Mycobacterium tuberculosis Complex

MICROBIOLOGY

Tuberculosis (TB) 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  (370). The other member of the complex, M. microti, is a rodent pathogen.  

EPIDEMIOLOGY

M. tuberculosis is the most important of the human pathogens. Recent analysis of the genomic sequences of M. tuberculosis isolates from different parts of world suggested that the bacillus emerged about 70,000 years ago and accompanied migrations of anatomically modern humans out of Africa (73).  Approximately one-third of the world's population, or 2 billion people, are thought to be infected with M. tuberculosis  (292). In 2013, 9 million people became ill with tuberculosis at an estimated incidence of 126 cases per 100,000 population (378) The number of incident cases has falling slowly at an average rate of 1.5% per year from 2000 to 2013. There were marked differences in tuberculosis rates between high and low burden countries. The estimated TB incidence was as high as 860 cases per 100 000 population in South Africa. In United States, the incidence rate of tuberculosis dropped to 3.0 cases per 100,000 population (9), 64.6% of tuberculosis cases occurred among foreign-born persons, and the incidence rate was 13 times greater than that of U.S.-born persons. Foreign-born children and US-born children with foreign-born parents had tuberculosis rates 32 times and 6 times higher than that of US-born children with US-born parents respectively (268). Tuberculosis is second only to HIV/AIDS as the greatest killer infectious disease worldwide accounting for 1.5 million deaths (378). In addition, the syndemic of human immunodeficiency virus (HIV)/tuberculosis co-infection has grown as a result of the considerable sociogeographic overlaps between the two epidemics (208). TB is the leading killer of HIV-positive people, causing 25% of all HIV-related deaths (379).

The prevalence of drug resistant TB, including multi-drug resistant disease (MDR-TB), has increased in many areas of the world (125). Globally in 2013, an estimated 480 000 people developed MDR-TB, accounting for around 5% of all estimated TB cases (380).  The MDR-TB constituted 3.5% among new TB cases and 20.5% among previously treated cases worldwide. By end of 2013, 100 countries had notified at least one case of XDR-TB, and the average proportion of MDR-TB cases with extensively drug-resistant (XDR-) TB worldwide was 9.0% (380). Among 1278 patients consecutive adults with locally confirmed pulmonary MDR tuberculosis started on secondline drug treatment from Jan 1, 2005, to Dec 31, 2008 in eight countries (Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand), 43·7% showed resistance to at least one second-line drug, 20·0% to at least one second-line injectable drug, 12·9% to at least one fluoroquinolone, 6·7%  (range 0·8-15·2% ) of patients had XDR tuberculosis, and previous treatment with second-line drugs was consistently the strongest risk factor for resistance to second-line drugs (56). Notwithstanding that, most cases of MDR-TB and XDR-TB resulted from primary transmission in some countries with high TB drug resistance burden (23). For areas with lower burden of drug resistance, molecular studies shows a relative low degree of clustering for MDR-TB in both United States (348) and United Kingdom (18) while restriction length polymorphism analysis in Hong Kong showed clustering among 65% of XDR-TB, with recent transmission estimated at 55% by the n-1 method (212). 

PATHOGENESIS 

Tuberculosis can develop through progression of recently acquired infection (primary disease), reactivation of latent infection, or exogenous reinfection (166). In immunocompetent individuals, approximately 3-10% of those with tuberculous infection will develop tuberculosis in the first 1-2 years after infection (337) and another 5% will develop tuberculosis during their lifetime. The risk is modified by the age of acquiring infection (e.g. being lowest in the age range of 5 to 9 years) (228) and many other host factors (222).  Exogenous reinfection is thought to be uncommon in immunocompetent persons residing in areas with a low prevalence of tuberculosis, but life-style- related factors and chronic diseases, such as active (218) or passive smoking (219), nutritional status (220) and diabetes mellitus (221) may significantly affect the risk of reactivation of endogenous infection. In the setting of HIV-1 infection, the risk of progressing rapidly to infection once infected with M. tuberculosis  (80), the risk of reactivation (81, 304, 305), and the risk of exogenous reinfection (47, 144, 318) are all increased compared to HIV-1 seronegative persons.  

CLINICAL MANIFESTATIONS 

Most tuberculosis occurs as pulmonary disease with 17% occurring at an extrapulmonary site, only (54). 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 (187). Co-infected persons are more likely to present atypically, potentially delaying the diagnosis of tuberculosis.  

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.

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 (132). 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 (136). 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 (332).

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 (136). 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 (178). 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 (85). 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 (137, 215). 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 (136).

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 (26). 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 (66, 308).  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.  

Female genital tuberculosis starts with a hematogenous focus in the endosalpinx, and may spread to the endometrium (50%), ovaries (30%), cervix (10%), and vagina (1%). A granulomatous ulcerating mass in the cervix may resemble carcinoma. Abdominal pain, menstrual disorders, or infertility are common complaints. Patients may present with the pictures of pelvic inflammatory disease with unresponsiveness to therapy. It is uncommon for patients to have systemic symptoms, and signs of old tuberculosis are often absent. Pregnancies are often ectopic in the presence of pelvic tuberculosis.

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.

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 (198).

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.

DIAGNOSIS 

Although tuberculosis shares many clinical and radiological features with other respiratory or non-respiratory diseases, symptoms remain an important tool to facilitate passive case-finding in general or enhanced symptom screening among those with HIV co-infection (217). Screening for the presence of anyone of a combination of relevant symptoms like current / recent cough, fever, night sweat and / or weight loss has been shown to give a  higher sensitivity than cough alone among people living with HIV (45, 291).  Chest x-ray may be normal in up to one-third of HIV-infected patients with sputum culture-confirmed TB (45), but when added to symptom screening among HIV-infected adults starting antiretroviral therapy, it can increase the diagnostic sensitivity from 74.5% to 96.1% (152).  

Patients suspected of having pulmonary tuberculosis should have at least two  sputum specimens examined for microscopic evidence of acid fast bacilli (AFB) and the front-loaded approach of collecting two spot sputum specimens within the same visit is as accurate as standard smear microscopy of specimens over separate days (86). Fluorescence microscopy requires lower work effort and shows a higher sensitivity and similar sensitivity as compared to conventional Ziehl-Neelsen (ZN) smear microscopy (326). Fluorescent light-emitting diode (LED) microscopy has qualitative, operational and cost advantages over both conventional fluorescence and Ziehl-Neelsen microscopy (376). However, in a recent study, fluorescent LED microscopy showed a higher sensitivity but lower specificity than ZN smear microscopy for diagnosis of pulmonary TB, thereby suggesting a need for appropriate training, quality management, and monitoring of performance in the field (78). 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 (370). 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 (16).  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. New phenotypic methods, such as non-radiometric commercial liquid culture +/- drug susceptibility testing (195), microscopic observation drug susceptibility (MODS) (243, 366),  colorimetric redox indicator methods (229) and nitrate reductase assay (70), may shorten the turn-over time for cuture detection and drug susceptibility testing, but none of them can be expected to provide the answer close to the point of care.  

Newer nucleic acid amplification tests allow for the rapid identification of organisms belonging to the M. tuberculosis complex (16).   Several NAAT are commercially available for the laboratory-based diagnosis of tuberculosis and some of them also allow detection of bacillary resistance to rifampicin and some other first- and second-line drugs (217).  Using culture as reference standard, most of them have similarly high sensitivity and specificity for the detection of tuberculosis, at least among sputum smear-positive patients (327, 345). However, unlike culture isolation, detection by NAAT does not necessarily imply viability of the detected microbes. The Xpert MTB/RIF (Cepheid, USA), an automated microfluidic real-time polymerase chain reaction assay, is able to detect M. tuberculosis complex DNA and resistance to rifampicin within 2 hours, thus showing potential for future deployment as a point-of-care test in resource-limited settings. As an initial test for diagnosis of tuberculosis, it has a pooled sensitivity of 89% and pooled specificity 99% (327). The pooled sensitivity is 98% in smear-positive case and 67% in smear-negative cases.  For extrapulmonary TB, the sensitivity of Xpert MTB/RIF varies substantially among different sample types (88). It should, however, be noted that the actual predictive value of a positive or negative value in fields is critically dependent on the prevalence of the target condition in the specific group being tested.  The WHO recommended that Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in adults and children suspected of having MDR-TB or HIV-associated TB. It may be used rather than conventional microscopy and culture as the initial diagnostic test in all adults and children suspected of having TB and as a follow-on test to microscopy in adults suspected of having TB but who are not at risk of MDR-TB or HIV-associated TB, especially when further testing of smear-negative specimens is necessary (377).

