do not severe malnutrition (defined as those with a recent unin- necessarily qualify for treatment of LTBI unless a sig- tended weight loss of more than 10% of their ideal body nificant risk factor for tuberculosis infection can be weight), and those with recent tuberculosis infection (defined as children 4 years of age with !10 mminduration of a tuberculin skin test or persons with A whole blood test measuring the release of interferon-g !10 mm increase in induration of a tuberculin skin test produced in response to stimulation by PPD has been within a 2-year period) School children, food-service approved by the US Food and Drug Administration and workers, and employees of enterprises with no increased may be used to diagnose latent tuberculosis The risk of tuberculosis exposure should no longer be interferon-g assay may be used as an alternative to TST or to confirm or deny LTBI in persons with either anequivocal TST or hypersensitivity to the tuberculin What are the current criteria for a positive tuberculin antigen (PPD) in the standard TST. A positive inter- feron-g assay should be considered an indicator of LTBI A standard tuberculin skin test consists of five tuberculin and appropriate treatment should be initiated as soon as units (0.1 ml) of purified protein derivative (PPD) admi- possible after active tuberculosis has been excluded nistered intracutaneously and usually on the volar surface Prior administration of BCG vaccine should not be taken of the arm. Administration by a person experienced in the into account when interpreting the TST or when decid- correct technique of intracutaneous injection is recom- ing whether or not treatment for LTBI should be insti- mended. The skin should be ‘read’ in 48–72 h and results tuted as long as the person meets criteria for both TST should be interpreted based upon the size of induration administration and TST positivity by the previously Once the level of induration is determined, the guidelines that follow should be used to decide if theTST is considered to be ‘positive’.
Active tuberculosis should always be excluded beforetreatment of LTBI is initiated. Any person with a positive Induration of 5 mm or greater is considered a positive test TST should undergo a detailed history, physical exam- for HIV-infected persons, for close contacts of persons ination, chest radiograph, and appropriate laboratory with infectious tuberculosis, for persons with an abnormal testing including mycobacterial cultures of sputum, urine Table 1. Treatment for latent tuberculosis infection in may be administered concurrentlywith nucleoside reverse transcriptaseinhibitors (NRTIs), protease inhibitors,or non-nucleoside reversetranscriptase inhibitors (NNRTIs).
must be used with twice-weeklydosing.
persons, those with fibrotic lesionson chest radiographs, or children.
of patients with isoniazid-resistant,rifampin-susceptible TB.
protease inhibitors or delavirdineshould not be administeredconcurrently with rifampin. Rifabutinwith appropriate dose adjustmentscan be used with protease inhibitors(saquinavir should be augmentedwith ritonavir) and NNRTIs(except delavirdine). Clinicians shouldconsult web-based updates forthe latest specific recommendations.
for treatment of LTBI for HIV-infectedor HIV-negative persons.
bInteractions with HlV-related drugs are updated frequently and are available at cStrength of the recommendation: A, both strong evidence of efficacy and substantial clinical benefit support recommendation for use. Should alwaysbe offered. B, moderate evidence for efficacy or strong evidence for efficacy but only limited clinical benefit supports recommendation for use. Shouldgenerally be offered. C, evidence for efficacy is insufficient to support a recommendation for or against use, or evidence for efficacy might not outweighadverse consequences (e.g., drug toxicity, drug interactions) or cost of the treatment or alternative approaches. Optional. D, moderate evidence for lackof efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered. E, good evidence for lack of efficacy or foradverse outcome support a recommendation against use. Should never be offered.
dQuality of evidence supporting the recommendation: I, evidence from at least one properly randomized controlled trial. II, evidence from at least onewell-designed clinical trial without randomization from cohort or case-controlled analytic studies (preferably from more than one center), from multipletime-series studies, or from dramatic results from uncontrolled experiments. III, evidence from opinions of respected authorities based on clinicalexperience, descriptive studies, or reports of expert committees.
eRecommended regimen for persons aged <18 years.
fRecommended regimens for pregnant women.
gThe substitution of rifapentine for rifampin is not recommended because rifapentine’s safety and effectiveness have not been established for patientswith LTBI.
and blood before latent tuberculosis is assumed or treated will be effective for most adult patients with the excep- tions noted above and for those exposed to known iso-niazid-resistant strains of M. tuberculosis. The 4-month What are the recommended treatment regimens for rifampin regimen should be used for those persons intol- erant of isoniazid and for those persons with known The current recommendations for the treatment of LTBI exposure to isoniazid-resistant strains. The 2-month are delineated in the modified recommendations from mended as an alternative treatment regimen for LTBI is recommended for patients infected with the HIV, was accompanied by an unacceptable rate of severe patients with fibrotic lesions on chest radiographs, and and potentially fatal hepatic injury It should no longer for children especially those less than 4 years of age.
