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Mycobacterium tuberculosis Complex Updated November, 2011 Dr. Chi Chiu Leung, Dr. Kwok Chiu Chang, Hsin-Yun Sun, M.D., Charles L. Daley, M.D.
Previous author: Henry F. Chambers, M.D., 1997 Edition, 2002 Edition
MICROBIOLOGY Guided Medline Search Tuberculosis is caused by one of several mycobacterial species that belong to the Mycobacterium tuberculosis complex. The human pathogens are M. tuberculosis, M. africanum, and M. bovis (197). The other member of the complex, M. microti, is a rodent pathogen. Schultz, M. Theobald Smith. Emerg Infect Dis. 2008. Dec; 14:1940-2. Ullman A. Pasteur-Koch: Distinctive Ways of Thinking about Infectious Diseases. Microbe 2007;2(8):383-387. Mackowiak PA, et al. On the Origin of American Tuberculosis. Clin Infect Dis 2005;41:515-518. Wirth, T et al. Mycobacterium tuberculosis and Homo sapiens: Microbiological and Anthropological Coevolution. Clin Infect Dis. 2009;48:v–vi. EPIDEMIOLOGY Guided Medline Search M. tuberculosis is the most important of the human pathogens. Approximately one-third of the world's population, or 2 billion people, are thought to be infected with M. tuberculosis (156). Tuberculosis is the most common cause of death from an infectious or parasitic agent among individuals over five years of age, accounting for 3 million deaths annually. In addition, one in three AIDS patients in the world will die of tuberculosis (168). Unfortunately, the prevalence of drug resistant tuberculosis, including multi-drug resistant disease (MDR-TB), has increased in many areas of the world (69). In the United States, tuberculosis cases have decreased to the lowest number in history while the proportion of cases in the foreign-born has increased to 50% (29). Fortunately, HIV-related cases and drug-resistant disease have declined in the United States, also. CLINICAL MANIFESTATIONS Guided Medline Search Most tuberculosis occurs as pulmonary disease with 17% occurring at an extrapulmonary site, only (29). However, as much as 70% of HIV-1 infected patients will have evidence of extrapulmonary disease or mycobacteremia once the CD4 count is below 100 cells µl/ml (106). Co-infected persons are more likely to present atypically, potentially delaying the diagnosis of tuberculosis. Achkar et al. Differences in Clinical Presentation among Persons with Pulmonary Tuberculosis: A Comparison of Documented and Undocumented Foreign-Born versus US-Born Persons. Clin Infect Dis. 2008 Nov 15;47(10):1277-83. Cain KP, et al. An Algorithm for Tuberculosis Screening and Diagnosis in People with HIV. N Engl J Med 2010;362(8):707-716. Central Nervous System Tuberculosis: Tuberculosis of the central nervous system can present as tuberculous meningitis, tuberculomas, or tuberculous spinal meningitis. It accounts for ~5% of cases of extrapulmonary tuberculosis. It is most often seen in young children. Rupture of a subependymal tubercle into the subarachnoid space rather than direct hematogenous seeding is believed to be the main precipitating cause. The base of the brain is the most pronounced site. Aneurysm, thrombosis, and focal hemorrhage infarction may occur due to vasculitis of local arteries or veins by M. tuberculosis. Involvement of perforating vessels to the basal ganglia and pons may lead to movement disorders. Vasculitis of branches of the middle cerebral artery may cause hemiparesis. The clinical spectrum of tuberculous meningitis ranges from chronic headache and subtle mental status changes to sudden, severe meningitis progressing to coma. A prodrome of malaise, intermittent headache, and low grade fever can be followed by protracted headache, vomiting, confusion, meningismus, and focal neurologic signs within 2 to 3 weeks. If untreated stupor, coma, seizures, and hemiparesis and death can occur within five to eight weeks after the onset of illness. Fever is not always present, and the peripheral white blood cell count is usually normal. Patients may have mild anemia or hyponatremia due to inappropriate antidiuretic hormone secretion. Paresis of cranial nerves, especially ocular nerves, is a frequent finding. Approximately three fourths of cases have evidence of concomitant extrameningeal tuberculosis, and 50% have abnormalities on chest X-ray. Tuberculomas are space-occupying lesions in the brain. They are usually multiple but can be single. Patients may present with seizures or other focal neurologic symptoms without evidence of systemic illness or meningeal inflammation. The meninges can become involved with encasement of the spinal cord by a gelatinous or fibrous exudates in advanced cases. Patients may have bladder or rectal sphincter weakness, hypesthesia, anesthesia, paresthesias in the distribution of a nerve root, or paralysis and pain resulting from nerve root or cord compression. Christie LJ, et al. Diagnostic Challenges of Central Nervous System Tuberculosis. Emerg Infect Dis 2008;14:1473-1475. Pleural Tuberculosis: Tuberculous pleurisy can occur within weeks to months after primary infection (early postprimary pleurisy), complicate chronic pulmonary tuberculosis, or develop concurrently in 10%-30% of cases with military tuberculosis. Early postprimary pleurisy usually affects adolescents and young adults. The effusion can resolve within several months in as many as 90% of cases; however, without treatment, 65% will relapse with chronic organ tuberculosis within 5 years (73a). Elderly patients with chronic pulmonary tuberculosis may have cirrhosis or congestive heart failure; so tuberculous pleurisy may be easily mistakenly attributed to underlying co-morbidities. Military tuberculosis may present with tuberculous polyserositis with bilateral pleural, peritoneal, and pericardial tuberculosis. The clinical course of tuberculous pleurisy may be low grade and subtle or abrupt and severe and can be confused with acute bacterial pneumonia. Patients usually have cough, pleuritic chest pain, and occasionally high fever. Night sweats, chills, weakness, dyspnea, and weight loss can also occur. The effusion is usually minimal to moderate in volume and almost always unilateral (unless military tuberculosis exists concurrently). Empyema can occur when a cavity ruptures into the pleural space; empyema is associated with bronchopleural fistula formation and frank pus. It is rapidly fatal if antituberculosis therapy is not given expeditiously. Lymphadenitis: Lymphadenitis is the most common form of extrapulmonary tuberculosis (73a). In HIV-negative persons, it is usually unilateral and located in the cervical or supraclavicular area. The most common site is the upper border of the sternocleidomastoid muscle. Patients usually present with a painless, red, firm mass without systemic symptoms. It is most often seen in young adult females. Children often have an ongoing primary infection, but other age groups seldom have concurrent extranodal tuberculosis. Mediastinal adenopathy is often seen in children with primary infection, but it is uncommon in young adults and elderly persons. Differential diagnosis of mediastinal adenopathy includes histoplasmosis, lymphoma, and cardinoma. Less commonly, tuberculosis can also cause fibrosing mediastinitis, and patients can present with dyspnea on exertion due to compression of pulmonary veins and arteries or superior vena cava syndrome. In individuals with AIDS, peripheral lymph node tuberculosis is always multifocal and associated with systemic symptoms, such as fever and weight loss. Mediastinal lymphadenopathy is frequent, and CT scan reveals multiple coalescing mediastinal masses with low-density centers, peripheral contrast enhancement, and no calcification. Abdominal lymphadenopathy in the intra-abdominal cavity is also common in AIDS patients. Lymph nodes can obstruct the biliary tract, ureters, or bowel. Abscesses in the liver, spleen, pancreas, or kidney can exist concurrently. Pericardial Tuberculosis: Pericardial tuberculosis is usually caused by extension from a contiguous focus of infection, such as mediastinal or hilar nodes, the lung, spine, or sternum. Dissemination to the pericardium can occur with military tuberculosis. The onset may be abrupt or insidious. Patients may present with dyspnea, orthopnea, dull retrosternal pain, a pericardial friction rub, or symptoms and signs of cardiac tamponade. Fever, weight loss and night sweats usually occur before cardiopulmonary complaints. A few patients present with findings of chronic constrictive pericarditis. A pleural effusion can be found in as many as 39% of cases with pericardial tuberculosis, and radiographic evidence of concurrent pulmonary tuberculosis in 32%-72% of cases (178). Bone and Joint Tuberculosis: One third of cases with skeletal tuberculosis involve the spine (Pott’s disease or tuberculous spondylitis). The disease can occur via hematogenous, contiguous, or lymphatic spread (73a). The anterior superior or inferior angle of the vertebral body is infected first, and later the intervertebral disk and adjacent vertebra. The lower thoracic spine is involved most frequently followed by the lumbar, the cervical, and the sacral spine. In countries with endemic tuberculosis, Pott’s disease usually develops in older children and young adults within one year after primary lung infection (103a). However, in industrialized countries, it is a disease of older persons due to late reactivation of tuberculosis. Evidence of other foci of tuberculosis and systemic symptoms are often absent. In the early stage, only back pain or stiffness is present. Diagnosis may be delayed with the sequelae of paralysis, deformity, or sinus formation. In 50% of cases, weakness or paralysis of lower extremities (Pott’s paraplegia) may present initially or develop after treatment has begun. It may be due to arachnoiditis, vasculitis, or compression of the cord. In addition, paraspinal cold abscesses develop in 50% or more of the cases. These abscesses may appear after treatment has been initiated, or it may only be visible by CT or MRI. The pus, confined by tight ligmentous investments, can dissect along tissue planes to present as a mass or a draining sinus in the supraclavicular space, above the posterior iliac crest in the Petit triangle, or in the groin, the buttock, or even the popliteal fossa. The abscess can also spread to distant vertebral bodies without affecting the intervening vertebrae, or perforate into the bowel forming a gas-filled psoas abscess. In reports prior to 1970’s, peripheral tuberculosis arthritis presented as an indolent, progressive monoarthritis in 90% of cases (42a). Systemic symptoms or extra-skeletal tuberculosis were occasionally absent. The hip or knee was most frequently involved. Indolent progressive inflammation develops weeks or months later. In reports after the late 1980’s, an older population was affected (73b, 115a). This population had more systemic symptoms, multiple joint involvement, and periarticular abscess formation. The earliest manifestation of tuberculous arthritis is pain, and the symptom may precede signs of inflammation and radiographic changes by weeks or months. Tenosynovitis of the hand, arthritis of the wrist, and carpal tunnel syndrome can also be caused by tuberculosis. Tuberculous osteomyelitis can affect all bones including the ribs, skull, phalanx, pelvis, and long bones. Tuberculosis is the most common infectious cause for single of multiple osteomyelitic rib lesions since other causes of osteomyelitis of the rib are rare. Disseminated (Miliary) Tuberculosis: The term, miliary tuberculosis, initially was used to describe the resemblance of the pathologic lesions to millet seeds. Now this term denotes any progressive disseminated tuberculosis spread hematogenously. It can be divided into three groups according to clinical presentations and histologic findings: 1) acute miliary tuberculosis, 2) cryptic miliary tuberculosis, and 3) nonreactive tuberculosis (73a). Acute miliary tuberculosis is associated with a brisk and histologically typical tissue reaction. In the prechemotherapy era, it occurred either soon after primary infection in children or young adults or as a terminal event in untreated chronic tuberculosis. Children have acute or subacute onset, high intermittent fevers, night sweats, and occasional rigors. Pleural effusion, peritonitis, or meningitis occurs in as many as two thirds of cases. The clinical course of young adults is usually more chronic and initially less severe. However, now older individuals are affected by miliary tuberculosis more frequently, and their underlying illnesses may obscure the diagnosis. Patients usually have nonspecific constitutional symptoms, such as fever, anorexia, weakness, and weight loss. They may have headache due to meningitis, abdominal pain resulting from peritonitis, or pleural pain caused by pleuritis. Patients may have normal white cell count, anemia, hyponatremia, elevation of alkaline phosphatase and transaminases. Fulminant miliary tuberculosis may be associated with severe refractory hypoxemia (adult respiratory distress syndrome) and disseminated intravascular coagulation. Cryptic miliary tuberculosis occurs in older patients with miliary tuberculosis; chest X-rays are normal and tuberculin test results are negative. Patients have a chronic clinical course characterized by mild intermittent fever, anemia, and, ultimately, meningeal involvement preceding death. Nonreactive tuberculosis is very rare and characterized by massive hematogenous dissemination of tubercle bacilli, “nongranulomatous” (“nonreactive”) tissue lesions, and often a septic presentation. Patients present with overwhelming sepsis, splenomegaly and subtle diffuse mottling on the chest X-ray. Hematologic abnormalities include leukopenia, thrombocytopenia, anemia, pancytopenia, leukemoid reactions, myelofibrosis, or polycythemia. Disseminated tuberculosis should be considered when pancytopenia is associated with fever and weight loss. Miliary tuberculosis developed in 10% of AIDS patients with tuberculosis and 38% of AIDS patients with extrapulmonary tuberculosis. AIDS patients usually have constitutional symptoms and hectic fevers. The chest X-ray is abnormal in 80% of cases and includes typical miliary mottling. The tuberculin skin test is positive in only 10% of patients, and sputum smears are positive in 25%. However, blood culture can be positive in 50%-60% of cases. Patients can also have abscesses of various soft tissue and organs, including the liver, spleen, pancreas, psoas muscle, mediastinum, neck, chest wall, abdominal wall, and prostate. Genitourinary Tuberculosis: This is mostly a disease of middle-aged adults, and the onset is usually insidious. Asymptomatic renal cortical foci may occur in all forms of tuberculosis. Unsuspected renal foci were noted in 73% of cases with pulmonary tuberculosis in an autopsy study (9a). In normal hosts, the interval between infection and active renal disease is usually years and sometimes decades. In two large series of renal tuberculosis comprising 78 and 102 cases, respectively, 61%-71% had primarily genitourinary symptoms; dysuria and gross hematuria are most common (32a, 161a). Constitutional symptoms occurred in only 14%-33% of cases. Skin tuberculin tests were positive in 88%-95%. 66%-75% had abnormal chest X-ray while only 7-38% had active pulmonary tuberculosis. Abnormal urinalysis was noted in 66%-93% of cases, and abnormal intravenous pyelogram (IVP) in 68%-93%. Pyuria, albuminuria, and hematuria were the most common laboratory abnormalities. Sterile pyuria is a typical finding of renal tuberculosis, but 12%-45% of patients had positive cultures for bacterial pathogens at the same time, which can mask the true diagnosis.