Clinically significant disease can be present even in the absence of a positive culture, due to poor specimen collection, contamination, failed recovery and/or low bacillary count (217). In a randomized trial in South Africa, sputum induction provided an adequate sample and a bacteriological diagnosis more frequently than instruction by a health-care worker, but did not result in a higher proportion of same-day diagnoses (278). The NAAT are not expected to overcome the intrinsic problems related to specimen collection from site of disease and its variable bacillary load. In a randomised multicentre trial comparing point-of-care Xpert MTB/RIF testing by a nurse with smear microscopy on adults with symptoms suggestive of active TB in 5 primary-care clinics in Africa, Xpert MTB/RIF testing resulted in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment (346).  However, there was no significant difference of TB-related morbidity in culture-positive patients who had begun anti-tuberculosis treatment as measured at 2 months and 6 months, partly because of high levels of empirical-evidence-based treatment in smear-negative patients.  Novel tools are being explored for their application on alternative biological samples, such as urine and exhaled breath, Urinary assay for lipoarabinomannan (LAM), a 17.3-kDa immunogenic glycolipid component of the mycobacterial cell wall, shows a moderate sensitivity of ~50% and a fairly high specificity of 83/100% for diagnosis of tuberculosis in HIV-infected patients (129), and the sensitivity is highest among patients with a low CD4 count < 50 cells per μL (243).

DRUG SUSCEPTIBILITY TESTING 

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 (83). 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 (83). 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 10 (38). Even in a patient who has cavitary tuberculosis, where the bacillary population may exceed 10 (24) organisms, the probability that simultaneous mutations will occur in the same organism leading to multiple resistance is exceedingly small (83).

Phenotypic drug susceptibility testing is often done indirectly on culture isolates.  Although direct drug susceptibility testing is possible with some of the drugs using commercial liquid media and will substantially decrease the turnover time, significant wastage occurs in situations where a high culture yield cannot be guaranteed and contamination, especially by non-tuberculous mycobacteria, may also be a source of concern.

Drug susceptibility testing of M. tuberculosis  should be performed on an initial isolate from all patients with tuberculosis  (16). 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) (253). 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 (253). With the proportion method, plates of drug-free agar and agar containing critical concentrations of antituberculosis drugs are inoculated with the isolate (362). 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) (154). 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 (253).  A World Health Organization (WHO) commissioned supported the recommended critical concentrations for isoniazid and rifampin in commercial broth-based systems, but further studies are needed to evaluate critical concentrations for ethambutol and streptomycin, and evidence is limited on the performance of DST for pyrazinamide and second-line drugs (167). Highly discordant drug susceptibility test (DST) results were also observed between Löwenstein–Jensen (LJ) medium and MGIT960 for Mycobacterium tuberculosis isolates with certain rpoB mutations (511Pro, 516Tyr, 533Pro, 572Phe, and several 526 mutations), with MGIT-DST failing to give a result or declaring the strains susceptible (295). In another study comparing the MGIT 960 System against LJ proportion method,  the critical concentrations of moxifloxacin (0.5  μg/mL), levofloxacin (1.0  μg/mL), kanamycin (2.5  μg/mL), and capreomycin (2.5  μg/mL) were concordant and reliable for testing 2nd line drug resistance, while further studies are required for ethionamide and ρ-aminosalicylic acid (195).

The short turn-over time of genotypic methods offers an attractive potentially for rapid detection and characterization of drug resistance in the fields. However, genome sequencing of Mycobacterium tuberculosis isolates discovered a large number of new genes, intergenic regions and nonsynonymous single nucleotide polymorphisms showing consistent associations with drug resistance, indicating that the genetic basis of drug resistance is more complex than previously anticipated (388).  Correlation between genotypic and phenotypic drug susceptibility is relatively good for rifampicin, isoniazid, fluoroquinolones, and aminoglycosides (48, 297) but is lower for other first-line (41, 65, 79, 270) and second-line drugs (41, 168).  Although Xpert MTB/RIF shows a pooled sensitivity is 95% and pooled specificity, 98% for rifampicin resistance detection (327), false-positives are still a matter of concern in settings with a low prevalence of rifampicin resistance.  Xpert MTB/RIF assay has an increased false-negative rate for detecting rifampin resistance with mixed MTBC infections when <90% of the organisms in the sample were rifampin resistant, and false-negative Xpert results and mixed MTBC infections were strongly associated with poor clinical outcome (387).  Currently commercially available NAAT may also be less sensitive than conventional phenotypic drug susceptibility testing in detecting the clinically important 1% resistant bacteria in patients harboring both rifampin-sensitive and rifampin-resistant bacillary strains, thus raising a theoretical concern over their ability to detect minor resistant clones emerging during the course of treatment (129).  

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 (194). A modified Ziehl-Neelsen stain and early secretory antigen target (ESAT)-6 in cerebrospinal fluid leukocytes may help to improve the sensitivity but further studies are required to confirm its clinical utility, especially in relation to its specificity and predictive values across different clinical settings (128). 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 (266).  A pooled sensitivity of 81% against culture and 63% against a composite reference standard for the Xpert MTB/RIF assay in a more recent meta-analysis (88).  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 (124). 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. The sensitivity of NAATs for pleural fluid is also limited, and the pooled sensitivity of Xpert MTB/RIF assay is only 46% against culture and 21 against a composite reference standard in a meta-analysis (88).  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%. 

Lymphadenitis

Fine-needle aspiration gives higher yields in AIDS patients as opposed to non-AIDS patients. Acid-fast stains 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. Lymph nodes should be excised completely with no drain left in place to avoid the possibility of postoperative fistula formation.  In a meta-analysis, the pooled sensitivity of Xpert MTB/RIF assay was 83% versus culture and 81% versus a composite reference standard, lending support to its role over conventional tests for diagnosis of TB in lymph nodes (88). 

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 (66, 308). 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% (132). However, the sensitivity dropped to 30% in patients with cirrhosis due to the poor humoral and T cell mediated response of cirrhotic patients (27). 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 (38). 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 (2).

SCREENING FOR LATENT TUBERCULOSIS INFECTION

As currently available methods cannot directly detect individuals who are latently infected with live M. tuberculosis, latent TB infection is defined by the presence of an M. tuberculosis-specific immune response in the absence of active TB in clinical practice (217). 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 meta-analyses 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 . When newly diagnosed active tuberculosis was used as a surrogate for latent tuberculosis infection, sensitivity of all tests was suboptimal (tuberculin skin test 77%, 95% confidence interval [CI] 71-82%; QuantiFERON-TB Gold  78%, CI 73-82%; QuantiFERON-TB Gold In-Tube 70%, CI 63-78%, and T-SPOT.TB 90%, CI 86 - 93%) although T-Spot.TB  had better performance (267). 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 QuantiFERON-TB Gold / QuantiFERON-TB Gold In-Tube of 98% (CI 96-99%) and T-Spot.TB of 93% (CI 86-100%).  Specificity of tuberculin skin test was high (97%, CI 95-99%) in non–BCG-vaccinated populations, but was low and highly heterogeneous in BCG-vaccinated populations. In a recent study, BCG given in infancy was also associated with discordant results between tuberculin skin test and interferon gamma release assay within the same individual, even though the observed risk ratio of 6.4 was substantially lower than those for BCG given post infancy (RR 8.1) and multiple BCG vaccinations (RR 20.0) (12).  Among HIV-infected subjects, the pooled sensitivity estimates were heterogeneous but higher for TSPOT (72%, CI 62-81%) than for QuantiFERON-TB Gold In-Tube (61%, CI 47-75%) in low-/middle-income countries, but neither IGRA was consistently more sensitive than the tuberculin skin test in head-to-head comparisons (50).  Studies which define the performance of INF-γ release assays in high-risk populations are needed.

Existing diagnostic tools for latent tuberculosis infection cannot accurately predict the future development of tuberculosis, and IGRAs only have a moderate predictive power (pooled incidence rate ratio between test-positive and test-negative, IRR: 2.1) marginally higher than that of tuberculin skin test (IRR: 1.6) in low/middle income countries (290). Neither tuberculin skin test nor IGRAs appear to show a good predictive power for the development of tuberculosis in immunocompromised subjects (223). Using host immune sensitization as a diagnostic marker biomarker is intrinsically limited by the potential variations in the time profile and magnitude of immune responses as well as the variable degrees of persistence of immune memory, leading to poor differentiation among remote, recent and inactive infection or disease (217).  Their suboptimal performing in predicting disease is also expected with the average lifetime tuberculosis risk of 10% after infection and the noises posed by ongoing transmission after testing especially in high tuberculosis burden areas (216).  Until suitable biomarkers capable of accurately predicting progression to active disease,  screening and treatment efforts for latent tuberculosis have to focused on groups with documented high disease risks within the local contexts to maximize cost-effectiveness (222, 381).

ANTIMICROBIAL THERAPY

Drug of Choice 

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.   