be used for preventive therapy but should continue to be Twice weekly directly observed therapy may be substi- used in multidrug regimens for the treatment of active tuted for daily therapy. The 6-month isoniazid regimen How should the physician treat latent tuberculosis logic information, clinical examination, pathological infection in patients with underlying liver disease? materials, radiographic information, microbiologic data Patients with LTBI who are at risk for or have a known including acid-fast smears, mycobacterial cultures, and liver disorder can still receive treatment for LTBI.
nucleic acid amplification testing for Mycobacterium tuber- Known active hepatitis or end-stage liver disease are culosis A positive TST is not diagnostic for active relative but not absolute contraindications to the treat- tuberculosis and a negative TST does not exclude the ment of LTBI with isoniazid or pyrazinamide. Clinical diagnosis. Combination chemotherapy for tuberculosis monitoring for unexplained anorexia, nausea, emesis, should be initiated if either the suspicion of active icterus, rash, darkened urine, fatigue, weakness, right tuberculosis is high or the patient is severely ill in a upper quadrant tenderness and fever should be employed clinical situation in which tuberculosis is a significant in all patients but it is especially important in pregnant consideration in the differential diagnosis of the illness women, women who are 0–3 months post-partum, HIV- Results of the TST, mycobacterial staining, cul- infected persons, and in persons with hepatitis B, tures, and nucleic acid amplification studies should all be hepatitis C, alcoholic hepatitis or known cirrhosis. These considered in deciding whether or not to continue treat- persons should undergo baseline measurements of serum ment for tuberculosis. If smears and cultures remain alanine aminotransferase (ALT), serum aspartate amino- negative at 2 months and there is neither clinical nor transferase (AST) and bilirubin as well as monthly clinical radiographic improvement, anti-tuberculosis therapy can monitoring for the signs and symptoms delineated above.
be stopped and other diagnoses considered. If mycobac- Routine laboratory monitoring (AST, ALT, bilirubin) terial cultures and nucleic acid amplification assays are should also be performed on those patients at high risk negative but the patient has a clinical or radiographic for or with known underlying liver disease as delineated response to the initial 2 months of treatment, therapy above All such patients should be educated in the should be continued and a diagnosis of culture-negative recognition of these non-specific symptoms and, if the tuberculosis should be made. If mycobacterial cultures or patient has any or all of these symptoms for over 48 h, nucleic acid amplification assays are positive, treatment the patient should immediately discontinue treatment for should be continued and the course of therapy should be LTBI and seek counsel from the treating physician directed by mycobacterial sensitivity testing and clinicaland radiographic response to treatment. If the initial Which patients with a positive tuberculin skin test are at suspicion for active tuberculosis is low and the mycobac- highest risk for reactivation tuberculosis? terial smears are negative, combination chemotherapy The lifetime risk of reactivation tuberculosis in the can be deferred until culture results are available and presence of a positive TST is estimated to be 5–10%, subsequent chest radiographs can be compared with the but may exceed 20% depending upon the size of the original radiographic data for interval changes. However, positive TST and the underlying conditions predisposing anti-tuberculosis chemotherapy should not be delayed if to active tuberculosis Underlying HIV infection or the suspicion for active pulmonary tuberculosis is high and there is no other diagnosis to explain the patient’s together with 10 mm or more of induration on the TST predicts the highest rate of subsequent activetuberculosis in the absence of treatment for LTBI.
What are the currently recommended treatmentregimens for active pulmonary tuberculosis? Once the diagnosis of pulmonary tuberculosis is either The number of reported cases of active tuberculosis in the highly suspected or proven, the initial phase of treat- United States continued to decline during 2003 . How- ment should be started. The initial phase of treatment ever, there were still 14 871 cases (5.1 cases per 100 000 lasts for 2 months and is followed, depending upon the population) reported and both the percentage decline in circumstances, by a 4 – 7-month continuation phase to overall cases (1.4%) and the percentage decline in the case complete therapy. delineates the currently rate from 2002 (1.9%) were the lowest since 1992 We recommended anti-tuberculosis drug regimens for are therefore far from eradicating tuberculosis in the Uni- active pulmonary tuberculosis Because a signifi- ted States and any decrease in either the intensity of cant percentage of Mycobacterium tuberculosis strains prevention or the adequacy of treatment of active tuber- in the United States are isoniazid-resistant at this time, culosis could easily result in another resurgence of the the initial phase of treatment should include isoniazid, disease similar to that seen from 1986 to 1992.