Renal tuberculosis may spread to the prostate, seminal vesicles, epididymis,
and testis in that order. In cases with male genital tuberculosis, 80% had
coexistent renal disease and most advanced renal tuberculosis is associated
with some male genital foci. The usual clinical manifestations are a tender
scrotal mass associated with a draining sinus or oligospermia unresponsive to
treatment. Genital foci can also result from lymphatic or hematogenous spread
and present as a painful testicular or scrotal mass. The presence of
epididymal or prostatic calcification suggests the diagnosis, but
nontuberculous chronic prostatitis may also have a similar presentation. Abdominal Tuberculosis: Abdominal tuberculosis can affect the gastrointestinal tract, the peritoneum, the liver, and the pancreas. Before effective antituberculous agents were available, 70% of patients with advanced pulmonary disease acquired gastrointestinal tuberculosis by swallowing infected secretions. However, fewer than 25% of cases with gastrointestinal tuberculosis have radiographic evidence of pulmonary tuberculosis. Tuberculosis can involve any gastrointestinal site from the oropharynx to the anus. Patients can present with nonhealing ulcers of the tongue or oropharynx, or nonhealing sockets after tooth extraction. An adjacent caseous node might result in esophageal stricture with obstruction, tracheoesophageal fistula formation, and rare fatal hematemesis from an aortoesophageal fistula. Patients might have ulcerative or hyperplastic lesions in the stomach or gastric outlet obstruction. Duodenal involvement may lead to symptoms of peptic ulcer or obstruction. Perforation, obstruction, enteroenteric and enterocutaneous fistula, massive hemorrhage, and severe malabsorption may follow small bowel involvement. The most typical site of enteric tuberculosis is the ileocecal area producing symptoms of pain, anorexia, diarrhea, obstruction, hemorrhage, and a palpable mass. Patients with anal tuberculosis might have ulcers, perianal warty growths, and fistulas. Rapose A, et al. Esophageal Perforation and Pneumomediastinum: Rare Complications of Tuberculosis Infect Dis Pract 2008;4:266-67. Tuberculous peritonitis results from either spread of adjacent tuberculous disease or military tuberculosis. The clinical picture has two types: plastic and serous. The plastic type is less common; characterized by tender abdominal masses and a “doughy abdomen”. The serous type presents with ascites often without signs of peritonitis. Patients usually have symptoms of fever, abdominal pain, and weight loss. The onset may be insidious or acute. Some cases were diagnosed at routine hernia repair, or during surgery for an unknown mass or an acute abdomen. Tuberculous peritonitis was often undiagnosed in patients having cirrhosis with ascites. Peritoneal dialysis patients may present with the clinical pictures of bacterial peritonitis unresponsive to routine antibiotics. Tuberculosis peritonitis in woman may mimic advanced ovarian cancer. Of 22 women with tuberculosis peritonitis, 90.9% had elevated CA-125 levels (mean 564.95 U/mL; range 3-2021 U/mL) and 77.3% had detectable pelvic masses (110a). Tuberculosis is a frequent cause of granulomatous hepatitis with elevated alkaline phosphatase and gamma-glutamyl transpeptidase levels that are out of proportion to bilirubin levels with normal or mildly elevated transaminase levels. Very rarely, tuberculosis granulomatous hepatitis causes jaundice without evidence of extrahepatic tuberculosis (primary tuberculosis of the liver). Focal hepatic tuberculosis describes single or multiple tuberculous abscesses occurring in patients with little natural immunity to tuberculosis and in children. Pancreatic tuberculosis may present with an abscess or a mass involving local nodes and resembling carcinoma. Abdominal lymph nodes may obstruct the biliary tract causing tuberculous ascending cholangitis. (Printable Version of Clinical Manifestations or Mycobacterium tuberculosis) LABORATORY DIAGNOSIS Guided Medline Search Patients suspected of having pulmonary tuberculosis should have three sputum specimens examined for microscopic evidence of acid fast bacilli (AFB) (6). In addition, specimens should be cultured in order to identify the specific mycobacterial species and for drug susceptibility testing. Patients with suspected extrapulmonary tuberculosis should have cultures obtained from these sites of infection whenever possible to establish a definitive diagnosis and to obtain an isolate for susceptibility testing. Mycobacteria of the M. tuberculosis complex grow slowly, dividing every 15 to 20 hours (197). Because of this slow growth, it can take over 3 weeks to see visible growth on standard culture media although in radiometric culture systems growth can be detected in as little as 10-14 days (6). The slow rate of growth has significant clinical implications because therapy must be begun in many patients before the diagnosis of tuberculosis is confirmed. In addition, drug susceptibility test results are seldom available at the initiation of treatment. Newer nucleic acid amplification tests allow for the rapid identification of organisms belonging to the M. tuberculosis complex (6). The primary use of tuberculin skin testing was detection of latent tuberculosis infection, especially in persons at risk for developing tuberculosis who would benefit by treatment of latent tuberculosis infection. The tuberculin skin test uses a relatively crude mix of antigens from Mycobacterium tuberculosis, and inoculation with intradermal antigens causes a delayed type hypersensitivity (DTH) response mediated by T lymphocytes with maximal induration at 48 to 72 hours. Therefore, false-positive reactions can occur in persons with previous bacilli Calmette-Guerin (BCG) vaccination or sensitization to nontuberculous mycobacteria, and false-negative reactions in those with active TB, immune suppression, or other severe illness. Two new T-cell-based tests for diagnosing latent tuberculosis infection have been developed and licensed for commercial distribution in recent years. One (QuantiFERON[QFT]-TB Gold) uses enzyme-linked immunosorbent assay to measure antigen-specific production of interferon-γ (INF-γ) by circulation T cells in whole blood, and the other (the T-SPOT.TB) uses the Elispot technique to measure peripheral blood mononuclear cells that produce INF-γ. Both tests use more specific M. tuberculosis antigens - ESAT-6, CFP-10, and TB7.7 - which are encoded in the genes in the region of different 1 (RD1) of the M. tuberculosis genome. RD1 region is deleted from the genome of M. bovis BCG and most nontuberculous mycobacteria except for M. marinum, M. kansasei, M. szulgai, or M. flavescens. The sensitivity, specificity, and reproducibility of these 2 ex vivo INF-γ release assays (IGRAs) for diagnosing latent tuberculosis infection in healthy and immune-suppressed persons were evaluated in a recent meta-analysis although the results were limited by no gold standard for latent tuberculosis infection and small samples with a widely varying likelihood of true-positive and false-positive test results (122a). When newly diagnosed active tuberculosis was used as a surrogate for latent tuberculosis infection, sensitivity of all tests was suboptimal (tuberculin skin test 71%, 95% confidence interval [CI] 0.65-0.74; QFT-TB Gold 76%, 95% CI 70-83%; Elispot 88%, 95% CI 81-95%) although Elispot had better performance. When persons were categorized into clinical gradients of tuberculosis exposure, sensitivity of 3 tests was similar. The specificity of INF-γ release assays was excellent with QFT-TB Gold of 97.7% (95% CI 96-99%) and Elispot of 92.5% (95% CI 86-99%) while that of tuberculin skin test was only 66% (95% CI 46-86%). Both assays were more specific than the tuberculin skin test in samples vaccinated with BCG. Elispot was more sensitive than the tuberculin skin test in 3 studies of immunocompromised samples. Discordant tuberculin skin test and INF-γ release assays reactions were frequent and largely unexplained even though varied definitions of positive test results might be part of the explanations. Studies which define the performance of INF-γ release assays in high-risk populations are needed. Pai M, et al. Systematic Review: T-Cell-based assays for the Diagnosis of Latent Tuberculosis Infection: An Update. Ann Intern Med 2008;149:177-184. Pai, M, Ramsay, O'Brien R. Table: Evidence-Based Tuberculosis Diagnosis. PLoS Medicine | www.plosmedicine.org 2008; 5:e156. Bakir M et al. Use of T Cell-based Diagnosis of Tuberculosis Infection to Optimize Interpretation of Tuberculin Skin Testing for Child Tuberculosis Contacts.Clin Infect Dis. 2009 Feb 1;48(3):302-12. Lighter, J. et al. Latent Tuberculosis Diagnosis in Children by Using the QuantiFERON-TB Gold In-Tube Test. PEDIATRICS Vol. 123 No. 1 January 2009, pp. 30-37 (doi:10.1542/peds.2007-3618) Guidelines: Nucleic Acid Amplification Tests in the Diagnosis of Tuberculosis. U.S. Centers for Disease Control. 2009 CNS Tuberculosis: Examination of cerebrospinal fluid (CSF) is the cornerstone of diagnosis. CSF should be sent for acid-fast stain and tuberculosis cultures. Large volumes (10-15 mL) of CSF from repeated lumber punctures are often required to identify an isolate or the bacilli. Acid-fast bacilli were only seen in 37% of cases on initial examination, but in 90% when fluids from four large-volume lumbar punctures were examined (109a). The cell count of CSF may range from 0 to 1500/mm3 with lymphocytic predominance. However, early in the course, one fourth of cases might have polymorphonuclear pleocytosis. Typically, the CSF protein is moderately elevated, ranging from 100 to 500 mg/dL, but is extremely high in patients with subarachnoid block with the range of 2 to 6 g/dL. The CSF glucose is characteristically low with the level less than 45 mg/dL in 80% of cases. The nucleic acid-based test (NAAT) is employed for the rapid detection of M. tuberculosis in CSF. However, the sensitivity and specificity varies considerably among different laboratories. The pooled sensitivity was 56% and the pooled specificity was 98% in a meta-analysis of NAATs for tuberculous meningitis (139a). It is important to keep in mind that a negative test of NAAT result neither excludes the diagnosis nor obviates the need for continued therapy. Tuberculomas, basilar arachnoiditis, cerebral infarction, and hydrocephalus can be noted in the brain CT or MRI in patients with tuberculous meningitis. The diagnosis of tuberculoma should be suspected based on clinical and radiographic findings. Confirmation by needle biopsy is mandatory. The diagnosis of spinal tuberculous arachnoiditis can be suspected by the high CSF protein level indicative of spinal block, MRI changes of nodular arachnoiditis, and tissue biopsy. Pleural Tuberculosis: Diagnosis of tuberculosis pleurisy is made by examination of the pleural effusion or pleura by biopsy. Pleural fluid have white cell counts of 500 to 2500 cells/mm3 with more than 90% lymphocytes in two third of cases. However, it was reported that 38% of cases had predominantly polymorphonuclear leukocytes and 15% had more than 90% polymorphonuclear leukocytes on the first tap (68a). A shift to lymphocytic predominance is observed in repeated taps. Mesothelial cells are sparse or absent, and eosinophils are rarely present. The pleural fluid protein usually exceeds 2.5 g/dL, and glucose is usually moderately low but