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 (244).  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 (244). 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. Rifampin and pyrazinamide have the greatest sterilizing capacity. The activity of pyrazinamide is seen in the first few months of therapy whereas that of rifampin persists through the course of therapy. In the absence of rifampin, the sterilizing activity of pyrazinamide may persist throughout the treatment course (5). 

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 (244). 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% (37, 342). The addition of isoniazid to streptomycin and para-aminosalicylic acid increased cure rates to 95% but required 18-24 months of therapy (38).  

In a series of studies conducted by the British Medical Research Council (BMRC) in East Africa (110, 111, 112, 113, 114) and the United States Public Health Service (USPHS) (256, 257), investigators demonstrated the importance of rifampin and pyrazinamide in shortening the duration of therapy for tuberculosis. A six month regimen of daily isoniazid, streptomycin, and rifampin compared favorably with the 18 month regimen of streptomycin, thiacetazone, and isoniazid for 2 months followed by thiacetazone and isoniazid for 16 months (114). In addition, short-course therapy was demonstrated to be efficient in converting sputum cultures to negative and relapse rates were low. 

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 (256, 257).  Addition of pyrazinamide beyond the initial two months was demonstrated to be unnecessary in several BMRC studies (115, 164, 310).  

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 (105, 108). The British Thoracic Society 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 (39). The USPHS Trial 21 studied daily, self-administered isoniazid and rifampin for six months with pyrazinamide given during the initial two months (77). 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 (72). 

Regimens of less than 6-months duration were shown to have unacceptably high relapse rates among smear positive pulmonary tuberculosis (115, 161, 162, 312), including noncavitary pulmonary disease with negative two-month sputum culture (186). However, among patients with smear negative disease, the relapse rate was only 2% using a 4-month regimen of streptomycin, isoniazid, rifampin, and pyrazinamide (162).  

 A number of phase II and III trials have evaluated the feasibility of further shortening the standard six-month regimen, using sputum culture conversion as surrogate markers of treatment efficacy   (43,75, 100, 101, 102, 186, 300, 355, 368) and clinical outcomes as efficacy endpoints (139, 180, 184, 186, 238). Only two phase II trials showed significantly better sputum culture conversion rates at 8 weeks that suggested potential for further development of shortening treatment with moxifloxacin (75) and high-dose rifapentine (102). All phase III trials failed to demonstrate the noninferiority of four-month regimens.

Recommended Treatment Regimens 

The current minimal acceptable duration of treatment for all adults and children with culture-positive tuberculosis is 6 months (15). The initial phase of the 6-month regimen should consist of isoniazid, rifampin, pyrazinamide and ethambutol (or streptomycin) given for 2 months. This phase of therapy can be administered daily (5 or 7 days-a-week) or intermittently (Table 4). Ethambutol (or streptomycin) can be discontinued as soon as the drug susceptibility results document susceptibility to the above drugs.  

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 (352). HIV infected patients should not receive this highly intermittent regimen because of a high relapse rate associated with acquisition of rifamycin monoresistance (360).   

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 (258).  

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 (94, 95) and clinical evidence (163, 310, 313) support the use of intermittent therapy.  

Multiple clinical trials have demonstrated the efficacy of twice-weekly and thrice-weekly treatment regimens  (163, 310, 313). Treatment in the continuation phase may also be given once weekly when rifapentine is given instead of rifampin (25, 339), but with a relatively higher risk of relapse (62), as well as an increased risk of acquired rifamycin resistance among HIV-infected subjects (360). 

Although intermittent regimens are generally efficacious, a systematic review of 6-month regimens involving 5208 patients in 32 cohorts has suggested that daily treatment throughout is significantly better than intermittent treatment in preventing relapse, with a non-significant difference between daily and intermittent treatment after the first two months (62). There are high levels of evidence for using daily dosing schedules to reduce the risk of treatment failure, recurrence and acquired rifamycin resistance, especially during the initial phase in the presence of cavitation, isoniazid resistance, and advanced HIV co-infection (61). 

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 (371). 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.   Directly observed therapy has been used successfully by a number of tuberculosis control programs and has been shown to be cost-effective (42, 249, 371).

 The use of directly observed therapy was associated with a decrease in primary drug resistance, acquired drug resistance and relapse in Tarrant County, Texas between 1980 and 1986 (371). If directly observed therapy 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 directly observed therapy, also. 

 When directly observed therapy cannot be used the patient should be treated with fixed-dose combined formulations (17). There are two combined formulations now available in the United States: a combination of isoniazid and rifampin (Rifamate®) and a formulation of isoniazid, rifampin, and pyrazinamide (Rifater®). Two tablets of Rifamate® contain conventional daily doses of both isoniazid (300 mg) and rifampin (600 mg). The Rifater® tablet that is available in the United States contained INH (50 mg), rifampin (120 mg), and pyrazinamide (300 mg): thus, six tables of Rifater® would contain the conventional daily dose of INH (300 mg) and pyrazinamide (1800 mg) but the rifampin dose (720 mg) is higher than usual; the rifampin dose is higher because the rifampin is less bioavailable in this formulation. 

There is no evidence indicating that fixed-dose combinations are superior to individual dosing of drugs (164, 314). Two clinical trials have suggested that fixed-dose combination drugs may be non-inferior to separate drugs (22, 214, 262). Although a systematic review with meta-analysis found a non-significant trend towards higher risk of failure or relapse with use of fixed-dose combination drugs (11),  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 (17, 214). Combined formulations are not a substitute for directly observed therapy, 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 (246). Positive two-month culture and cavitation on the chest radiograph are both independent risk factors for relapse (25).  Among pulmonary TB patients given standard six-month regimens with daily or intermittent treatment in the two-month initial phase, and twice-weekly in the continuation phase (25), the risk of relapse significantly increased from 1.7% to 20.8% in the presence of initial cavitation and positive two-month culture. This substantial increase in the relapse risk was also observed among patients with pan-susceptible pulmonary TB treated with standard 6-month daily regimens, with an adjusted odds ratio of 15.56 (95% CI 2.56-98.71) (185).   On the other hand, 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. 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 (30). 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. Whether it is necessary to extend treatment among patients with initial cavitation or positive two-month culture only is controversial, as the corresponding relapse risk was much lower (5-6%) when treatment was largely twice-weekly (25), and about 1.8%-2.2% when treatment is given daily throughout (62), and 2.2%-3.3% when treatment is daily in the two-month initial phase and thrice-weekly in the continuation phase (62). As noted above, giving treatment daily instead of intermittently especially during the two-month initial phase would probably help reduce the risk of treatment failure or recurrence (61).

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 (106), the current recommendations are to treat extrapulmonary forms of disease in adults the same as pulmonary disease (17). The exception to this recommendation is CNS disease for which there is 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 (17). 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 (10, 27, 104, 190, 285). HIV-infected patients are at increased risk of developing tuberculous meningitis but the outcomes of treatment do not appear to be altered (27, 104, 285,384). 

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 (120) and pyrazinamide (97, 118, 279, 374) penetrate well into the CSF reaching concentrations equal to serum. In contrast, rifampin (96, 120, 374), ethambutol (31, 281, 283), and the aminoglycosides (120) penetrate the meninges only in the setting of inflammation.  Of the second line agents, ethionamide and cycloserine penetrate the blood-brain barrier with or without inflammation (157).  Ofloxacin has been shown to penetrate the CSF well in the setting of purulent meningitis (282). Because several of these drugs penetrate into the CSF only in the setting of inflammation, a theoretical concern would be that co-administration of corticosteroids would result in a lower CSF drug concentration.  However, Kaojarern and colleagues (190) reported no significant difference in the CSF concentrations of isoniazid, pyrazinamide, rifampin, or streptomycin between patients who had received corticosteroids and those who had not. 

Use of rifampin at higher dose or levofloxacin may have survival benefit for patients with TB meningitis. An open-label RCT of TB meningitis in Indonesia found a significant lower risk of six-month mortality among patients given intravenous high-dose rifampin (35% vs. 65%) in comparison with oral rifampin 450 mg daily in the first two weeks of treatment, with a hazard ratio (HR) of 0.42 (95% CI 0.2-0.91) (299). An observational cohort study of mortality among HIV-infected patients with TB meningitis found a significantly higher risk of death among patients given standard TB regimens than those initially given levofloxacin, ethionamide, pyrazinamide, and a double dose of rifampin and isoniazid for a median duration of 7 days (adjusted hazard ratio 2.05, 95% CI 1.2-3.5) (13). An open-label RCT of TB meningitis in India evaluated the use of levofloxacin (10 mg/kg, maximum 500 mg) instead of rifampin (10 mg/kg, maximum 450 mg) given with isoniazid, pyrazinamide, prednisolone and aspirin, and found a significantly better six-month survival rate in the levofloxacin arm (hazard ratio 2.13, 95% CI 1.04-4.34) with similar disability (189).

