TUBERCULOSIS
Etiologic agent
Mycobacteria belong to the family Mycobacteriaceae and the
order actinomycetales. M. tuberculosis is a rod-shaped, non-spore forming, thin
aerobic bacterium measuring 0.5um by 3um. Mycobateria are often neutral on gram
staining. However, once stained, the bacilli cannot be decolorized by acid
alcohol; this characteristic justifies their classification as acid fast
bacilli. Acid fastness is due mainly to the organisms’ high content of mycolic acids,
long chain cross-linked fatty acids and other cell wall lipids. In the
mycobacterial cell wall, lipids are linked to underlying arabinogalactan and peptidoglycan. This structure confers very low
permeability of the cell wall, thus reducing the effectiveness of most
antibiotics. Another molecule in the mycobacterial cell wall, lipoarabinimannan is involved in the
pathogen-host interactionand facilitates the survival of M. tuberculosis within
macrophages.
From exposure to infection
M. tuberculosis is most commonly transmitted from a person
with infectious pulmonary tuberculosis to others by droplet nuclei, which are
aerosolized by coughing, sneezing or speaking. The tiny droplets dry rapidly
and may remain suspended in the air for several hours and may reach the
terminal air passages when inhaled.
The probability of contact with a person who has an
infectious form of tuberculosis, the intimacy and duration of that contact, the
degree of infectiousness of the case and the shared environment in which the contact
takes place are all important determinants of the likelihood of transmission.
Severeal studies on close contact situations have clearly demonstrated that
tuberculosis patients whose sputum contains AFB visibly by microscopy are the
most likely to transmit the infection. The most infectious patients have
cavitary pulmonary disease or much less common, laryngeal tuberculosis and
produce sputum containing as many as 10^5-10^7 AFB/mL. Patients with sputum
smear-negative/culture positive TB are less infectious and those with
culture-negative pulmonary disease and extrapulmonary TB are essentially
non-infectious.
From infection to disease
The risk of developing disease after being infected depends
largely on endogenous factors, such as the individual’s innate immunologic and
nonimmunologic defenses and level of function of cell-mediated immunity (CMI). Clinical
illnesses directly following infection is classified as primary tuberculosis
and is common among children up to 4 years of age and among immunocompromised
persons. When infection is acquired later in life, the chance is greater that
the mature immune system will contain it at least temporarily. The majority of
infected individuals take time about 1-2 years before they ultimately develop
the disease.
Among the infected persons, the incidence of TB is highest
during late adolescence and early adulthood; with unclear reasons. The
incidence among women peaks at 25-34 years old.
A variety of disease and conditions favor the development of
active TB. The most potent factor for TB among infected person is clearly HIV
co-infection, which suppresses cellular immunity.
Pathogenesis &
Immunity
Infection & Macrophage Invasion
The interaction of M. TB with the human host begins when
droplet nuclei containing microorganisms from infectious patients are inhaled.
The majority of inhaled bacilli trapped in the upper airways and expelled by
ciliated mucosal cells, and a fraction (<10%) reach the alveoli. Alveolar
macrophages that have not yet been activated phagocytize the bacilli. Invasion of macrophages by mycobacteria
results largely from binding of the bacterial cell wall with a variety of
macrophage cell-surface molecules, including complement receptors, mannose
receptors, immunoglobulin receptor and type-A scavenger receptors. Phagocytosis
is enhanced by complement activation leading to opsonization of bacilli with C3
activation products, such as C3b. After the phagosome forms, the survival of
M.TB within it seems to depend on reduced acidification due to lack of
accumulation of vesicular proton-adenosine triphosphatase. A complex series of
events is probably generated by the bacterial cell-wall glycolipid
lipoarabinomannan (LAM). LAM inhibits the intracellular increase of Ca2+. Thus
the Ca2+/calmodulin pathway is impaired, and the bacilli may survive within the
phagosome.
*** (impair in
Ca2+/calmodulin pathway disrupt the maturation process of phagosome)
Host response
In the initial stage of host-bacterium interaction, either
fusion between phagosome and lysosomes occurs, preventing bacillary survival,
or the bacilli begin to multiply, ultimately killing the macrophage. A variety
of chemoattractants that are released after cell lysis recruit additional
immature monocyte-derived macrophages, including dendritic cells, which migrate
to the draining lymph nodes and present mycobacterial antigens to
T-lymphocytes. At this point, the development of CMI and humoral immunity
begins.
About 2-4wks after infection, two hosts responses o M.TB
develop; a macrophage-activating CMI response and a tissue-damaging response.