rarely less than 20 mg/dL. The pH is almost always 7.3 or lower. Acid-fast stains of the pleural fluid are usually negative, but cultures are positive in 25% to 30% of cases. Pleural needle biopsy can yield granulomas in 75%. Culture of a needle biopsy specimen can be positive in 25% of cases in which the histology is nonspecific. On the other hand, cases complicating chronic pulmonary tuberculosis are more likely to have positive pleural acid-fast smears (50%) and positive cultures (60%), but are less likely (25%) to demonstrate granulomas on pleural biopsy. Repeated pleural biopsy has been suggested by some investigators as an approach to establish the diagnosis; on the other hand, the combination of histologic examination and culture of the initial pleural biopsy has a sensitivity of 90%. McGrath EE, et al. Diagnostic Tests for Tuberculosis pleural effusion. Eur J Clin Microbiol Infect Dis 2010;29:1187-1193. Tovar M, et al. Improved diagnosis of pleural tuberculosis using the microscope-observation drug-susceptibility technique. Clin Infect Dis. 2008;46:909-12. Lymphadenitis: Fine-needle aspiration gives higher yields in AIDS patients as opposed to non-AIDS patients. Acid-fast stain are positive in the great majority of AIDS patients as is the culture. However, cytologic and histologic findings are less specific in AIDS patients. Lymph node biopsy may be necessary if a diagnosis is not made by five needle aspiration. Definitive diagnosis requires biopsy with culture. Lymph nodes should be excised completely with no drain left in place to avoid the possibility of postoperative fistula formation. Pericardial Tuberculosis: In areas of high endemicity of tuberculosis, a presumptive diagnosis based on physical findings and radiologic examination is often made, but the diagnosis is difficult to establish. In countries with low prevalence of tuberculosis, the diagnosis is easily overlooked. A definitive diagnosis can be made by pericardiocentesis or pericardial biopsy. The specimens should be submitted for biochemical studies, acid-fast stain, tuberculosis culture, and histological examination for granulomatous inflammation. The characteristics of tuberculous pericardial and pleural fluid are similar. Acid-fast stain of tuberculous pericardial fluid is rarely positive, but cultures are positive in 50%. Polymerase chain reaction (PCR) for mycobacterial DNA is a sensitive test. Echocardiography may reveal multiple loculations which is suggestive of tuberculosis. Bone and Joint Tuberculosis: In the absence of coexistent extra-articular tuberculosis, diagnosis almost always requires biopsy to obtain infected materials for acid fast stains and culture. Smear and cultures of pus or tissue from the spine are positive in only 50% of cases, while histologic studies demonstrate granulomas with or without caseation in three fourths of cases. Histologic features compatible with tuberculosis warrant empiric antituberculosis chemotherapy, although other chronic infections, such as fungi and nontuberculous mycobacteria, can cause identical clinical and histologic pictures. Initially, radiographs reveal only soft tissue swelling; osteopenia, periarticular bony bony destruction, periosteal thickening, and eventually destruction of cartilage and bone will follow. Disseminated (Miliary) Tuberculosis: A diffuse infiltrate on chest X-ray is the most common finding that leads to the diagnosis. Cultures of sputum, gastric contents, urine, and CSF are positive in most cases. However, smears of sputum and pulmonary secretions are positive in less than one third of cases. Thus, a search for cutaneous eruptions, sinus tracts, scrotal masses, and lymphadenopathy during the physical examination is important to localize sites for biopsy. Blood cultures for M. tuberculosis may also be positive. Transbronchial biopsy is the direct method to obtain tissue. The bone marrow and liver biopsy are also high yield procedures that can often lead to the correct diagnosis. The finding of caseating granulomas or acid-fast bacilli is diagnostic. The presence of noncaseating granulomas may be sufficient indication for empiric antituberculosis chemotherapy, although other diseases should be sought. Genitourinary Tuberculosis: Culture with three morning urine specimens for mycobacteria can make the diagnosis in 80%-90% of cases (32a, 161a). Cytologic studies and culture of material obtained by fine-needle biopsy may be diagnostic if a renal abnormality is present and urine cultures are negative. The intravenous pyelogram (IVP) findings are characteristic, although they are nonspecific in the early stages. In the late stages, the IVP may reveal papillary necrosis, ureteral strictures, “pipe stem” changes, “corkscrewing,” “beading,” hydronephrosis, gross parenchymal cavitation, and autonephrectomy. Focal calcification is suggestive for tuberculosis. The clinical findings are usually unilateral, although microscopic changes are almost always seen bilaterally. During healing, ureteral cicatrization and obstruction may occur. IVPs should be monitored during therapy to see if intervention is indicated. The diagnosis of genital tuberculosis is usually established by surgery although cultures of menstrual blood or endometrial scrapings may be positive. Abdominal Tuberculosis: Diagnosis of abdominal tuberculosis can be made by peritoneocentesis, CT- or echocardiography-guided drainage procedures, panendoscopy, colonoscopy, laparoscopy, or surgery. Specimens should be submitted for microscopy, biochemical, microbiological, and histologic studies. The peritoneal fluid is exudative with leukocytes of 500 to 2000 cells/mL. Typically, lymphocytes predominate, but polymorphonulcear leukocytes are more abundant in the early stage. Acid-fast stain of peritoneal fluid is seldom positive, and culture is positive in only 25%. The sensitivity and specificity of adenosine deaminase activity in ascitic fluid is about 90% (70a). However, the sensitivity dropped to 30% in patients with cirrhosis due to the poor humoral and T cell mediated response of cirrhotic patients (10). The utility of ascitic fluid PCR assays to detect tuberculosis peritonitis has not been well established. The most common CT finding of gastrointestinal tuberculosis is concentric mural thickening of the ileocecal region, with or without proximal intestinal dilatation (18). Peritoneal thickening, omental caking, and the presence of ascites with fine mobile septations on ultrasound and CT imaging may suggest the diagnosis of tuberculosis peritonitis (1). Danchaivijitr N, et al. Diagnostic Accuracy of MR Imaging in Tuberculosis Spondylitis. Journal of the Medical Association of Thailand. 2007:90(8):1581-1589. Boehme CC, et al. Rapid Molecular Detection of Tuberculosis and Rifampin Resistance. New Engl J Med 2010:Epub ahead of publication. Small PM, et al. Tuberculosis Diagnosis - Time for a Game Change. New Engl J Med 2010:Epub ahead of publication. (Printable Version of Laboratory Diagnosis for Mycobacterium tuberculosis) PATHOGENESIS Guided Medline Search Tuberculosis can develop through progression of recently acquired infection (primary disease), reactivation of latent infection, or exogenous reinfection (96). In immunocompetent individuals, approximately 3-10% of those with tuberculous infection will develop tuberculosis in the first 1-2 years after infection (181) and another 5% will develop tuberculosis during their lifetime. Exogenous reinfection is thought to be uncommon in immunocompetent persons residing in areas with a low prevalence of tuberculosis. In the setting of HIV-1 infection, the risk of progressing rapidly to infection once infected with M. tuberculosis (39), the risk of reactivation (40, 159,160), and the risk of exogenous reinfection (24, 78, 170) are all increased compared to HIV-1 seronegative persons. Review Article: Jain SK, et al. Why is duration of Tuberculosis therapy so long?: Sterilization or "persisters" Microbe 2008;3(6):285-292.
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo Drug resistance occurs in M. tuberculosis through chromosomal mutations that confer resistance to individual antituberculosis drugs. In vitro work suggests these mutations occur spontaneously and at predictable rates, and that mutations resulting in resistance to a particular drug are not linked to mutations resulting in resistance to other drugs (41). For example, mutations conferring resistance to isoniazid and rifampin occur with an estimated frequency of approximately 1 in 3 X 108 and 1 in 2 X 1010 mutations per bacterium per generation, respectively (41). All populations of M. tuberculosis will therefore have a certain number of naturally occurring drug-resistant mutants and this probability will be influenced by the size of the bacterial population and the rate of replication. The probability that resistance will develop to isoniazid and rifampin, in nature, is the product of each of the separate probabilities, or 1 in 6 X 1018. Even in a patient who has cavitary tuberculosis, where the bacillary population may exceed 109 organisms, the probability that simultaneous mutations will occur in the same organism leading to multiple resistance is exceedingly small (41). Drug susceptibility testing of M. tuberculosis should be performed on an initial isolate from all patients with tuberculosis (6). If the patient’s culture remains positive after 3 months of therapy, repeat susceptibility testing should be performed. Testing should be performed using a standard methodology such as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (128). The NCCLS recommends that drug susceptibility testing be performed with isoniazid (two concentrations), rifampin, ethambutol, and pyrazinamide. Second-line drugs should be tested if there is resistance to rifampin alone or to ≥ 2 drugs. Drug resistance can be detected by a variety of in vitro methods that are usually contingent on demonstrating growth of the organism in the presence of a "critical" concentration of antituberculosis drug. The two most commonly used qualitative methods are the proportion method and the BACTEC method. The agar proportion method has been proposed as the reference method for all antituberculosis drugs except pyrazinamide for which BACTEC is the reference method (128). With the proportion method, plates of drug-free agar and agar containing critical concentrations of antituberculosis drugs are inoculated with the isolate (194). For most drugs, resistance is determined by comparing the number of colony forming units (CFU) on drug-containing versus drug-free media, with clinically significant resistance being defined as greater than 1% growth on drug-containing media relative to drug-free media. Rapid broth-based methods (e.g., BACTEC, MIGIT, etc.) are recommended for initial susceptibility testing of first-line agents. Growth at the critical breakpoint concentration (e.g., 1 mg/ml of INH) indicates resistance. The BACTEC method allows for the determination of minimal inhibitory concentrations (MICs) which provide the opportunity to compare the level of resistance with the concentration of a drug actually attainable in human serum (Table 1) (86). The clinical use of MICs in the treatment of tuberculosis is of unclear significance, however, and susceptibility and resistance are defined based on breakpoint concentrations (128). Iseman MD. Extensively Drug-Resistant Mycobacterium tuberculosis: Charles Darwin Would Understand. Clin Infect Dis. 2007;45:1415–6.