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 (17). 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 (2, 10, 98, 175, 288, 334). A retrospective study of HIV-negative patients with TB meningoencephalitis found no significant differences between the standard 6-month TB regimen and a 12-month regimen (isoniazid and rifampin for 12 months supplemented by pyrazinamide and ethambutol in the first two months) in the frequency of treatment failure, treatment failure, mortality, and late consequences (250). 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 earlier studies were small in size and many did not use a rifampin-based regimen (19, 99, 114, 140, 202, 265, 280, 363).  Studies have demonstrated a benefit of corticosteroids over standard therapy alone in terms of survival, and /or frequency of sequelae (116, 141, 307). 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 (307). Adjunctive therapy with dexamethasone significantly reduced the risk of death (relative risk, 0.69; CI 0.52 - 0.92; P=0.01) but no significant reduction in severe disability at 9 months of follow up in a randomized controlled trial among 545 patients with tuberculosis meningitis and over 14 years of age in Vietnam (344).  However, longer term follow-up suggested trend probable survival benefit up to at least two years but no overall five-year survival benefit, except perhaps for patients with grade 1 tuberculosis meningitis (349).  In an meta-analysis, corticosteroids (either dexamethasone or prednisolone)  reduced the overall risk of death (RR 0.78, CI 0.67 - 0.91) in 7 trials involving 1140 participants (with 411 deaths) and the risk of death or disabling residual neurological deficit (RR 0.82, CI 0.70 - 0.97) in three of the trials (720 participants) with data on disabling residual neurological deficit (286). Adverse events (gastrointestinal bleeding, bacterial and fungal infections and hyperglycaemia) were mild and treatable. Most authorities recommend corticosteroids in patients who present with CNS dysfunction (17). Dexamethasone (or its equivalent) is often 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".  

Pleural tuberculosis

 A 6-month regimen consisting of isoniazid and rifampin was shown by Dutt and colleagues (109) to be as effective as regimens of longer duration. Two prospective randomized double-blind trials, demonstrated that use of corticosteroids did not reduce the development of residual pleural thickening (209, 382). In one study (209), administration of corticosteroids was associated with a more rapid resolution of symptoms and a more rapid radiographic resolution of pleural liquid. However, Wyser and colleagues (382) could not demonstrate any added benefit of corticosteroids on symptoms compared to complete drainage of the fluid. A systematic review of corticosteroids for tuberculous pleurisy located six eligible RCT or quasi-RCTs, and found insufficient evidence for evaluating the effects of corticosteroids on morbidity and mortality (123). Treatment of tuberculous empyema usually requires prolonged drainage often with surgical intervention.

Lymph Node tuberculosis

Prospective studies of 6-9 months duration in adults (40, 49, 386) and 6 months of intermittent therapy in children (182) have been shown to be very effective. A RCT suggested that a daily self-administered 6-month regimen was comparable with a twice-weekly, directly observed, 6-month regimen by clinical response and relapse risk (181). During the course of therapy, lymph nodes may enlarge, new nodes may appear, and nodes may spontaneously drain and create fistulas (49, 155, 210). 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 (210). 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 (17). 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 (332). 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 (331). 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 (150).  A systematic review of interventions for treating tuberculous pericarditis located four eligible trials, and found that steroids might reduce mortality but with insufficient clinical evidence (232). 

Based on the data described above, adults and children with tuberculous pericarditis should receive adjunctive corticosteroid treatment (17). 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 (234, 235, 236, 287,353, 354). A randomized trial demonstrated no additional benefit of surgical debridement or radical operation in combination with chemotherapy compared with chemotherapy alone (236). A systematic review of routine surgery in addition to chemotherapy for treating spinal TB located only two eligible RCTs, with insufficient evidence to recommend routine surgery (188). Although a prospective cohort study of TB spine patients in China found it feasible to reduce the TB treatment duration from an average of 9 months to 4.5 months with thorough focus debridement, bone grafting, and internal fixation(367), the treatment duration might have been selected by treatment response.  Nonetheless, 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 (17). Myelopathy with or without functional impairment usually responds to chemotherapy alone (235, 271). When tuberculosis affects another joint, chemotherapy is usually sufficient unless extensive joint destruction has occurred.

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 (315). 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 (17).   

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 (143, 172). 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% (138, 272, 341, 384).

Isolated Resistance to Isoniazid

Effective treatment regimens for patients with isolated isoniazid resistance are readily available. Patients may be treated with a combination of rifampin, ethambutol (or streptomycin), and pyrazinamide for a total of 6 months duration (163, 311).  If the patient was begun on the standard four-drug regimen, isoniazid can be stopped when the drug resistance is noted. Instead of stopping the pyrazinamide at 2 months, the drug is continued for the full six months along with rifampin and ethambutol (or streptomycin). The patient can also be treated with rifampin and ethambutol for 12 months (159, 390) preferably with pyrazinamide included in the regimen for at least the first 2 months or longer. And finally, one study reported low relapse rates with a regimen consisting of six to nine months of rifampin and ethambutol supplemented for the first two months with streptomycin and pyrazinamide (338). 

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 (330). 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.   

Isolated Resistance to Rifampin

Isolated resistance to rifampin has been relatively unusual in the past. However, recent reports have described an increase in the frequency of mono-rifampin resistant isolates among person with HIV-1 infection (35, 260). Unfortunately, the loss of rifampin from the standard treatment regimen prolongs the duration of therapy. Isolated rifampin resistance can be treated with isoniazid and ethambutol for 18 months (32). As with isolated isoniazid resistance, pyrazinamide should be added for at least the first two months of the regimen. Additionally, 9 months of isoniazid, pyrazinamide, and streptomycin given either two or three times per week was associated with a 6% relapse rate (160).  

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 rifampin, the two most important antituberculosis drugs, efficacy is decreased and therapy must be prolonged significantly. The duration of therapy will depend on the agents used and the extent of disease. Most authorities recommend a four or five drug treatment regimen, including an injectable (17, 143, 172). The oral medications should consist of any first-line agents that are available, plus a fluoroquinolone if the MDR isolate is susceptible, and other second-line agents. Patients who can be treated with a fluoroquinolone have a much better chance of cure (80% or greater); conversely, patients infected with a fluoroquinolone-resistant isolate are at high risk for relapse or treatment failure (341, 384). When used as a primary agent in the treatment of tuberculosis, ethambutol should be given at a dose of 25 mg/kg instead of 15mg/kg. The patient should be treated for at least 18 to 24 months. The injectable agent should be continued for 6 months beyond culture conversion or when the maximum cumulative dose has been reached. Surgical resection should be considered if culture conversion has not occurred by 6 months, particularly in patients with resistance to all first-line agents (173, 284).

In line with clinical evidence for the essential roles of fluoroquinolones (23, 126, 211, 241, 384), second-line injectable drugs (SLID) (23, 60, 126, 240), pyrazinamide (23, 203), ethionamide (23, 68, 203,204), and possible cycloserine and para-aminosalicylic acid (6, 23), the World Health Organization (WHO) has recommended using at least four likely effective drugs plus pyrazinamide in the initial-phase treatment of MDR-TB (127). Based on systematic reviews of observational data, WHO has recommended an initial treatment phase of at least 8 months, and a treatment duration of at least 20 months overall (127). A few studies have evaluated and provided clinical evidence for treating MDR-TB with at least 5 likely effective drugs including fluoroquinolone and a SLID on treatment outcomes (130, 247, 347, 359).  Contrary to the belief of treating MDR-TB for at least 18 months, it has been proven possible to effectively treat simple MDR-TB patients within 15 months with levofloxacin-based regimens, and second-line treatment-naïve MDR-TB with the "nine-month Bangladesh regimen" comprising high-dose gatifloxacin, ethambutol, clofazimine, and pyrazinamide, supplemented by kanamycin, high-dose isoniazid, and prothionamide in the initial four months (20, 356).  In the treatment of fluoroquinolone-resistant MDR-TB, and extensively drug-resistant TB (XDR-TB), defined as MDR-TB with additional bacillary resistance to any fluoroquinolone and any SLID, it is often beneficial to use later-generation fluoroquinolones (176, 185), and WHO Group 5 drugs, which comprise high-dose isoniazid and mainly repurposed agents such as linezolid, clofazimine, meropenem-clavulanate, and thioridazine (63). Two Korean and one Shanghai study in China found no significant difference between moxifloxacin and levofloxacin in the treatment of ofloxacin-resistant MDR-TB (183, 199, 207). A systematic review of fluoroquinlone-resistant or XDR-TB treated with regimens containing WHO group of 5 drugs showed that linezolid use significantly increased the probability (95% CI) of favorable outcome (sputum culture conversion, cure, or treatment completion in the absence of death, default, treatment failure, or relapse) by 57% (10% to 124%) in a Poisson regression model, and by 55% (10% to 121%) by meta-analysis, with no significant add-on effect from other WHO Group 5 drugs (63). A high risk of peripheral neuropathy has prohibited prolonged use of  linezolid (324), which is often required to achieve stable cure. The risk of peripheral neuropathy is still substantial (25% to nearly 50%) after reducing the daily dosage of linezolid to 300 mg (199, 206). Giving linezolid intermittently may help reduce linezolid toxicity and enable prolonged treatment to achieve stable cure (64).