pyrazinamide, ethambutol and rifampin. The initialphase of treatment may be administered daily for 8 When should treatment for active tuberculosis be weeks, daily for 2 weeks then twice weekly for 6 weeks, or thrice weekly for 8 weeks. If the original sputum The following factors should be considered when decid- cultures were positive, repeat sputum cultures should ing to begin antituberculosis chemotherapy: epidemio- be obtained at the end of 2 months of treatment. These cultures will help guide the remainder of the treatment under the column entitled ‘Range of total doses’. Strict adherence to tracking the number of doses taken willresult in a greater number of patients achieving comple- The continuation phase of treatment follows the initial tion of treatment and fewer patients experiencing relapse phase. The duration of the continuation phase is usually 4 months. The continuation phase should last7 months if the patient has cavitary pulmonary tuber- How should patients with interruptions in therapy be culosis with a drug-susceptible organism and the spu- tum cultures at the end of 2 months of treatment are Interruptions in treatment that occur in the early phase of still positive; if the patient did not receive pyrazina- therapy are more serious than those occurring in the mide during the first 2 months of treatment; or if the continuation phase because the pulmonary bacillary load patient was treated with once weekly isoniazid and is greatest in the early phase and the potential for the rifapentine by directly observed therapy for the initial development of antimicrobial resistance parallels the phase and the sputum culture at the end of 2 months is number of actively reproducing tubercle bacilli There is minimal evidence-based medicine to supportany standardized approach to interruptions in treatment.
How does treatment for HIV-infected patients differ However, the New York City Bureau of Tuberculosis Control has developed the following guidelines that Anyone who develops active pulmonary tuberculosis have also been used by many physicians and organiza- should be counseled about and tested for HIV infection tions treating patients with active tuberculosis: HIV-infected patients who strictly adhere to stan-dard treatment regimens do not have an increased risk of (1) If interruption occurs in the initial phase of treat- treatment failure or relapse However, if an HIV- infected patient requires treatment for active tuberculosis, (a) for interruption in treatment <14 days, treatment certain factors must be taken into account in HIV- should be continued and the targeted number of infected patients that do not affect the treatment of tuberculosis in HIV-non-infected patients. Drug –drug (b) for interruption in treatment !14 days, treatment interactions, especially between protease inhibitors or should be restarted from the beginning.
(2) If interruption occurs in the continuation phase of rifampin, may result in either toxic blood levels of rifam- treatment and the patient has received !80% of pin or non-therapeutic blood levels of various antiretro- viral agents. Rifabutin has fewer drug–drug interactions (a) if the initial sputum acid-fast bacillus (AFB) with these agents and may be a potent and pertinent smear was negative, further treatment may not alternative therapeutic agent in these patients In the initial phase of treatment of active pulmonary tuber- (b) if initial sputum AFB smear was positive, treat- culosis, twice weekly treatment regimens should not be ment should be continued to the planned total used in HIV-infected patients with CD4þ cell counts under 100 cells/ml to avoid an unacceptable rate of treat- (3) If interruption occurs in the continuation phase of ment failure or relapse. Thrice weekly or daily regimens treatment and the patient has received <80% of should be used under these circumstances. In the con- tinuation phase of treatment, the once weekly isoniazid– (a) if the lapse in treatment was <3 months, con- rifapentine regimen should not be used for HIV-infected tinue treatment to the full course of the planned patients regardless of CD4þ count. In those HIV- (b) if the lapse in treatment was !3 months, restart 100 cells/ml, neither the once weekly nor the twice the four-drug course of treatment from the begin- weekly regimens are acceptable because of higher fail- Since persons with treatment interruptions have already What does ‘completion of treatment’ mean? declared themselves as non-compliant, every effort pos- Completion of treatment is more accurately measured by sible should be made to enroll these persons in directly the total number of antituberculosis doses taken than by observed therapy protocols. The treating physician must the duration of treatment. Therefore the 6-month mini- be extremely vigilant in this situation so that treatment mum ‘duration’ of treatment is only applicable if the interruptions do not result in treatment failures or early appropriate number of doses are taken within that relapses. The appropriate use of ‘total doses received’ as a 6-month time frame. The acceptable number of total measure of ‘completion of therapy’ cannot be overem- doses for completion of treatment is shown in phasized as a measure of adequacy of treatment.
How should the physician treat patients with active amikacin, kanamycin or a fluoroquinolone may be tuberculosis and pre-existing liver disease? used for treatment in these circumstances.