ANTIMICROBIAL THERAPY Smart search Drug of Choice Guided Medline Search Tuberculosis must be treated with at least two drugs to which the isolate is susceptible. The duration of the treatment regimen, expected drug toxicities, and overall effectiveness will depend on the drugs used. Currently, there are 11 drugs approved by the United States Food and Drug Administration (FDA) for treating tuberculosis. The fluoroquinolones and rifabutin, drugs that are commonly used to treat drug-resistant tuberculosis and HIV-related tuberculosis, respectively, do not have FDA approval for the treatment of tuberculosis. The available first and second-line drugs, the recommended doses, and common side effects are listed in Tables 2 and 3, respectively. Guideline: ATS/CDC/IDSA. Practice Guidelines for the Treatment of Tuberculosis. MMWR 2003;52 (RR-11). Cain KP, et al. An Algorithm for Tuberculosis Screening and Diagnosis in People with HIV. N Engl J Med 2010;362(8):707-716. Model of Antituberculosis Chemotherapy: The primary goals of antituberculosis chemotherapy are to kill tubercle bacilli rapidly, prevent the emergence of drug resistance, and eliminate persistent bacilli from the host's tissues in order to prevent relapse (124). In order to accomplish these goals, multiple antituberculosis drugs must be given for a relatively long time. Our current approach to the treatment of tuberculosis is based on data from numerous in vivo and in vitro studies and arises from a theoretical model of chemotherapy which incorporates our current understanding of the specific activities of the antituberculosis drugs as well as the biology of M. tuberculosis in the host tissues.
M. tuberculosis is thought to exist in three separate populations that are
defined by their growth characteristics and the environment in which they are
located (124). The first and largest population consists of rapidly growing extracellular bacilli. It is this population that is most likely to harbor
resistant organisms. Drugs, such as
isoniazid, that kill rapidly multiplying
M. tuberculosis during the early course of therapy, are said to
possess early bactericidal activity and act to prevent the emergence of
resistance. The second population consists of organisms that are growing more
slowly, often in an acidic environment. A third population is characterized by
spurts of growth interspersed with periods of dormancy. Elimination of these
last two populations would be expected to prevent relapse and shorten the
duration of therapy; this property is referred to as sterilizing capacity.
Duration of Therapy Soon after streptomycin became available for the treatment of tuberculosis, it was recognized that monotherapy frequently resulted in treatment failure due to the development of in vitro resistance to the drug (123). Addition of para-aminosalicylic acid (PAS) to a regimen of streptomycin prevented the development of acquired resistance to either agent and was more effective than either agent alone; however, cure rates were only in the range of 70% (17, 184). The addition of isoniazid to streptomycin and para-aminosalicylic acid increased cure rates to 95% but required 18-24 months of therapy (18).
In a series of studies conducted by the British Medical Research Council (BMRC)
in East Africa (56-60) and the United States Public Health Service (USPHS)
(131, 132), investigators demonstrated the importance of
A USPHS Trial demonstrated that isoniazid and rifampin were as effective as the standard regimen of streptomycin, isoniazid and ethambutol and the rifampin-containing regimen converted the sputum cultures to negative two weeks faster than the standard regimen (131, 132). Addition of pyrazinamide beyond the initial two months was demonstrated to be unnecessary in several BMRC studies (61, 94,164). Other studies from the United States and the British Thoracic Society (BTS) helped to refine our current approach to short-course therapy and demonstrated that a short intensive phase followed by a longer continuation phase of therapy was effective. Isoniazid and rifampin for 9 months was successful in 95% of smear negative or smear positive patients in Arkansas when given daily for one month followed by twice-weekly (51,54). The BTS demonstrated that isoniazid and rifampin for 6-months, supplemented during the first two months with streptomycin and pyrazinamide or streptomycin and ethambutol, were as effective as a nine month regimen of isoniazid and rifampin with ethambutol in the first two months (19). The USPHS Trial 21 studied daily, self-administered isoniazid and rifampin for six months with pyrazinamide given during the initial two months (38). Ethambutol was added if isoniazid resistance was suspected. The relapse rate was only 3.5% despite the fact nearly 17% of the patients were felt to be nonadherent. And finally, investigators in Denver reported a low relapse rate using a 6-month regimen which consisted of two weeks of daily isoniazid, rifampin, pyrazinamide and streptomycin followed by 6-weeks of these four drugs twice weekly, followed by 18 weeks of twice weekly isoniazid and rifampin (35). Regimens of less than 6-months duration were shown to have unacceptably high relapse rates among smear positive pulmonary tuberculosis (61, 91, 92, 164). However, among patients with smear negative disease, the relapse rate was only 2% using a 4-month regimen of streptomycin, isoniazid, rifampin, and pyrazinamide (92). Review Article: Jain SK, et al. Why is duration of Tuberculosis therapy so long?: Sterilization or "persisters" Microbe 2008;3(6):285-292. Recommended Treatment Regimens
The current minimal acceptable duration of treatment for all adults and
children with culture-positive tuberculosis is 6 months (7). The initial phase
of the 6-month regimen should consist of
isoniazid,
Based on the results of a recently published clinical trial, it appears that HIV negative patients with pulmonary tuberculosis who do not have cavities on the initial chest radiograph and who have negative sputum smears after completing 2 months of therapy may be treated with once weekly rifapentine and isoniazid in the continuation phase (188). HIV infected patients should not receive this highly intermittent regimen because of a high relapse rate associated with acquisition of rifamycin monoresistance (193). Treatment should be considered completed when the total number of doses has been taken; not solely on the duration of therapy. A reasonable "window" in which to complete the 2-month initial phase of therapy is 3 months. Similarly, the 4-month continuation phase should be completed within 6 months. For example, if the patient was started on a daily treatment regimen given 7 days-a-week, therapy (182 doses) should be completed within 9 months. Otherwise, the treatment duration should be extended. Interruptions in treatment are common during the course of therapy. Interruptions that occur during the initial phase of therapy, when the bacillary population is highest, are more important than when they occur during the continuation phase. The duration of interruption and the bacteriologic status of the patient prior to and after the interruption are also important considerations. There are no data from clinical trials to assist with the management of treatment interruptions. However, the New York City Bureau of tuberculosis Control has developed a reasonable approach to managing treatment interruptions (133). McIlleron H, Willemse M, et al. Isoniazid plasma concentrations in a cohort of South African children with tuberculosis: implications for international pediatric dosing guidelines. Clin Infect Dis. 2009 Jun 1;48:1547-53. Intermittent Administration: Nonadherence to the treatment regimen is the most common cause of treatment failure, relapse, and acquired drug resistance. Administration of therapy on an intermittent basis facilitates supervision of therapy, improving adherence. Both laboratory (44, 45) and clinical evidence (93, 162, 165) support the use of intermittent therapy.
Multiple clinical trials have demonstrated the efficacy of twice-weekly and
thrice-weekly treatment regimens (93, 162,
165). A recent multicenter
randomized controlled trial evaluated the efficacy of a once weekly regimen
(188). Patients received a standard 4-drug 2-month initial phase of therapy,
given daily or intermittently. After two months of therapy, patients were
randomized to receive either
isoniazid and rifapentine once weekly or
isoniazid and
Administration of the Treatment Regimen: As noted previously, nonadherence to the treatment regimen is the major cause of treatment failure, relapse, and development of acquired-drug resistance (198). In order to prevent the emergence of acquired drug resistance and ensure completion of therapy, directly observed therapy (DOT) should be considered in all patients. DOT has been used successfully by a number of tuberculosis control programs and has been shown to be cost-effective (21, 126, 198). The use of DOT was associated with a decrease in primary drug resistance, acquired drug resistance and relapse in Tarrant County, Texas between 1980 and 1986 (198). If DOT is not possible for all patients, priority should be given to patients with the following conditions: smear positive pulmonary tuberculosis, treatment failures and relapses, drug resistance, HIV infection, previous nonadherence to therapy, substance abuse, psychiatric illness, or memory deficits. Children and adolescents should be treated with DOT, also.
When DOT cannot be used the patient should be treated with fixed-dose
combined formulations (7). There are two combined formulations now available
in the United States: a combination of
isoniazid and
There is no evidence indicating that fixed-dose combinations are superior to individual dosing of drugs (94,166). However, the theoretical advantage of reducing the risk of inadvertent monotherapy, the ease of administration, and the potential for reducing medication error make them preferable to individual medications (7). Combined formulations are not a substitute for DOT, however. When Parenteral Therapy is Required: Isoniazid, rifampin, the aminoglycosides and polypeptides, and fluoroquinolones are available in parenteral forms that can be administered intravenously to patients. Although isoniazid and streptomycin are not approved for intravenous use, they can be used safely by mixing the parenteral drug in 100 cc of normal saline and administering the solution intravenously over one hour. Management of Patients at Increased Risk of Relapse: Some patients may be at increased risk of relapse after completing a standard course of therapy. Identification of predictors for increased risk of relapse would allow providers to alter therapy in such individuals with the aim of decreasing the rate of relapse. A positive sputum culture after 2 months of treatment has been associated with relapse or failure. In 7 clinical trials conducted by the BRMC, the regimens with the highest proportion of patients with a positive culture after 2 months of therapy were associated with a higher likelihood of relapse (125). As note previously, data from USPHS Study 22 showed an increased rate of relapse in patients who had a positive culture at 2 months (188). Cavitation on the chest radiograph was also an independent risk factor for relapse. The presence of cavitation on the chest radiograph and a positive culture after completing 2 months of therapy was associated with a 22% rate of failure or relapse compared with 2% for patients with neither risk factor. If patients had either cavitation or a positive culture at 2 months, 5-6% had failure or relapse. The best way to decrease the risk of relapse has not been determined. However, a controlled clinical trial of the treatment of silicotuberculosis demonstrated that simply extending the duration of the continuation phase from 4 to 6 months decreased the rate of relapse from 22% to 7% (95). Therefore, it seems prudent to extend the continuation phase from 4 to 7 months in hopes of decreasing the relapse rate in patients who have both cavitary pulmonary tuberculosis and a positive culture at the end of the initial phase (2 months) of therapy. Extension of the continuation phase should be considered for patients who have either cavitation or a positive culture at two months, if there are breaks in therapy, evidence of a poor response, or the patient is HIV-infected. Treatment of Extrapulmonary tuberculosis Extrapulmonary Disease: The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary disease. Although there have been fewer chemotherapy trials with extrapulmonary tuberculosis (52), the current recommendations are to treat extrapulmonary forms of disease in adults the same as pulmonary disease (7). The exception to this recommendation is CNS disease for which there are insufficient data to determine the appropriate length of therapy. In children, current guidelines advocate extending the duration of therapy to 12 months in patients with CNS or disseminated disease (7). These guidelines are based on the clinical judgment of experts in the field; no studies document the advantage of this practice. Tuberculosis of the Brain and Meninges: Treatment of tuberculosis involving the brain and/or meninges can be particularly challenging because of the high frequency of neurologic sequelae and high mortality rate associated with this form of extrapulmonary disease (3, 10, 50, 97, 153). HIV-infected patients are at increased risk of developing tuberculous meningitis but the outcomes of treatment do not appear to be altered (10, 50, 153, 204).