The Food and Drug Administration, and the European Medicine Agency, have respectively approved bedaquiline (or Sirturo, a novel diarylquinoline) and delamanid (or Deltyba, a novel nitro-dihydro-imidazooxazole) for the treatment of adult pulmonary MDR-TB when an effective treatment regimen cannot otherwise be provided. Two phase II RCTs of MDR-TB showed that bedaquiline significantly increased sputum culture conversion rate at 8 weeks (93), 24 weeks and 120 weeks (92), and significantly increased cure rates at 120 weeks (92), with potentials for preventin acquired resistance to companion drugs (91). A phase II RCT and a cohort study of MDR-TB respectively showed that delamanid significantly increased two-month sputum culture conversion rates (142), and significantly reduced mortality when used for at least 6 months in comparison with 2 months or less.

PA-824 (a novel nitroimidazo-oxazine) and sutezolid (a linezolid analog) are two other novel drugs with potentials for treating MDR-TB that have been evaluated in Phase II RCTs of early bactericidal activities (89, 90, 364). PA-824 with moxifloxacin and pyrazinamide is considered potentially suitable for treating MDR-TB (90).

All patients with MDR-TB should be treated with directly observed therapy 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 (172). Peak and trough serum levels may be determined to optimize therapy since bioavailability and clearance of most antituberculosis medications is not predictable (Table 6).   

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% (16). 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 (107) demonstrated that a 4-month regimen containing isoniazid and rifampin was associated with a low relapse rate (1.2%). However, it must be noted that the level of drug resistance in the population was extremely low and in many circumstances the drug susceptibility test results are not available at the initiation of therapy. Thus, a standard 4-drug regimen should be initiated in tuberculosis suspects. If after 2 months all cultures are negative, the continuation phase can be shorted by 2 months and the patient treated for a total of 4 months (17).  

Underlying Medical Conditions  

Children and Adolescents

 Several controlled and observational studies have evaluated 6-month regimens in children (28, 174, 201, 294, 343, 351, 358). 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 (343,358). 

Children with disseminated or meningeal tuberculosis should be treated for 9-12 months because of inadequate data to support a 6-month regimen (17). The American Academy of Pediatrics recommends that children and adolescents with HIV-related tuberculosis should be treated for 9 months (14). 

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 (350) 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. Directly observed therapy should be used in all children with tuberculosis. In general, parents should not be relied on to supervise the directly observed therapy.  

Pregnancy and Breast-Feeding

Untreated tuberculosis represents a greater risk to the fetus than does treatment of tuberculosis (84, 177, 320). Thus, treatment of tuberculosis in 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 (357). Given the lack of data regarding the teratogenicity of pyrazinamide, it has not been recommended in pregnant women (17). However, pyrazinamide is recommended for routine use in pregnancy by the World Health Organization (375) and the International Union Against tuberculosis and Lung Disease (121). In addition, some jurisdictions in the United States have used pyrazinamide in pregnant cases without reported adverse effects (84). 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 (333) 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 conventional dosing should be used in the setting of renal insufficiency (3, 34, 119, 225, 274). Pyrazinamide is also metabolized hepatically but its metabolites may accumulate in patients with renal failure (117, 225). Ethambutol is approximately 80% cleared by the kidneys so it may accumulate in patients with renal insufficiency (333). 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 (225). 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 them. In addition, approximately 40% of the dose is removed via hemodialysis (231). 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 (226).  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 (226). The fluoroquinolones undergo varying degrees of renal clearance depending on the drug.  For example, levofloxacin undergoes greater renal clearance than ciprofloxacin or moxifloxacin (135). Persons taking cycloserine, ethambutol, or aminoglycosides (polypeptide) should have serum drug concentrations measured in order to avoid drug-related toxicities and ensure effective dosing (17).  

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

Advanced age, extensive TB disease, malnutrition, alcoholism, chronic viral hepatitis B and C infections, HIV infection  and organ transplant  have been associated with increased risk of drug-induced hepatotoxicity during treatment of TB (302, 385). Additive toxicity may also occur between anti-tuberculosis drugs and other drugs, e.g. immunosuppressive drugs, acetaminophen and anticonvulsants. Genetic associations have also been reported for polymorphisms in glutathione S-transferase, CYP2E1 and N-acetyltransferase 2 (slow acetylator phenotype) (33, 169). 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. Drug regimens with fewer potentially hepatotoxic agents might be considered for patients with underlying hepatic disease these patients, often with omission of pyrazinamide (302, 385).  The American Thoracic Society (ATS) recommended monitoring of patients at risk for hepatotoxicity during anti-tuberculosis treatment by liver function test.  However, such a risk-based approach could miss 33.3% of early hepatotoxicity and 77.8% of late hepatotoxicity occurring within and after two weeks of treatment respectively (309).  Further studies are therefore required to delineate the exact role of regular biochemical monitoring in the treatment of TB. Transient changes in bilirubin and transaminase levels are relatively common during anti-tuberculosis chemotherapy, and they probably represent minor liver injury, with the liver adapting with resolution of such injury in most people (369). Zimmerman initially noted that patients with concurrent marked elevations in serum alanine transaminase (ALT) and total bilirubin levels had at least a 10% chance of mortality from liver failure (391), and some modifications of this "Hy’s law"might also help to improve its predictive power (296). Treatment with hepatotoxic TB drugs should be interrupted when i) ALT exceeds three times upper limit of normal (ULN) in the presence of relevant symptoms (e.g. anorexia, nausea, vomiting, epigastric distension, right upper abdominal discomfort, malaise and weakness) or hyperbilirubinemia with total bilirubin exceeding two times ULN; or ii) ALT exceeds five times ULN irrespective of symptoms (302). Other causes of deranged liver function, such as viral hepatitis, should be excluded.  

The best approach to reintroducing TB treatment after recovery of liver function is still unclear. In a randomized control trial (21), the risk of recurrent hepatotoxicity due to simultaneous reintroduction of isoniazid, rifampicin and pyrazinamide (13.8%) was not significantly different from sequential reintroduction in full doses (10.2%) and gradually increased doses (8.6%). Apart from a possible type 2 error with the small sample size, a 13.8% risk of recurrent hepatotoxicity is by no means low, taking into account its highly unpredictable course.  If the patient’s hepatitis was severe, reintroducing one drug at a time may be the safer approach, rifampicin, with its lower hepatotoxicity risk, can be introduced first, with or without ethambutol (302, 385).  Isoniazid may be added if there is no increase in ALT after 3 to 7 days. Pyrazinamide may be withheld if previous hepatitis was severe, with duration of therapy extended to 9 months. If rifampicin and isoniazid cannot be reintroduced together, one of them may be substituted by a fluoroquinolone such as levofloxacin or moxifloxacin for a total duration of 1 year. If neither isoniazid nor rifampicin can be used, other secondline drugs, especially cycloserine, may be added to the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone, with treatment continued for a total of 18-24 months. 

No hepatoprotective agent has been convincingly shown to provide useful protection against hepatotoxicity during treatment. In a randomized trial, N-acetylcysteine reduced the rise of ALT and AST at 1 and 2 weeks after the start of treatment with the standard TB regimen (21). However, with the small sample size, short follow-up and unclear outcome definition, further studies are required to confirm the findings.

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 (59, 122, 191, 193, 277, 360). This study 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 (59, 122, 191, 193).  

A consistent finding in all the treatment studies is a high mortality rate among HIV-1 seropositive patients (261, 276, 277, 317). 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 (59, 122, 251, 277). Several investigators in sub-Saharan Africa have reported a higher mortality among HIV-1 infected patients who took non-rifampin containing regimens (263, 264, 276), highlighting the importance of rifampin-containing short-course regimens in the treatment of HIV-related tuberculosis.  

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 (360). Second, a recent report described 6 of 183 patients in a clinical trial who relapsed with rifamycin monoresistance (56). All patients had advanced HIV disease. Therefore, twice-weekly administration is not recommended in patients with advanced immunodeficiency (e.g., < 100 CD4 cells/µl) (56). 

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 nine months. Directly observed therapy should be used in all patients with HIV-related tuberculosis.  