Patients with active tuberculosis and known liver disease (6) Once the AST decreases to under two times the should be treated with regimens that include potentially upper limit of normal and symptoms resolve, the hepatotoxic drugs (isoniazid, rifampin, pyrazinamide) because of the known effectiveness of regimens that rifampin and pyrazinamide) should be restarted in include these medications. In all of these patients, fre- sequential order with weekly clinical and laboratory quent, probably once monthly, clinical and laboratory monitoring. The offending hepatotoxic agent, when monitoring should be performed to detect progressive found, should be eliminated from the therapeutic hepatic damage Recommended therapeutic options include each of the following: rifampin, pyrazinamideand ethambutol for 6 months, thereby avoiding isoniazid; When should multi-drug-resistant tuberculosis be isoniazid and rifampin for 9 months with ethambutol supplementation until isoniazid and rifampin suscept- Patients with tuberculosis caused by strains of M. tuber- ibility is verified, thereby avoiding pyrazinamide; rifam- culosis resistant to isoniazid and rifampin have a higher pin and ethambutol for 12 months with concomitant use rate of treatment failure and are at an increased risk for of a fluoroquinolone for the first 2 months in patients with the development of extended drug-resistance. Drug- resistant strains are more likely to occur in patients withcavitary pulmonary tuberculosis when large numbers ofrapidly multiplying bacilli are present; in patients receiv- How should the physician approach drug-induced ing inappropriate drugs or insufficient doses of appro- priate drugs and in patients who are non-compliant with Once treatment for pulmonary tuberculosis is started, an appropriate drug regimen. The treatment of drug- routine monitoring of liver enzymes is not routinely resistant tuberculosis is beyond the scope of this review.
recommended except in the case of persons with under- When multidrug-resistant tuberculosis is suspected or lying hepatic disease or in those persons receiving other proved, treatment should be undertaken only by or in hepatotoxic medications that might act synergistically to concert with a physician experienced in the intricacies of produce an increased likelihood of drug-induced hepa- titis The treating physician should use his or hercommon sense and clinical judgment in this regard.
Anyone with the development of fever, chills, jaundice The treatment of active and latent tuberculosis continues or other signs/symptoms of hepatitis should undergo to be a challenging, energizing and sometimes frustrating immediate serum analysis for liver enzyme levels. It is activity for physicians engaged in its practice. The inter- not unusual for patients to develop a small transient rise ested reader should consult current standard recommen- in the AST or ALT (over three times normal levels) at the dations as published jointly by the CDC/ATS/IDSA for initiation of anti-tuberculosis treatment. Drug-induced detailed aspects about the treatment of tuberc hepatitis is defined as follows: serum AST level greaterthan or equal to three times the upper limit of normal in the presence of symptoms or greater than or equal to five Papers of particular interest, published within the annual period of review, have times the upper limit of normal in the absence of symp- Drug-induced hepatitis can be caused by isoniazid, Small PM, Fujiwara PI. Management of tuberculosis in the United States.
N Engl J Med 2001; 345:189 –200.
rifampin or pyrazinamide. If drug-induced hepatitis is Centers for Disease Control and Prevention. Treatment of tuberculosis.
diagnosed, the physician should do the following: American Thoracic Society, CDC, and Infectious Diseases Society ofAmerica. MMWR 2003; 52(RR-11):1–77.
This is a comprehensive review of almost every aspect of the treatment of active (1) Discontinue isoniazid, rifampin and pyrazinamide.
tuberculosis as well as an updated treatise on each of the anti-tuberculosis agents (2) Discontinue any other medications that may cause as used in the treatment of tuberculosis today.
Centers for Disease Control and Prevention. Targeted tuberculin testing andtreatment of latent tuberculosis. MMWR 2000; 49(RR-6):1–54.
(3) Question the patient about the use of other hepato- Jasmer RM, Nahid P, Hopewell PC. Latent tuberculosis infection. N Engl (4) Obtain serologic testing for hepatitis A, B, and C.
Mazurek GH, LoBue PA, Daley CL, et al. Comparison of a whole-blood (5) Start treatment with two new non-hepatotoxic anti- interferon-g assay with tuberculin skin testing for detecting latentmycobacterium tuberculosis infection. JAMA 2001; 286:1740–1747.
tuberculosis medications and continue these agents Centers for Disease Control and Prevention. Update: Adverse event data and until the cause of the hepatotoxicity has been deter- revised American Thoracic Society/CDC recommendations against the use of mined. Streptomycin, ethambutol, capreomycin, rifampin and pyrazinamide for treatment of latent tuberculosis infection. UnitedStates, 2003. MMWR 2003; 52: 735–738.
Horsburgh CR Jr. Priorities for the treatment of latent tuberculosis infection in Centers for Disease Control and Prevention. Trends in tuberculosis: United the United States. N Engl J Med 2004; 350:2060 –2067.
States, 1998–2003. MMWR 2004; 53:210–214.
This is a comprehensive approach to the use of an epidemiologic model toestimate the lifetime risk of developing active tuberculosis. Using this information,the author describes the characteristics of patients with LTBI who should be New York City Bureau of Tuberculosis Control. Clinical policies and proto- targeted for completion of a full course of treatment for LTBI.
cols. 3rd ed. Bureau of Tuberculosis Control: New York; 1999.


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