Not all of the antituberculosis medications penetrate the blood-brain
barrier well, thus the antituberculosis drugs should be selected carefully
when treating CNS disease.
Isoniazid (66) and pyrazinamide (47,
64, 147, 201)
penetrate well into the CSF reaching concentrations equal to serum. In
contrast,
Chemotherapy should be initiated with the standard 4-drug treatment regimen. After 2-months of 4-drug therapy, PZA and EMB (or streptomycin) may be discontinued and INH and RIF continued for an additional 4 to 10 months (7). There are few randomized studies to guide the treatment of tuberculous meningitis thus, the optimum duration of treatment is not known. Prospective studies have demonstrated that short-course regimens of 6-12 months duration are effective in the treatment of tuberculous meningitis (1, 3, 48, 102, 155, 180). Extremes of age and the level of CNS dysfunction at presentation have been associated with a poor prognosis. A number of studies have examined the use of corticosteroids as adjunctive treatment in tuberculous meningitis. Unfortunately, most of the studies were small in size and many did not use a rifampin-based regimen (8, 49, 62, 75, 76, 113, 139, 148, 195). Studies have demonstrated a benefit of corticosteroids over standard therapy alone in terms of survival, and /or frequency of sequelae (62, 76, 161). In a study from China, the use of steroids was associated with a 50% reduction in mortality from tuberculous meningitis in patients who presented with Stage 2 (CNS dysfunction, no coma) or 3 (both CNS dysfunction and coma) CNS dysfunction (161). Therefore, most authorities recommend corticosteroids in patients who present with CNS dysfunction (7). Dexamethasone (or its equivalent) is given in an initial dose of 0.2 mg/kg for three weeks and tapered over the next 2 to 3 months. If the patient's clinical condition worsens during tapering of the corticosteroids the dose should be increased and the taper slowed. Repeated lumbar punctures should be considered to monitor changes in the CSF, especially early in the course of therapy. In some cases CNS tuberculomas appear during therapy or the patient's clinical condition worsens due to a "paradoxical reaction". Alffenaar JWC, et al. Pharmacokinetics of Moxifloxacin in Cerebrospinal Fluid and Plasma in Patients with Tuberculous Meningitis. Clin Infect Dis 2009;49:1080-1082.
Pleural tuberculosis: A 6-month regimen consisting of
isoniazid and
Lymph Node tuberculosis: Prospective studies of 6-9 months duration in adults (20, 25, 206) and 6 months of intermittent therapy in children (105) have been shown to be very effective. During the course of therapy, lymph nodes may enlarge, new nodes may appear, and nodes may spontaneously drain and create fistulas (25, 87, 115). These changes are seldom the sign of failure but simply a vigorous immunological reaction referred to as a paradoxical reaction. Surgical resection is not usually necessary given the excellent results with chemotherapy (115). However, in some cases, repeated aspirations or surgical drainage are needed for large fluctuant nodes. Pericardial tuberculosis: Patients with tuberculous pericarditis should be treated with standard short-course antituberculosis chemotherapy. Additionally, corticosteroids should be given when the diagnosis of tuberculosis is clear (7). In patients with acute effusive pericarditis, corticosteroids reduced the need for repeated pericardiocentesis and significantly lowered mortality in those who received corticosteroid therapy compared with those who received placebo (178). Patients with later effusive-constrictive pericarditis who received corticosteroids in a randomized double-blind controlled trial had significantly more rapid clinical resolution compared to patients who received placebo. Corticosteroid-treated patients also had a lower mortality and needed pericardiectomy less frequently but the differences did not reach statistical significance. (177). In neither study did corticosteroids decrease progression to constriction or in the need for pericardiectomy. A small randomized study of HIV infected patients with pericardial tuberculosis reported a reduced mortality in patients who received corticosteroids (83). Based on the data described above, adults and children with tuberculous pericarditis should receive adjunctive corticosteroid treatment (7). For adults the dose is 60 mg of prednisone (or its equivalent) for 4 weeks followed by 30 mg for 4 weeks, 15 mg for 2 weeks, and 5 mg for the 11th and final week. Children should be treated with doses proportionate to their weight beginning with approximately 1 mg/kg and tapering as in adults. Bone and Joint tuberculosis: Disease affecting the spine (Pott's Disease) is common and usually affects the thoracolumbar region. Most patients will respond to standard short-course antituberculosis treatment (120-122, 154, 189, 190). A randomized trial demonstrated no additional benefit of surgical debridement or radical operation in combination with chemotherapy compared with chemotherapy alone (122). However, patients with evidence of cord compression, proven or suspected spinal instability due to destruction of contiguous vertebrae, or gross abscess formation should undergo surgical debridement and fixation in addition to standard chemotherapy (7). Myelopathy with or without functional impairment usually responds to chemotherapy alone (121, 141). When tuberculosis affects another joint, chemotherapy is usually sufficient unless extensive joint destruction has occurred. Danchaivijitr N, et al. Diagnostic Accuracy of MR Imaging in Tuberculosis Spondylitis. Journal of the Medical Association of Thailand. 2007:90(8):1581-1589. Disseminated (Miliary) tuberculosis: Disseminated tuberculosis is associated with a high mortality rate and thus, therapy should be initiated as soon as miliary disease is suspected. The standard treatment regimen should be begun. Parenteral therapy may be necessary in patients who are too ill to take oral medications (see section: When Parenteral Therapy is Required). Corticosteroid therapy may be beneficial in patients with severe hypoxemic respiratory failure. Genitourinary tuberculosis: Renal tuberculosis is treated with a standard treatment regimen. If ureteral obstruction is present procedures to relieve the obstruction, such as stenting, should be used. Surgery is seldom necessary although in some cases a poorly functioning kidney may be removed particularly in the setting of chronic flank pain or hypertension.
Abdominal tuberculosis: Abdominal tuberculosis including peritoneal and
intestinal disease should be treated for 6 months with a standard treatment
regimen. Adjunctive corticosteroids were examined in a small study in which
patients with peritoneal tuberculosis were allocated on alternate basis to
receive corticosteroids for 4 months (167). Four of 24 patients in the control
group developed fibrotic complications compared with none of the 23 patients
in the steroid group but the difference was not statistically significant.
Therefore, corticosteroids are not recommended for the routine treatment of
abdominal tuberculosis (7). (Printable Version of Treatment of Extrapulmonary tuberculosis) Treatment of Drug Resistant tuberculosis The treatment regimen in proved drug resistant disease will depend on the results of drug susceptibility tests (both current and prior) and the patient's previous history of treatment. Investigators from the National Jewish Medical Center have reported that patients who have taken a drug for over one month in the past have less effect from that drug, even if in vitro drug susceptibility tests show the isolate to be susceptible (77, 99). If drug susceptibility test results are not yet available, as is often true at the initiation of therapy, the drug susceptibility patterns in the community or known source case may be useful in designing a treatment regimen. At least three drugs to which the isolate is susceptible and ideally which the patient has never taken before, should be used to initiate treatment. As drug susceptibility data becomes available, the regimen may need to be altered. The goals of selecting a treatment regimen are to maximize efficacy, minimize toxicity, and ensure completion of therapy. In highly resistant cases, this may be difficult to do. Table 5 lists several possible options for the treatment of drug resistant tuberculosis depending on the drug resistance pattern. It is important to note that most clinical trials have examined the efficacy of various treatment protocols in, primarily, drug susceptible cases, and that few studies have examined the treatment of drug resistant cases. However, recent studies, using a variety of different treatment regimens and approaches, have reported treatment success rates varying from 75% to 80% (74, 142,183, 205). Review Article: Mitnick CD, et.al. Comprehensive Treatment of Extensively Drug-Resistant Tuberculosis. N Engl J Med. 2008 Aug 7;359(6):563-74
Isolated Resistance to Isoniazid:
Effective treatment regimens for patients
with isolated
isoniazid resistance are readily available. Patients may be
treated with a combination of
Some clinicians favor continuing isoniazid despite known resistance to this agent, particularly if there is low level resistance, in hope of killing any subpopulations that might retain some susceptibility to isoniazid. The benefit of this practice is unclear; one study demonstrated similar rates of bacteriologic failures in patients with low-level isoniazid resistance compared to patients with high-level resistance (176). On the other hand, given the uncertain benefit and the well-documented risk of hepatotoxicity with isoniazid, many experts favor stopping the drug when any level of resistance is noted. Cattamanchi A et al. Clinical Characteristics and Treatment Outcomes of Patients with Isoniazid-monoresistant Tuberculosis.Clin Infect Dis. 2009 Jan 15;48(2):179-85.
Isolated Resistance to Rifampin: Isolated resistance to
Isolated Resistance to Ethambutol, Pyrazinamide, or Streptomycin: Isolated resistance to ethambutol, pyrazinamide, or streptomycin will have little impact on the efficacy of the regimen. Loss of ethambutol or streptomycin from the regimen will not decrease the efficacy or change the total duration of therapy. Loss of pyrazinamide, however, will require prolonging the duration of therapy from 6 to 9 months.
Resistance to at Least Isoniazid and Rifampin (MDR-TB):
With the loss of
isoniazid and
All patients with MDR-TB should be treated with DOT under the supervision of someone with experience in treating drug-resistant cases. Some authorities recommend initial hospitalization to permit observation of toxicity and intolerance, particularly in patients with high levels of drug resistance (99). Peak and trough serum levels may be determined to optimize therapy since bioavailability and clearance of most antituberculosis medications is not predictable (Table 6). Review Article: Mitnick CD, et al. Comprehensive Treatment of Extensively Drug-Resistant Tuberculosis. N Engl J Med. 2008 Aug 7;359(6):563-74. Smear and Culture Negative tuberculosis Failure to isolate M. tuberculosis from appropriately collected specimens
in tuberculosis suspects does not exclude the diagnosis of tuberculosis. The
sensitivity of culture in pulmonary tuberculosis is approximately 90% (6).
Patients who, based on clinical and radiographic evaluations, are thought to
have tuberculosis, should be started on the standard antituberculosis regimen.
If the smears and cultures are negative, the patient should be evaluated for
evidence of clinical and/or radiographic improvement after approximately 2-3
months of antituberculosis chemotherapy. If the patient has improved on
antituberculosis therapy he/she is reportable as a case of clinical tuberculosis. Because of the lower burden of disease these patients may be
treated with shorter treatment regimens. Dutt and Stead (53) demonstrated that
a 4-month regimen containing
isoniazid and
Underlying Medical Conditions Children and Adolescents: Several controlled and observational studies have evaluated 6-month regimens in children (11, 101, 112, 157, 185, 187, 192). These regimens have been demonstrated to be effective with success rates greater than 95% and low rates of adverse effects. Although most of the studies used daily administration of medications, two studies used twice or thrice weekly dosing with good results (185, 192). Children with disseminated or meningeal tuberculosis should be treated for 9-12 months because of inadequate data to support a 6-month regimen (7). The American Academy of Pediatrics recommends that children and adolescents with HIV-related tuberculosis should be treated for 9 months (4). Some experts prefer to use three rather than four drugs, omitting ethambutol from the treatment regimen. Because of the difficulty in assessing visual acuity in young children some providers do not feel they can monitor the child adequately for optic neuritis. However, it is important to note that ethambutol has been used safely in children (186) and that toxicity is rare when the drug is used at the 15 mg/kg/d dose. Ethambutol should be used whenever underlying drug resistance is suspected. DOT should be used in all children with tuberculosis. In general, parents should not be relied on to supervise the DOT.
Thee S, et al.
Ethambutol in paediatric tuberculosis: aspects of
ethambutol serum concentration, efficacy and toxicity in children.