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., rifampin>rifapentine>rifabutin) can induce the hepatic cytochrome P450 enzyme system resulting in an increase in the metabolism and decrease in the serum concentration of certain antiretroviral drugs (52). Rifabutin produces the least induction of the cytochrome P450 system and early study results suggest that rifabutin is just as effective as  rifampin in the treatment of tuberculosis (56, 145, 233, 303). A recent report described the successful use of  rifabutin and antiretroviral agents given concurrently (255) in the treatment of tuberculosis. All 25 patients responded to antituberculosis therapy and 20 of 25 patients achieved viral loads of < 500 copies/ml. When rifabutin is combined with antiretroviral agents, its dose and the dose of the antiretroviral drugs may require adjustment (44, 52).  

 The antiretroviral drugs belong to one of four main classes, nucleoside (NRTIs), nucleotide 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 (44, 52). Thus, these drugs may alter the serum concentration of drugs, such as rifabutin, that are metabolized by the P450 enzymesystem.   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 (264).  

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.  To balance between the competing risks related to delayed antiretroviral therapy (ART) and ART-related immune reconstitution inflammatory syndrome, early initiation of ART is indicated (1, 29, 252), preferably within 2 weeks after starting TB treatment for patients with a CD4 of <50 cells/μL, except in case of central nervous system involvement (349). 

However, another clinical trial in middle-income countries where ART, initiation of ART in HIV-infected patients with active TB at 4 weeks was not associated with survival advantage when compared to initiation of ART at 12 weeks (227).  In another international trial among HIV-positive TB patients with CD4 cell counts > 220 cells per μL in Africa, starting ART early after 2 weeks of TB treatment or delayed ART at the end of 6 months of TB did not differ significantly in the composite primary endpoint of failure, recurrence, and/or death within 12 months (239).

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) or AIDSinfo website (http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/27/hiv-tb).  

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 (254, 372). Narita and colleagues (254) 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 (372). In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, incidence of immune reconstitution inflammatory syndrome (IRIS) was 19.5 , 7.5  and 8.1 per 100 person-years respectively among patients with ART initiated within 4 weeks of starting TB treatment , within 4 weeks of completion of the intensive phase and within 4 weeks after TB therapy completion, respectively (252).  More severe IRIS cases occurred in with ART initiated within 4 weeks of starting TB treatment with higher hospitalization rates (42% vs. 14%) and longer time to resolution (70.5 vs. 29.0 days) than patients in the other 2 groups.

Mild paradoxical reactions may be managed with nonsteroidal anti-inflammatory 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. 

Alternative Therapy 

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 cannot 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 cannot be used, isoniazid and ethambutol should be given for a minimum of 18 months with pyrazinamide during at least the initial 2 months (32). For patients with extensive disease, another agent such as a fluoroquinolone or an aminoglycoside may be useful. 

 If isoniazid cannot be used, rifampin, ethambutol and pyrazinamide should be given for a minimum of 6 months (163). Another option is to give rifampin and ethambutol for a minimum of 12 months with pyrazinamide included at least during the first 2 months (390).  

ADJUNCTIVE THERAPY 

Surgery 

Resectional surgery or drainage of a tuberculous empyema (Eloesser flap) may be necessary in some patients with multi-drug resistant disease (172, 173, 284). 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 (172).  

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 (196, 365). 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 (365). Thalidomide also inhibits the production of TNF-alpha. Klausner and associates (196) 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 (196). 

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 (76) 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 (332). 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 (30).

ENDPOINTS FOR MONITORING THERAPY 

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 directly observed therapy, 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 (17). 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 (17). 

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 (17). 

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, although a meta-analysis of RCTs involving rapid and slow acetylators suggested that rapid acetylators were more likely than slow acetylators to have microbiological failure and adverse drug reactions (273). There are not sufficient data to formulate an evidenced-based approach to measuring and interpreting serum drug concentrations in this setting (17). 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 (17, 275).  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 (17). Over 90% of patients who are treated with standard short-course therapy will be culture negative after two months of therapy (17). In patients who remain culture positive beyond this juncture, repeat drug susceptibility tests should be sent and the patient should be placed on directly observed therapy. If the patient is already on directly observed therapy, 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.  

VACCINES

Bacille Calmette Guèrin (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% (53, 133, 134). 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 (71). 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 (133, 134).  In more recent studies, BCG appears to protect against infection by M. tuberculosis as measured by current diagnostic tools for latent TB infection (298).  

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 (53, 267). 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 (53).

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 (36, 148, 329). 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 (134). 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 (53). 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 (392). However, in some areas of the world the vaccine is targeted to high-risk groups, administered in adolescence. The practice of multiple vaccinations  throughout childhood and adolescence has largely been stopped (392).  

Adverse Effects 

Vaccination with BCG usually results in a local inflammatory reaction that can persist for months in some cases (53, 134). 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 (53, 134). 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  (53). 

Vaccine development often offers the greatest potential for effective implementation on a population scale to expedite control or even elimination of many infectious diseases. Historically, vaccines were often developed by the "identify, kill / attenuate, administer" approach to mimic the sequence of events following natural infection or cross-infection. Unfortunately, TB is a notable example that there is no long-lasting community after recovery and relapse or reinfection disease does occur at a considerable frequency (361). During the long period of successful co-evolution, the tubercle bacillus has developed ways to evade or manipulate our host immune responses and acquired an ability to enter into a prolonged "latent" or "dormant" state (293). Improved understanding of the complex pathophysiology will be required to expedite the identification of suitable biomarkers of protective immunity, and hopefully, the development of a vaccine that outperforms the natural pathogen in stimulating protective host immune responses (190). As the pulmonary TB in adults is the key transmission link for this airborne infection, a vaccine targeted to adolescents/adults could also have a greater impact than one targeted at infants. Even if only short duration, low efficacy vaccines are likely to be feasible (197).  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 (134, 190), and a number of them are in phase I or II clinical trials (149, 325, 340).  

PREVENTION

Treatment of Latent tuberculosis Infection  

General

Screening and treatment of latent TB infection is generally targeted at high risk groups. In a recent clinical trial, mass screening and treatment had no significant effect on tuberculosis control in South African gold mines, despite the successful use of isoniazid in preventing tuberculosis during treatment (67).  Isoniazid is the most widely used drug for the treatment of latent tuberculosis infection (LTBI). Randomized controlled trials have established protective efficacy of isoniazid therapy for 6 to 12 months among non-HIV-infected (319) and HIV-infected subjects (8) with latent infection by M. tuberculosis.  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 (256, 320). However, field effectiveness has been compromised by hepatotoxicity as well as suboptimal acceptance and adherence (213).  Six months of isoniazid therapy also confers a high degree of protection and is more cost-effective (322). 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 (15).

A two-month short-course regimen containing rifampin and pyrazinamide that was initially recommended for the treatment of LTBI (15) is no longer recommended for most patients with LTBI because of high rates of hepatotoxicity (55, 57). 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 (147, 151). However, reports of severe liver injury associated with rifampin and pyrazinamide has resulted in new modified recommendations for the use of rifampin and pyrazinamide (55, 57). 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 (57). A total of 11 (23%) of the cases died, including two patients with HIV infection.  Isoniazid plus rifampicin for 3 months has proven efficacy in the treatment of LTBI, but adverse effects may be more frequent than isoniazid or rifampicin monotherapy in field application  (213). Rifampicin monotherapy for 3 to 4 months is well tolerated, but efficacy data are currently limited to a single trial among silicosis patients, and concerns remain over possible selection of rifampicin-resistant mutants, especially among HIV-infected individuals. The efficacy of weekly rifapentine plus isoniazid for 12 weeks has recently been established in two clinical trials, one among predominantly non-HIV-infected subjects (328) and the other among HIV-infected individuals (230).

Recommended Regimens

Several regimens are recommended for the treatment of LTBI in high-risk individuals who have a positive tuberculin skin test (Table 7) (15).  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 (57). 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 (15). In a randomized controlled trial, 3 months of rifampin was more effective than 6 months of isoniazid (165). Because the patients receiving rifampin had a relatively high rate of tuberculosis, 4 months of rifampin is recommended instead of three.

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, the role of preventive treatment for MDR-TB contacts remains uncertain with the currently highly limited treatment, and variable risks of developing either drug-susceptible TB or MDR-TB (213).  The CDC published recommendations for the management of persons exposed to MDR-TB cases (51). 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.  A computerized Markov model of total treatment cost suggested that preventive treatment with moxifloxacin/ethambutol would be preferable to other combinations of pyrazinamide, ethambutol, ethionamide, and PA-824 (158). 

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 (15). 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 (107) and it is more cost-effective than 9 months of isoniazid (179).  