Int J Tuberc Lung Dis 2007;11:965-971. Pregnancy and Breast-Feeding: Untreated tuberculosis represents a greater risk to the fetus than does treatment of tuberculosis (42, 103, 171). Thus, treatment of tuberculosis in a pregnant women should be initiated whenever the probability of tuberculosis is moderate to high. The initial treatment should consist of isoniazid, rifampin, and ethambutol which, can be used safely in the setting of pregnancy. The one clear contraindication during pregnancy is the use of aminoglycosides; in 40 pregnant women who received streptomycin, 17 percent of the babies had eighth nerve palsies with deficits ranging from mild hearing loss to deafness (191). Given the lack of data regarding the teratogenicity of pyrazinamide, it has not been recommended in pregnant women (7). However, pyrazinamide is recommended for routine use in pregnancy by the World Health Organization (202) and the International Union Against tuberculosis and Lung Disease (67). In addition, some jurisdictions in the United States have used pyrazinamide in pregnant cases without reported adverse effects (42). If pyrazinamide is not included in the initial regimen, the minimum duration of therapy is 9 months. Breast-feeding should not be discouraged in women being treated with first-line drugs. All of the antituberculosis medications are found in breast milk (174) but the dosages are small and toxicity in the infant is not expected. End-Stage Renal Disease: Renal insufficiency complicates the management of tuberculosis because some antituberculosis drugs are cleared by the kidneys and some are removed by hemodialysis. In order to avoid low peak serum concentrations, the dosing interval should be decreased instead of decreasing the dose of the antituberculosis drug. In general, three times a week dosing of renally cleared medications should provide adequate serum concentrations while avoiding unwanted toxicity (Table 6). Isoniazid and rifampin are metabolized hepatically so conventionial dosing should be used in the setting of renal insufficiency (2, 14, 65, 116, 143). Pyrazinamide is also metabolized hepatically but its metabolites may accumulate in patients with renal failure (63, 116). Ethambutol is approximately 80% cleared by the kidneys so it may accumulate in patients with renal insufficiency (179). Therefore, pyrazinamide and ethambutol should be dosed at a longer interval. Isoniazid, ethambutol, and pyrazinamide are cleared by hemodialysis to some degree; only PZA and its metabolites are cleared to a significant degree (116). Rifampin is not cleared by hemodialysis. Therefore, supplemental dosing is not necessary for isoniazid, rifampin, or ethambutol. By dosing pyrazinamide after hemodialysis, no supplemental dosing is required. Aminoglycoside and polypeptide antibiotics must be adjusted in patients with renal failure because the kidneys excrete essentially all of the drug. In addition, approximately 40% of the dose is removed via hemodialysis (118). The dosing interval should be increased, as with ethambutol and pyrazinamide. Ethionamide and clofazimine are not cleared by the kidneys, nor are they removed by hemodialysis (117). Cycloserine is excreted primarily by the kidneys and it is cleared by hemodialysis. Thus, an increase in dosing interval is recommended and the drug should be given after dialysis. PAS undergoes some renal clearance and is modestly cleared by hemodialysis but no change in dosing is necessary if the granule formulation is used (117). The fluoroquinolones undergo varying degrees of renal clearance depending on the drug. For example, levofloxacin undergoes greater renal clearance than ciprofloxacin or moxifloxacin (73). Persons taking cycloserine, ethambutol, or aminoglycosides (polypeptide) should have serum drug concentrations measured in order to avoid drug-related toxicities and ensure effective dosing (7). Unfortunately, there are no data to develop recommendations for dosing of antituberculosis medications in persons undergoing peritoneal dialysis. In general, all of the antituberculosis should be dosed after hemodialysis in order to facilitate directly observed therapy and to avoid premature removal of drug. Hepatic Failure: The treatment of tuberculosis in patients with underlying liver disease can be challenging because three of the first-line agents, isoniazid, rifampin, and pyrazinamide, are potentially hepatatoxic. Most providers use one of two treatment regimens when treating patients with significant liver disease in hope of decreasing the risk of drug-induced liver injury. As noted previously, a 6-month regimen of rifampin, ethambutol, and pyrazinamide has been shown to have good efficacy (93, 207). Another option is to treat the patient with isoniazid, rifampin, and ethambutol for 9 months (reference). Both treatment regimens contain two potentially hepatotoxic drugs and there are no data comparing the frequency of hepatoxicity between the treatment regimens. For patients with advanced liver disease, a regimen with only one or no hepatoxic drug should be used (e.g.,ethambutol, an aminoglycoside, a fluoroquinolone, and cycloserine could be used in this setting). A rifamycin should be used whenever possible. HIV-Related tuberculosis Treatment of tuberculosis in patients with HIV infection follows the same principles of treatment in HIV negative patients. However, the treatment of HIV-related tuberculosis requires close monitoring because of the potential for drug-drug interactions and paradoxical reactions. There have been at least six prospective studies of 6-month regimens for the treatment of tuberculosis in HIV infection patients in which relapse data were reported (32, 68, 108, 109, 146, 193). This studies differed in a number of ways including, design, patient population, eligibility criteria, frequency of dosing, treatment supervision and outcome definitions; therefore, it is difficult to make meaningful comparisons. However, all of the studies reported good early clinical and microbiologic responses to therapy and failure rates were similar to those in HIV negative cases. Recurrence rates varied among the studies with most reporting relapse rates of 5% or less (32, 68, 108, 109). A consistent finding in all the treatment studies is a high mortality rate among HIV-1 seropositive patients (136, 145, 146,169). Deaths that occur in the first two months of therapy may be due to advanced tuberculosis but mortality during the continuation phase of therapy is usually due to advanced HIV disease (32, 68, 127, 146). Several investigators in sub-Saharan Africa have reported a higher mortality among HIV-1 infected patients who took non-rifampin containing regimens (137, 138, 145), highlighting the importance of rifampin-containing short-course regimens in the treatment of HIV-related tuberculosis. Review Article: Pillay T, Khan M, Moodley J, Adhikari M, Coovadia H. Perinatal tuberculosis and HIV-1: considerations for resource-limited settings. Lancet Infect Dis. 2004 Mar;4(3):155-65. Treatment Recommendations: HIV infected patients with tuberculosis should be treated with the same treatment regimens as HIV negative patients with two exceptions. First, a once-weekly rifapentine regimen is not recommended because of a high relapse rate and high frequency of acquired rifampin monoresistance (193). Second, a recent report described 6 of 183 patients in a clinical trial who relapsed with rifamycin monoresistance (31). All patients had advanced HIV disease. Therefore, twice-weekly administration is not recommended in patients with advanced immunodeficiency (e.g., < 100 CD4 cells/µl) (31). The 6-month regimen should be considered the minimum duration of therapy. If there is evidence of a slow or suboptimal response to therapy, treatment should be prolonged to 9 months. Directly observed therapy should be used in all patients with HIV-related tuberculosis. Gao XF, et al. Rifapentine vs. rifampicin for the treatment of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis. 2009 Jul;13:810-9. Karim SSA, et al. Concurrent Antiretroviral/TB Treatment Decreases Mortality in HIV Patients. CAPRISA Newsletter September 2008.Karim SS. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;362;(8):697-706. Concurrent Administration of Antiretroviral Drugs and Rifamycins: Successful therapy for tuberculosis requires that HIV-infected patients take three to four drugs for a minimum of six months. Some of the antituberculosis drugs can interact adversely with medications that are commonly used by HIV-1 infected individuals, such as antiretroviral drugs. Understanding these drug-drug interactions can prevent unwanted drug toxicity and possible treatment failures.
The rifamycin derivatives (i.e.,
The antiretroviral drugs belong to one of four main classes, nucleoside (NRTIs), neucleotide reverse transcriptase inhibitors (NtRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). The NRTIs and NtRTIs do not have clinically relevant drug interactions with the rifamycins and so no adjustment in doses is required. However, the NNRTIs and PIs, depending on the drug, may either inhibit or induce cytochrome p-450 enzymes (22, 27). Thus, these drugs may alter the serum concentration of drugs, such as rifabutin, that are metabolized by the P450 enzyme systeM. The potential benefit of PIs must be weighed against the importance of rifampin in treating HIV-related tuberculosis. The loss of a rifamycin from the treatment regimen is likely to delay sputum conversion and prolong the treatment duration, and may be associated with poorer outcomes (138). HIV infected patients with tuberculosis who are not already receiving antiretroviral drugs, should be started on antituberculosis medications first. Beginning 4 antituberculosis drugs plus several antiretroviral drugs may result in overlapping drug toxicities and drug-drug interactions that are difficult to manage. However, not treating HIV infection may also have adverse effects. In a recent study form Dean and colleagues (43), HIV infected patients with tuberculosis who had CD4 cell counts < 100 cells/µl were twice as likely to develop an AIDS-defining illness during the course of therapy as those with > 100 CD4 cells/µl. However, 54% of the patients developed a drug-related toxicity and in one-third the drug regimens had to be interrupted or stopped. Thus, the provider must balance the risk of the patient developing other AIDS- related problems with the risks of developing drug-related toxicities and potential nonadherence. A reasonable approach is to begin antiretroviral therapy is patients with advanced immunodeficiency such as CD4 cell counts less than 100 cells/µl but after a few weeks of antituberculosis therapy. For patients who are clinically stable and whose CD4 cell count is > 100 cells/µl, the antiretroviral therapy should be delayed until the end of the 2-month initial phase of antituberculosis therapy. Current guidelines for the treatment of HIV infection should be followed for individuals with CD4 cell counts greater than 100 cells/µl (33). As new antiretroviral drugs and more pharmacokinetic data become available, recommendations are likely to be modified. Because the recommendations are frequently revised, providers are encouraged to obtain the most up to date information at the CDC website (www.cdc.gov/nchstp/tb). Editorial Comment: Sun, HY. Efavirenz-based antiretroviral therapy is a better choice for HIV-positive patients treated with rifampicin-based antituberculous therapy. 2009.
Guidelines: CDC. Managing
Interactions in the Treatment of HIV Related Tuberculosis. 2007.
Available from URL:
http://www.cdc.gov/tb/tb_hiv_ Paradoxical Reactions: Patients with tuberculosis may have a temporary exacerbation of symptoms, signs, or radiographic findings after beginning antituberculosis therapy. The apparent worsening is not related to failure of therapy, but instead, it represents a vigorous immunological reaction. Prior to HIV infection, paradoxical reactions were described in patients with tuberculosis, particularly those with cervical lymphadenitis and CNS tuberculomas. However, these reactions appear to be more common in HIV infected patients, particularly those receiving antiretroviral therapy. Paradoxical reactions have been reported in 6 to 36% of HIV-infected patients (129, 199). Narita and colleagues (129) reported that among HIV infected patients who were taking antiretroviral agents, 36% developed paradoxical worsening after beginning antituberculosis therapy compared with 7% of those who were not taking antiretroviral agents and 1% of HIV negative cases. In contrast other investigators have described paradoxical worsening in only 7% of HIV infected patients and the reaction was not associated with antiretroviral therapy (199). Mild paradoxical reactions may be managed with nonsteroidal antiinflammatory agents. More severe reactions such as high fever, airway compromise from enlarging lymph nodes, and sepsis syndrome should be treated with corticosteroids (e.g., prednisone 1mg/kg) and tapered over several weeks. Review Article: Meintjes G, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8(8):516-523. Alternative Therapy Guided Medline Search In some circumstances, either because of underlying in vitro resistance or intolerance to a first-line drug, an alternative regimen must be used instead of the standard 6-month regimen. If pyrazinamide can not be included in the treatment regimen, or the isolate is determined to be resistant to pyrazinamide, a regimen consisting of isoniazid, rifampin and ethambutol should be given for the initial two months followed by isoniazid and rifampin for 7 months. This regimen can be given either daily or twice a week in the intermittent phase. If a rifamycin can not be used, isoniazid and ethambutol should be given for a minimum of 18 months with pyrazinamide during at least the initial 2 months (13). For patients with extensive disease, another agent such as a fluoroquinolone or an aminoglycoside may be useful. If isoniazid can not be used, rifampin, ethambutol and pyrazinamide should be given for a minimum of 6 months (93). Another option is to give rifampin and ethambutol for a minimum of 12 months with pyrazinamide included at least during the first 2 months (207).