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 (269) and Uganda (373) 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 (147, 151). However, the revised recommendations (57) 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 (15). Therapy should be supplemented with pyridoxine (10-50 mg a day) to help prevent peripheral neuropathy. Routine treatment of anergic HIV infected patients is not recommended (15, 146).  However, in a recent study among people infected with HIV-1 concurrently receiving antiretroviral therapy in South Africa, the effect of isoniazid preventive therapy was NOT restricted to patients who were positive on tuberculin skin test or interferon gamma release assay, suggesting a need for isoniazid preventive therapy in all patients receiving antiretroviral therapy in moderate or high incidence areas (289).

 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 (15). In addition, since exogenous reinfection has been demonstrated in AIDS patients (47, 144, 318), treatment of LTBI should be given even if the person has been treated previously.

In a meta-analysis, antiretroviral therapy is strongly associated with a reduction in TB incidence across all CD4 count strata (336).  The role of prolonged isoniazid therapy among HIV-infected individuals remains controversial as the results are conflicting in two published trials (236, 301). There is also no clear evidence to support the use of chemoprophylaxis for previously fully treated TB patients subsequently put on immunosuppressive therapy.  Primary isoniazid prophylaxis has not been found effective among HIV-exposed children (224).  

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 (15). Although isoniazid is secreted in breast milk, the concentration is low and no toxicity occurs in the infant (333). 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.  

ENDPOINTS FOR MONITORING TREATMENT FOR LTBI 

There is currently no effective way for monitoring the efficacy of treatment for LTBI other than prolonged follow-up for subsequent development of disease. IFN-γ ELISPOT has not been found to be a useful biomarker of treatment efficacy in LTBI (4).  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 (15). 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 (200). 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 (321). A recent publication from Seattle reported a lower rate of isoniazid-induced hepatitis, approximately 10-fold lower than that reported by Kopanoff (200). The weekly rifapentine plus isoniazid regimen for 12 doses caused less hepatotoxicity as compared to 9 months of daily isoniazid (328).

Most patients receiving isoniazid therapy require minimal monitoring that consists of monthly symptom review (15). 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 with underlying chronic or acute liver disease, who 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 (55, 57). 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 (57). 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 (57).

 

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 (166). Epidemiologic studies have demonstrated that contacts to cases that 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 (17). 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 (24) California State Guidelines require that such individuals receive at least 4 days of antituberculosis therapy before being transferred to a high-risk setting (46).  

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Figure 1.  Monitoring Patients Receiving Isoniazid

Table 1.   Dosages, Pharmacokinetics and Minimal Inhibitory Concentrations of Antituberculosis Medications

Drug	Usual Adult Daily Dosage*	Peak Serum Concentration (µg/ml)	Usual MIC (range)†(µg/ml)
First-line oral drugs:
Isoniazid	300 mg	3 - 5	0.01 - 0.025
Rifampin	600 mg	8 - 29	0.06 - 0.25
Rifabutin	300 mg	0.3-0.9	0.125-1.0
Pyrazinamide	30 mg/kg	20 - 60	6.2 - 50
Ethambutol	15 - 25 mg/kg	3 - 5	0.5 - 2.0
Injectable drugs:
Streptomycin	15 mg/kg	35 - 45	0.25 - 2.0
Amikacin	15 mg/kg	35 - 45	0.5 - 1.0
Kanamycin	15 mg/kg	35 - 45	1.5 - 3.0
Capreomycin	15 mg/kg	35 - 45	1.25 - 2.5
Second-line oral drugs:
Ofloxacin**	400 mg b.i.d.	4-6	0.25 - 2.0
Levofloxacin**	500 mg qd	3-5	0.12-1.0
Moxifloxacin**	400 mg qd	3-5	0.031-0.12
Gatifloxacin**	400 mg qd	3-5	0.007-0.12
Ethionamide	250 mg b.i.d. or t.i.d.	1 - 5	0.3 - 1.2
Aminosalicylic acid	3 g q.i.d.	40 - 70	Not known
Cycloserine	250 mg b.i.d. or t.i.d.	20 - 35	Not known

* Q.D. denotes daily, b.i.d. denotes twice a day, t.i.d. three times a day, and q.i.d. four times a day.
** Expect a 1 ug/ml increase in peak serum concentration for every 100 mg/dose
+MIC denotes minimal inhibitory concentration for drug-susceptible organisms.
Sources: Adapted from reference 274 (with permission) and personal communication with Charles Peloquin, Pharm.D

Table 2. First Line Drugs [Download PDF]

Drug	Dose in mg/kg (Maximum Dose)						Adverse Reactions	Comments
	Daily		2 Times/Week*		3 Times/Week*
Isoniazid	Children 10-20 (300 mg)	Adults 5 (300 mg)	Children 20-40 (900 mg)	Adults 15 (900 mg)	Children 20-40 (900 mg)	Adults 15 (900 mg)	Hepatic enzyme elevation Hepatitis Peripheral neuropathy Central nervous system (mild) Drug interactions	Hepatitis risk increases with age and alcohol consumption Pyridoxine can prevent peripheral neuropathy
Rifampin	Children 10-20 (600 mg)	Adults 10 (600 mg)	Children 10-20 (600 mg)	Adults 10 (600 mg)	Children 10-20 (600 mg)	Adults 10 (600 mg)	GI upset Drug interactions Hepatitis Bleeding problems Flu-like symptoms Rash	Significant interactions with -methadone -birth control pills -many other drugs Colors body fluids orange May permanently discolor soft contact lenses
Rifabutin	Children –	Adults 5 (300 mg)	Children –	Adults 5 (300 mg)	Children –	Adults 5 (300 mg)	Rash Hepatitis Fever Thrombocytopenia With increased levels:   Arthralgias, uveitis, leukopenia	Significant interactions with -methadone -birth control pills -many other drugs Colors body fluids orange May permanently discolor soft contact lenses
Rifapentine**	Children –	Adults –	Children –	Adults –	Children –	Adults –	Rash Hepatitis Fever Thrombocytopenia	Significant interactions with -methadone -birth control pills -many other drugs Colors body fluids orange May permanently discolor soft contact lenses
Pyrazinamide	Children 15-30 (2 g)	Adults 15-30 (2 g)	Children 50-70 (4 g)	Adults 50-70 (4 g)	Children 50-70 (3 g)	Adults 50-70 (3 g)	Hepatitis Rash GI upset Joint aches Hyperuricemia Gout (rare)	Treat hyperuricemia only if patient has symptoms
Ethambutol	Children 15-25	Adults 15-25	Children 50	Adults 50	Children 25-30	Adults 25-30	Optic neuritis	Not recommended for children too young to be monitored for changes in vision unless tuberculosis is drug resistant
Streptomycin	Children 20 (1 g)	Adults 15 (1 g)	Children 25-30 (1.5 g)	Adults 25-30 (1.5 g)	Children 25-30 (1.5 g)	Adults 25-30 (1.5 g)	Ototoxicity Renal toxicity	Avoid or reduce dose in adults > 60 years old

Notes:  Children ≤ 12 years old. Adjust weight-based dosages as weight changes.
*All regimens administered 2 or 3 times a week should be used with directly observed therapy
**Rifapentine is dosed once weekly at 10 mg/kg (max 900 mg daily) during the continuation phase, only.
Source. Adapted from reference #17

Table 3. Second Line Drugs [Download PDF]

Drug	Daily Dose (Max. Dose)	Adverse Reactions	Monitoring	Comments
Capreomycin	15 mg/kg  (1 g)	Toxicity-auditory -vestibular -renal	Assess vestibular and hearing function Measure renal function and serum drug levels	After bacteriologic conversion, dosage may be reduced to 2-3 times per week
Kanamycin	15 mg/kg  (1 g)	Toxicity-auditory -vestibular -renal	Assess vestibular and hearing function Measure renal function and serum drug levels	After bacteriologic conversion, dosage may be reduced to 2-3 times per week
Amikacin	15 mg/kg (1 g)	Renal toxicity          Chemical imbalance Hearing loss             Dizziness Vestibular dysfunction	Assess hearing function Measure renal function and serum drug levels	Not approved by FDA for TB treatment After bacteriologic conversion, dosage may be reduced to 2-3 times per week
Ethionamide	15-20 mg/kg  (1 g)	GI upset                  Metallic taste Hepatotoxicity           Bloating Hypersensitivity	Measure hepatic enzymes	Start with low dosage and increase as tolerated May cause hypothyroid condition, especially if used with PAS
Para-aminosalicylic acid	150 mg/kg (12 g)	GI upset Hypersensitivity Hepatotoxicity Sodium load	Measure hepatic enzymes Assess volume status	Start with low dosage and increase as tolerated Monitor cardiac patients for sodium load
Cycloserine	15-20 mg/kg (1 g)	Psychosis                 Headaches Convulsions             Rash Depression                Drug interactions	Assess mental status Measure serum drug levels	Start with low dosage and increase as tolerated Pyridoxine may decrease CNS effects
Ofloxacin	400-800 mg/day	GI upset                  Drug interactions Dizziness                 Headaches Hypersensitivity        Restlessness	Drug interactions	Not approved by FDA for TB treatment Should not be used in children Avoid: antacids, zinc, iron, sucralfate
Levofloxacin	500-750 mg/day	GI upset                  Drug interactions Dizziness                  Headaches Hypersensitivity        Restlessness	Drug interactions	Not approved by FDA for TB treatment Should not be used in children Avoid: antacids, iron, zinc, sucralfate
Moxifloxacin	400 mg/day	GI upset                  Drug interactions Dizziness                Headaches Hypersensitivity        Restlessness	Drug interactions	Not approved by FDA for TB treatment Should not be used in children Avoid: antacids, iron, zinc, sucralfate
Gatifloxacin	400 mg/day	GI upset                  Drug interactions Dizziness                 Headaches Hypersensitivity        Restlessness	Drug interactions	Not approved by FDA for TB treatment Should not be used in children Avoid: antacids, iron, zinc, sucralfate