Low DE. Fluoroquinolones for Treatment of Community-Acquired Pneumonia and Tuberculosis: Putting the Risk of Resistance into Perspective. Clin Infect Dis 2009;48:1361-1363. Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis. 2012 Feb 8.[Epub ahead of print]. Fouad M, et al. Moxifloxacin as an alternative or additive therapy for treatment of pulmonary tuberculosis. Ann Pharmacother. 2011;45:1439-44. ADJUNCTIVE THERAPY Guided Medline Search Surgery Resectional surgery or drainage of a tuberculous empyema (Eloesser flap) may be necessary in some patients with multi-drug resistant disease (99, 100, 152). The prior probability of treatment failure, based on the extent of disease and level of drug resistance, should be used to decide in whom resectional surgery is indicated. Patients with MDR-TB who have localized disease, who have failed treatment, and who have adequate pulmonary reserves, should also be considered for surgery. Iseman and colleagues reported that resectional surgery offered some benefit to such patients compared with historical controls (99). Immunomodulators in the Treatment of tuberculosis Tuberculosis has been associated with the production of a number of cytokines, including tumor necrosis factor (TNF-alpha). Given the high levels of TNF-alpha, and other cytokines, that have been documented in HIV-related tuberculosis, drugs that inhibit the production of TNF-alpha may have a role in the treatment of tuberculosis (110, 196). Pentoxifylline inhibits the synthesis of TNF-alpha by mononuclear phagocytes and the effect of the cytokine on target cells. In a double-blind, placebo-controlled trial, pentoxifylline was reported to be associated with a decrease in plasma HIV RNA and serum B2-microglobulin in HIV-1 infected patients with tuberculosis (196). Thalidomide also inhibits the production of TNF-alpha. Klausner and associates (110) conducted a small randomized study in which HIV-1 infected patients with tuberculosis were treated with standard antituberculosis therapy and thalidomide or placebo. HIV-1 infected patients with tuberculosis who took thalidomide had a decrease in serum TNF-alpha levels and HIV-1 RNA levels. In addition, the patients who took thalidomide had a significant weight gain compared to those who took placebo. Although 6 out of 20 patients developed a rash, preliminary data suggest that a lower dose may decrease the risk of hypersensitivity and still provide clinical benefit (110). Interferon-gamma, a cytokine produced mainly by CD4 T-lymphocytes, can activate alveolar macrophages that are important effector cells in host immunity against M. tuberculosis. Condos and colleagues (37) reported their experience with the use of aerosolized interferon-gamma in the treatment of multidrug-resistant tuberculosis. Five patients were treated with 500 ug of interferon-gamma three times a week for one month along with their regular antituberculosis medications. Sputum acid-fast smears became negative in all patients and the time to positive culture increased, suggesting the mycobacterial burden had decreased. Further studies are necessary to evaluate these new and potentially useful approaches to treatment. CNS Tuberculosis Ventricular shunting may be beneficial for patients with tuberculous meningitis if symptomatic hydrocephalus supervenes. In India, the treatment of tuberculoma, is antimicrobial chemotherapy without resection. Pericardial Tuberculosis Surgical drainage via a subxiphoid pericardial window can provide tissue for diagnosis obviating the need for recurrent pericardiocentesis. Surgical drainage does not decrease either mortality or the need for pericardiectomy. This procedure is associated with a 2% mortality (178). Pericardiectomy is usually indicated if hemodynamic compromise persists for 6 to 8 weeks, and should be performed early. However, two thirds of patients do well without surgery. Bone and Joint Tuberculosis: Surgery is necessary only when serious joint instability requires fusion, and then only after antituberculosis chemotherapy has failed. Genitourinary Tuberculosis: Tuberculosis of either the female or male genital tract can be successfully managed by standard antituberculosis chemotherapy. Surgery is needed only for residual large tubo-ovarian abscesses (11a).
ENDPOINTS FOR MONITORING THERAPY Guided Medline Search Patients who are being treated for tuberculosis must be monitored closely in order to detect possible drug toxicities (Tables 2 and 3) and document response to therapy. Additionally, for those not receiving DOT, close monitoring allows for the assessment of adherence. Adults treated for tuberculosis should have baseline measurements of hepatic enzymes (AST, ALT, and alkaline phosphatase), serum bilirubin, creatinine, a complete blood count, and a platelet count (7). Serum uric acid concentration should be measured if the patient will be receiving pyrazinamide. A baseline measurement of both visual acuity (Snellin chart) and red-green color discrimination should be obtained in all patients treated with ethambutol. Most children do not need baseline laboratory measurements except for the assessment of visual acuity for those being treated with ethambutol (7). All patients should be monitored clinically for adverse reactions during the treatment period. Patients should be seen at least monthly and all baseline laboratory values, which were abnormal, should be repeated. Some providers repeat hepatic enzymes at least once during therapy, usually after one month of therapy. Patients receiving ethambutol should be questioned monthly regarding visual disturbances and they should have ophthalmologic assessments of visual acuity and red-green color perception every 2-3 months if the drug is to be administered for a prolonged time (7). If a patient develops one of the common drug-related toxicities (e.g., rash, hepatitis) that can be caused by more than one of the antituberculosis drugs, the best approach is to stop all drugs, allow the side effect to improve or resolve, and then add the drugs back one at a time every few days. There are still uncertainties about the use of "therapeutic" drug monitoring during the course of therapy for tuberculosis. There are not sufficient data to formulate an evidenced-based approach to measuring and interpreting serum drug concentrations in this setting (7). It is important to note that most of the "normal" values (Table 1) have been determined in small numbers of healthy volunteers. Until more outcome-based data become available monitoring of serum drug concentrations should be limited to the following: 1) patients with treatment failure that is not explained by nonadherence or drug resistance; 2) persons with medical conditions that may result in very abnormal pharmacokinetics; 3) in the management of multi-drug resistant tuberculosis using second-line agents. (7, 144) When serum drug concentrations are measured, the blood specimen should be drawn two hours after dosing except in the case of aminoglycosides, for which blood should be obtained 30-60 minutes following a dose for determination of peak concentrations and just prior to the next dose for trough. For pulmonary tuberculosis, the most important parameter to monitor in order to document response to therapy is the conversion of sputum smears and cultures to negative. Serial chest radiographs during therapy are seldom necessary but an end of treatment radiograph provides a useful baseline against which subsequent examinations can be compared. During treatment, a sputum specimen for microscopic examination and culture should be obtained at monthly intervals until 2 consecutive specimens are culture negative (7). Over 90% of patients who are treated with standard short-course therapy will be culture negative after two months of therapy (7). In patients who remain culture positive beyond this juncture, repeat drug susceptibility tests should be sent and the patient should be placed on DOT. If the patient is already on DOT, consideration should be given to checking serum levels of the antituberculosis agents. Patients with pulmonary tuberculosis who have negative pretreatment sputums should be followed clinically and radiographically for evidence of improvement on therapy. In patients with extrapulmonary disease, the nature of the repeat evaluations will depend on the site of involvement. Monitoring for signs of nonadherence is very important. Pill counts and patient interviews may give some indication of missed doses. In addition, repeat uric acid levels, if low, may be a sign of nonadherence since the levels are usually elevated above baseline while taking pyrazinamide. A spot urine check to look for the orange discoloration caused by rifamycins is useful and inexpensive. And finally, there are commercially available urine dipstick tests to evaluate for isoniazid metabolites. Kwon et al. Treatment Outcomes for HIV-uninfected Patients with Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis. Clin Infect Dis. 2008 Aug 15;47(4):496-502 VACCINES Guided Medline Search Bacille Calmette Gučrin (BCG) Vaccine BCG is derived from a strain of M. bovis attenuated through years of serial passage in culture. There are several different BCG vaccines available and the efficacy of these vaccines in controlled clinical trials has ranged from 0 to 80% (28, 71, 72). The trials have varied in important variables including vaccine strains, routes of administration, dosage, age at vaccination, geographical area and different study populations. A recent meta-analysis suggested an overall protective effect of 51% in preventing tuberculosis disease (34). However, protection against meningitis was 64% and versus disseminated disease it was 78%. The authors reported that the majority of the differences in the results of the various BCG studies could be attributed to two factors: 1) the efficacy of vaccination increased with increasing distance from the equator, and 2) the better the study methodology, the more likely the trial was to show protection. Exposure to environmental mycobacteria with resultant cross-immunity has also been argued to be a major factor responsible for variation in vaccine efficacy (71, 72). Indications BCG vaccination is not generally recommended in the United States because of the low risk of infection with M. tuberculosis, the variable effectiveness of the vaccine against pulmonary tuberculosis, and the potential for the vaccine to interfere with the interpretation of the tuberculin skin test (28). The Centers for Disease Control and Prevention recommends that BCG vaccination be considered for an infant or child who has a negative tuberculin skin test if the following conditions are present: 1) the child is exposed continually to an untreated or ineffectively treated patient who has infectious pulmonary tuberculosis, and the child cannot be separated from the presence of the infectious patient or given long-term primary treatment for infection, or 2) the child is exposed continually to a patient who has infectious multidrug-resistant pulmonary tuberculosis, and the child cannot be separated from the source-case (28). Recent decision analyses have suggested that BCG vaccination in health care workers would be the most effective preventive intervention in the setting of exposure to MDR-TB (16, 82, 175). However, most health care workers are not exposed to drug resistant strains and as drug resistance strains decline in the United States, the vaccine is unlikely to be used. Therefore, BCG vaccination of health care workers should be considered on an individual basis and rarely recommended. Doses, Schedules Most BCG vaccines come in a freeze-dried forM. The most common mode of administration is by intradermal injection of 0.1 mL into the dermis of the upper arm (72). However, the dose will depend on the strain used and the method of application. For example, the Tice strain, available in the United States, is administered percutaneously with 0.3 ml of the reconstituted vaccine delivered through a multipuncture disc (28). Some manufacturers recommend half this dose in children less than one year of age. Most individuals receive a single vaccination soon after birth or at first contact with a health professional. However, in some areas of the world the vaccine is targeted to high-risk groups, administered in adolescence, or multiple vaccinations are given throughout childhood and adolescence. Adverse Effects Vaccination with BCG usually results in a local inflammatory reaction that can persist for months in some cases (28, 72). The lesion may be tender, erythematous, and openly weeping. With healing, the lesion leaves a depressed scar. Regional lymph nodes can become enlarged and tender, sometimes creating fistulas. More serious complications though rare can include, focal osteitis or osteomyelitis, and disseminated mycobacterial infection. Osteitis is probably the most common serious complication of BCG vaccination occurring in 3/100,000 vaccinations and usually involving the lower extremities (28, 72). Most cases of disseminated disease occur in immunocompromised individuals. The safety of BCG vaccination in HIV -infected adults has not been determined. The WHO currently recommends BCG vaccination for asymptomatic HIV-infected children who are at high risk for infection with M. tuberculosis (28). Research continues in the search for a new and better vaccine for tuberculosis. A number of candidate vaccines are currently under investigation. The most common types of vaccines being studied are naked DNA vaccines, recombinant BCG and subunit vaccines (72).
PREVENTION Guided Medline Search Treatment of Latent tuberculosis Infection General: Isoniazid is the most widely used drug for the treatment of latent tuberculosis infection (LTBI). Clinical trials have demonstrated that the daily administration of isoniazid therapy for 12 months reduces the risk of developing tuberculosis by more than 90% in subjects who complete a full course of therapy (70, 98). Six months of isoniazid therapy also confers a high degree of protection and is more cost-effective (173). Recent re-analysis of data from previous clinical trials evaluating the efficacy of isoniazid therapy demonstrated that the effectiveness of isoniazid decreased significantly if < 9 months of isoniazid were taken. Thus, the CDC recommends a 9-month treatment regimen in all latently infected persons, regardless of HIV serostatus (5). A two-month short-course regimen containing rifampin and pyrazinamide that was initially recommended for the treatment of LTBI (5) is no longer recommended for most patients with LTBI because of high rates of hepatotoxicity (30, 31a). Two randomized clinical trials demonstrated that two months of rifampin and pyrazinamide was as efficacious as 6-12 months of isoniazid in HIV infected patients and the two-month regimen was associated with a similar rate of side-effects (81, 84). However, recent reports of severe liver injury associated with rifampin and pyrazinamide has resulted in new modified recommendations for the use of rifampin and pyrazinamide (see below) (30, 31a). Between October 2000 and June 2003, the CDC received reports of 48 patients who had confirmed cases of drug-induced hepatotoxicity: 33 (69%) occurred in the second month of treatment (31a). A total of 11 (23%) of the cases died, including two patients with HIV infection. Recommended Regimens: Several regimens are recommended for the treatment of LTBI in high-risk individuals who have a positive tuberculin skin test (Table 7) (5). The drugs and regimens are listed in Table 8. The preferred regimen is 9 months of isoniazid. Six months of isoniazid may be used in HIV negative patients if resources do not permit a 9-month regimen. Isoniazid may be administered on a daily basis or twice-weekly; if given intermittently, the isoniazid dose should be increased and all doses should be administered under direct observation. Pyridoxine (B6) should be given to persons at increased risk for peripheral neuropathy. Such patients include persons with HIV infection, diabetes mellitus, end-stage renal disease, and those who abuse alcohol. Pyridoxine should also be given to pregnant women and persons with a seizure disorder. The typical dose of pyridoxine is 10 to 50 mg per day. Because of the cases of liver injury described above, the CDC recently published modified recommendations for the use of rifampin and pyrazinamide (31a). The 2-month regimen should generally not be used to treat LTBI and it should never be offered to patients who 1) are concurrently taking other medications associated with liver injury, 2) drink excessive amounts of alcohol, even if alcohol use is discontinued during treatment, 3) have underlying liver disease or 4) have a history of INH-associated liver injury. If the potential benefits of this regimen outweigh the risk of liver injury associated with it, use of rifampin and pyrazinamide might be considered in carefully selected patients, but only if 1) the preferred regimens judged not likely to be completed and 2) oversight by a clinician with expertise in the treatment of LTBI can be provided. Clinicians should dispense no more than a 2-week supply of medications.
Rifampin alone for 4 months is also a recommended regimen (5).
In a randomized controlled trial, 3 months of rifampin was more effective than
6 months of isoniazid (95). Because the patients receiving
rifampin had a relatively high rate of tuberculosis, 4 months of rifampin is
recommended instead of 3.
Special Circumstances Contacts to Drug-Resistant Cases: Contacts to cases with isoniazid-resistant disease should be treated with rifampin (600 mg/day) for 4 months. Unfortunately, for contacts to cases of MDR-TB, there are no good choices for therapy. The CDC have published recommendations for the management of persons exposed to MDR-TB cases (26). Decisions on therapy must be based on the likelihood that the contact is newly infected with a drug resistant strain, and the likelihood that the contact, if infected, will develop tuberculosis. If, after evaluating these considerations, the contact is felt to have an intermediate to high likelihood of having been recently infected with a multidrug-resistant strain of M. tuberculosis, and particularly if the individual has an increased risk for the development of tuberculosis, a treatment regimen for LTBI should be administered. For contacts of MDR-TB cases, two oral drugs to which the isolate is susceptible should be given for 6-12 months. Persons with Fibrotic Lesions on the Chest Radiograph: Patients with a positive tuberculin skin test and an abnormal chest radiograph consistent with inactive tuberculosis, should be treated with either 9 months of isoniazid or 4 months of rifampin with or without isoniazid (5). Although there have been no comparative trials of these two regimens, the failure rate among such patients given the four-month regimen is very low (53) and it is more cost-effective than 9 months of isoniazid (104). Underlying Medical Conditions Treatment of LTBI in the HIV-1 Infected Patient: Isoniazid therapy is very effective in preventing persons infected with M. tuberculosis from developing tuberculosis, regardless of HIV-1 serostatus. Randomized placebo-controlled studies in Haiti (140) and Uganda (200) demonstrated significant reductions in tuberculosis in patients taking 6-12 months of isoniazid compared with placebo. As described above, two randomized clinical trials have demonstrated that two months of rifampin and pyrazinamide are as efficacious as 6-12 months of isoniazid in HIV infected patients (81, 84). However, the revised recommendations (31a) described previously also apply to HIV infected patients. Therefore, the two month regimen of rifampin and pyrazinamide should generally not be offered to HIV infected patients with LTBI. The current ATS/CDC recommendations are to provide isoniazid (300 mg/day) for 9 months to any HIV-1 infected person with a positive tuberculin skin test (≥ 5 mm), or who is a close contact to an infectious case, as long as they have no evidence of active tuberculosis (5). Routine treatment of anergic HIV infected patients is not recommended (5, 80). Therapy should be supplemented with pyridoxine (10-50 mg a day) to help prevent peripheral neuropathy. HIV-1 infected individuals who are close contacts to persons with infectious tuberculosis should receive treatment for possible latent infection regardless of the results of the tuberculin skin test, as long as active tuberculosis has been ruled out (5). In addition, since exogenous reinfection has been demonstrated in AIDS patients (24, 78, 170), treatment of LTBI should be given even if the person has been treated previously.
Pregnant Women: Although pregnancy is not a contraindication to the administration of isoniazid, the drug should be withheld until after delivery in most patients. In women who are HIV-1 seropositive or who are believed to have been infected during pregnancy, isoniazid should be given during pregnancy (5). Although isoniazid is secreted in breast milk, the concentration is low and no toxicity occurs in the infant (174). Thus, isoniazid therapy should not be withheld from nursing mothers. Pyridoxine (vitamin B6) should be given to pregnant women who are taking isoniazid. Because pyrazinamide is not recommended routinely during pregnancy, the short course regimen of rifampin and pyrazinamide is not recommended. Finnell SM et al. Latent Tuberculosis Infection in Children: A Call for Revised Treatment Guidelines. Pediatrics. 2009 Mar;123(3):816-22. Iseman MD. Extensively Drug-Resistant Mycobacterium tuberculosis: Charles Darwin Would Understand. Clin Infect Dis. 2007;45:1415–6. ENDPOINTS FOR MONITORING TREATMENT FOR LTBI The most important drug-related toxicity of isoniazid is drug-induced hepatitis. Elevation of serum aminotransferase activity occurs in 10-20% of persons taking isoniazid (5). In most persons, the enzyme level returns to normal despite continuing the medication. The risk of isoniazid-induced hepatitis increases with age. In a USPHS surveillance study conducted among over 13,000 participants, the frequency of probable isoniazid-induced hepatitis was as follows: < 20 years, 0 cases per 1000 persons; 20 to 34 years, 3 cases per 1000 persons; 35-49 years, 12 cases per 1000 persons 50-64 years, 23 cases per 1000 persons; > 64 years, 8 cases per 1000 persons (111). Daily alcohol ingestion also increased the risk of hepatitis. Some data suggest that African-American and Hispanic women, and possibly post-partum women, may be at increased risk of developing isoniazid-induced hepatitis (172). A recent publication from Seattle reported a lower rate of isoniazid-induced hepatitis, approximatley 10-fold lower than that reported by Kopanoff (134). Most patients receiving isoniazid therapy require minimal monitoring that consists of monthly symptom review (5). Patients should be questioned regarding the presence or absence of symptoms such as nausea, vomiting, dark urine, abdominal pain, anorexia, rash, tingling in the hands and feet, etc. For certain populations at increased risk of developing isoniazid-induced hepatitis, more careful monitoring is indicated (Figure 1). The following patients should have baseline serum transaminases measured: patients who have underlying chronic or acute liver disease, have had a previous reaction to isoniazid, are HIV-infected, are pregnant or postpartum. For these persons, or those with abnormal liver function tests on the baseline measurement, periodic determinations are indicated. Recent reports from the CDC have described 48 cases of severe liver injury related to rifampin and pyrazinamide short-course therapy,11 of whom died (30, 31a). Two of the patients who died were infected with HIV. Based on these reports, the CDC recommends more careful clinical and laboratory monitoring in patients receiving this short-course regimen (31a). All patients should be seen at 2, 4, and 6 and 8 weeks for clinical and laboratory monitoring and at 8 weeks to document completion of therapy. A serum aminotransferase (AT) and bilirubin should be measured at baseline, 2, 4, and 6 and 8 weeks of therapy. Treatment should be stopped if the AT is greater than five times the upper limit of normal in an asymptomatic person, if the AT is above normal in a symptomatic patient, or if the bilirubin is greater than normal (31a).
INFECTION CONTROL All untreated cases of pulmonary tuberculosis are infectious to some degree. Sputum smear positive cases of tuberculosis are the most infectious by virtue of the large number of bacilli being shed. Treatment with antituberculosis medications results in a rapid decline in the number of bacilli that is associated with a decrease in the infectivity of the patient (96). Epidemiologic studies have demonstrated that contacts to cases who have been started on therapy do not appear to convert their skin test. Hospital infection control programs are based on the results of sputum smear examinations. Smear positive suspects must be kept in negative pressure isolation rooms until they have converted the AFB smears to negative and they have demonstrated a clinical and/or radiographic response to therapy (7). Similarly, patients with positive AFB smears can not be discharged to high-risk environments like jails, residential facilities, etc. until they have converted their smears to negative. For TB suspects with negative sputum smears who have a high probability of active disease there is great deal of variation in how they are managed. Studies have demonstrated that smear negative culture positive cases can transmit tuberculosis. For example, Behr and colleagues in San Francisco demonstrated that approximately 17% of secondary cases resulted from a smear negative source case. (9) California State Guidelines require that such individuals receive at least 4 days of antituberculosis therapy before being transferred to a high-risk setting (23). Guideline: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Controlling Tuberculosis in the United States. Am J Respir Crit Care Med 2005;172:1169-1227. Guideline: International Standards for Tuberculosis Care (Endorsed by IDSA) World Health Organization, 2006.
Figures and Tables Figure 1. Monitoring Patients Receiving Isoniazid Table 1. Dosages, Pharmacokinetics and Minimal Inhibitory Concentrations of Antituberculosis Medications
Table 2. First Line Drugs
Table 3. Second Line Drugs
Table 4. Drug Regimen For
Culture-positive Pulmonary tuberculosis
Table 5. Selected Treatment Regimens for Drug-Resistant tuberculosis.
Table 6.
Dosing Recommendations in Patients
Receiving Chronic Hemodialysis
Table 7. Criteria for Positive Tuberculin Skin Test, By Risk Group
Table 8. Recommended Treatment Regimens for LTBI
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