Notes: Doses for children same as for adults. Use these drugs only in consultation with a clinician experienced in the management of
drug-resistant TB.
Adjust weight-based dosages as weight changes.  Source: Adapted from reference #17

Table  4.  Drug Regimen For Culture-positive Pulmonary Tuberculosis [Download PDF]

INITIAL PHASE			CONTINUATION PHASE
Regimen	Drugs	Interval and Doses‡	Regimen	Drugs	Interval and Doses‡ #
1	INH RIF PZA EMB	Seven days per week for 56 doses (8 weeks)	1A 1B	INH /RIF INH/RIF	Seven days per week for 126 doses (18 weeks) Twice-weekly for 36 doses (18 weeks)
2	INH RIF PZA EMB	Seven days per week for 14 doses (2 weeks) thentwice-weekly for 12 doses (6 weeks)	2	INH/RIF	Twice-weekly for 36 doses (18 weeks)
3	INH RIF PZA EMB	Thrice-weekly for 24 doses (8 weeks)	3	INH/RIF/ PZA/EMB*	Thrice-weekly for 54 doses (18 weeks)
4+	INH RIF EMB	Seven days per week for 56 doses (8 weeks)	4 A 4 B	INH/RIF INH/RIF	Seven days per week for 196 doses (28 weeks) Twice-weekly for 56 doses (28 weeks)

INH = isoniazid, RIF = rifampin, RPT = rifapentine, PZA = pyrazinamide, EMB = ethambutol
‡When directly observed therapy is used drugs may be given 5 days per week and the necessary number of doses adjusted accordingly.
#Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month continuation phase.
* Options 1 C and 2B should only be used in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial the chest radiograph (see text).
Source:  Adapted from reference 17.
*Same experts believe that INH and RIF can be confirmed without PZA and EMB in the continuation phase.
+This regimen should be used only in special circumstances (see text)

Table 5.Selected Treatment Regimens for Drug-Resistant Tuberculosis. [Download PDF]

Resistance to:	Treatment Regimen	Duration of Therapy	Comments
Isoniazida	Rifampin Ethambutol Pyrazinamide	6-9 months	Pyrazinamide for entire duration
Isoniazida	Rifampin Ethambutol	12 months	Consider addition of pyrazinamide
Rifampina	Isoniazid Ethambutol	18 months	Consider addition of pyrazinamide
Isoniazid and ethambutola	Rifampin Pyrazinamide Fluoroquinolone Injectableb	9 -12 months
Isoniazid and rifampina	Ethambutol Pyrazinamide Fluoroquinolone Injectableb	18 months after culture conversion	Consider surgery
Isoniazid, rifampin, ethambutola	Pyrazinamide Fluoroquinolone Injectableb Plus 2 othersc	24 months after culture conversion	Consider surgery
Isoniazid rifampin, pyrazinamide†	Ethambutol Fluoroquinolone Injectableb Plus 2 othersc	24 months after culture conversion	Consider surgery
Isoniazid, rifampin, ethambutol, pyrazinamide†	Fluoroquinolone Injectableb Plus 3 othersc	24 months after culture conversion	Surgery if possible

Adapted from Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993;329:784-791, with permission (172).
^a ± streptomycin resistance
^b streptomycin, amikacin, kanamycin, or capreomycin.  Injectable should be continued for at least 6 months, if possible.
^c ethionamide, cylcoserine, or para-aminosalicylic acid.  In some cases, rifabutin, amoxacillin/cavulanic acid, imipenem, clofazamine, thiacetazone.

Table 6:  Dosing Recommendations in Patients Receiving Chronic Hemodialysis [Download PDF]

Drug	Recommended dose*
Isoniazid	5-10mg/kg/day daily (max 300 mg/day) or 900 mg three times/week
Rifampin	600 mg/day or three times/week (max 600 mg/day)
Pyrazinamide	25-35 mg/kg/day three times/week
Ethambutol**	15-25 mg/kg/day three times/week
Levofloxacin	750-1000 mg/day three times/week
Cycloserine**	250-500 mg three times/week
Ethionamide	250-500 mg qd
PAS	4 gm b.i.d
Clofazimine	100-200 mg qd
Streptomycin**	12-15 mg/kg/dose two-three times/week
Capreomycin**	12-15 mg/kg/dose two-three times/week
Kanamycin**	12-15 mg/kg/dose two-three times/week
Amikacin**	12-15 mg/kg/dose two-three times/week

*The medications may be given after dialysis
** Monitor serum drug concentrations to avoid drug toxicity.

 

Table 7. Criteria for Positive Tuberculin Skin Test, By Risk Group [Download PDF]

Reaction ≥ 5 mm	Reaction ≥ 10 mm	Reaction ≥ 15 mm
HIV infection	Immigration within the past 5 years from high prevalence country	Persons with no risk factors
Recent contact to infectious case	Injection drug users
Fibrotic lesions on chest radiograph consistent with prior TB	Residents and employeesof high-risk settingsb
Patients with organ transplants or other immunosuppressed patientsc	Mycobacteriology laboratory personnel
	Persons with high-risk clinical conditionsd
	Children younger than 4 yr of age or infants, children, and adolescents exposed to adults at high-risk

^a For persons who are otherwise at low risk and are tested at the start of employment, a reaction of ≥15 mm is considered positive.
^bPrisons and jails, nursing homes and other long-term facilities for the elderly, hospitals and other health-care facilities, residental facilities for patients with acquiried immunodeficiency syndrome (AIDS), and homeless shelters.
^c Receiving the equivalent of ≥ 15 mg/d of prednisone for one month or more. Risk of TB in patients treated with corticosteroids increases with higher dose and longer duration.
^dSilicosis, diabetes mellitus, chronic renal failure, some hematologic disorders (e.g, leukemias and lymphomas), other specific malignancies (e.g., carcinomas of the head and neck), weight loss of ≥ 10 % of ideal body weight, gastrectomy, and jejunoileal bypass
Adapted from reference 15 with permission

Table 8.  Recommended Treatment Regimens for LTBI [Download PDF]

Drug	Dose (max. dose)	Interval and Duration	Comments
INH	5 mg/kg/day (300 mg)	Daily for 9 m	Preferred regimen
INH	15 mg/kg/day (900 mg)	Twice-weekly* for 9 m	Directly observed therapy must be used
INH	5 mg/kg/day (300 mg)	Daily for 6 m	Not for HIV + patients
INH	15 mg/kg/day (900 mg)	Twice-weekly* for 6 m	Not for HIV + patients. Directly observed therapy must be used
RIF	10 mg/kg/day   (600 mg)	Daily for 4 mo	For persons who do not tolerate isoniazid or pyrazinamide or contacts to isoniazid-resistant cases
RIF + PZA	10 mg/kg/day  (600 mg)  +  15-20 mg/kg/day	Daily for 2 m	Should generally not be used (see text)
RIF + PZA	10 mg/kg/day (600 mg) + 40 mg/kg/day	Twice-weekly* for 3 m	Should generally not be used (see text). Directly observed therapy must be used.
Rifapentine     + INH	10.0–14.0 kg: 300 mg 14.1–25.0 kg: 450 mg 25.1–32.0 kg 600 mg 32.1–49.9 kg 750 mg ≥50.0 kg: 900 mg 15 mg/kg/day (900 mg)	Weekly* for 12 doses	#Not recommended for: children aged <2 years, HIV-infected patients receiving antiretroviral treatment, pregnant women or women expecting to become pregnant during treatment and patients who have LTBI with presumed INH or RIF resistance.

* Under Directly observed therapy 
# Watch out for update in CDC website; May change with further data
INH = isoniazid, RIF = rifampin, PZA = pyrazinamide
Source: Adapted from reference 15 and 111

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