The macrophage activating response is
a T cell mediated phenomenon resulting in the activation of macrophages that
are capable of killing and digesting tubercle bacilli. The tissue-damaging response is the result of a
delayed-type hypersensitivity (DTH) reaction to various bacillary antigens; it
destroys unactivated macrophages that contain multiply bacilli but also causes
caseous necrosis of the involved tissues. Although both of these responses can inhibit
mycobacterial growth, it is the balance between the two that determines the
form of TB that will develop subsequently.
Granuloma formation
With the development of specific immunity and the
accumulation of large numbers of activated macrophages at the site of the
primary lesion, granulomatous lesions are formed. This lesion consists of
accumulations of lymphocytes and activated macrophages that evolve towards
epithelioid and giant cell morphologies. Initially, the tissue damaging
response can limit mycobacterial growth within macrophages. As stated, this
response mediated by various bacterial products, produces early solid necrosis
in the center of the tubercle. Although the M.TB can survive, its growth is
inhibited by low oxygen tension and low pH. At this point, some lesions may
heal by fibrosis, with subsequent calcification, whereas inflammation and
necrosis occur in other lesions.
The
macrophage-activating response
CMI is critical at this early stage. In majority infected
individuals, local macrophages are activated when bacillary antigens (processed by macrophages) stimulate T
lymphocytes to release a variety of lymphokines. These activated macrophages
aggregates around the lesion’s center and effectively neutralize tubercle
bacilli without causing further tissue destruction. In the central part of the
lesion, the necrotic material resembles soft cheese (caseous necrosis) a
phenomenon that may also observed in other conditions such as neoplasms. Even
when healing takes place, viable bacilli may remain dormant within macrophages
or in the necrotic material for many years. These healed lesions in the lung
parenchyma and hilar lymph nodes may later undergo calcification.
The Delayed-Type Hypersensitive Reaction
In a minority of cases, the macrophage-activating response
is weak, and mycobacterial growth can be inhibited only by intensified DTH
reactions, which lead to lung tissue destruction. The lesion tends to enlarge further, and the
surrounding tissue is progressively damaged. At the center of lesion, the
caseous material liquefies. Bronchial walls as well as blood vessels are
invaded and destroyed, and cavities are formed. The liquefied caseous material
containing large numbers of bacilli is drained through bronchi. Within the
cavity, tubercle bacilli multiply, spill into airways and are discharged into
environment through expiratory maneuvers such as talking and coughing.
In the early stages of infection, bacilli are usually
transported by macrophages to regional lymph nodes, from which they gain access
to the bloodstream and disseminate widely throughout the body. The resulting
lesions may undergo the same evolution as those in the lungs, although most
tend to heal. In young children with poor natural immunity, hematogenous
dissemination may result in fatal military TB or tuberculous meningitis.
Role of Macrophages and Monocytes
While CMI confers partial protection against M.TB, humoral
immunity plays a less well-defined role in protection. In the case of CMI, 2
types of cells are essential; macrophages (which directly phagocytize tubercle
bacilli) and –cells (which induce protection through the production of
cytokines, especially IFN-gamma.
After infection, alveolar macrophages secrete various
cytokines responsible for a number of events as well as systemic effects.
Monocytes & macrophages attracted to the site are key components of immune
response. Their primary mechanism is probably related to production of nitric
oxide, which has antimycobacterial activity and increases synthesis of
cytokines such as TNF-alpha and IL-1, which in turn regulate release of
reactive nitrogen intermediates. In addition, macrophages can undergo
apoptosis, a defensive mechanism to prevent release of cytokines and bacilli
via their sequestration in the apoptotic cell.
CLINICAL
MANIFESTATIONS
(1) Pulmonary tuberculosis
Pulmonary tuberculosis can be categorized as
primary or post-primary (secondary)
Primary disease
Primary pulmonary TB occurs soon after the initial infection
with tubercle bacilli. This form of disease often seen in children who live in
areas with high TB transmission. The middle and lower lung zones are the areas
that most commonly involved in primary TB as the air is distributed here. The
lesion forming after infection is usually peripheral and accompanied in more
than half of cases by hilar and paratracheal lymphadenopathy, which may not
detectable on CXR. In majority cases, the lesions heals spontaneously and may
later be evident as a small calcified nodule (Ghon lesion)
In children and in persons with impaired immunity, the
primary pulmonary TB may progress rapidly to clinical illness. The initial
lesion increased in size and can evolve indifferent ways. Pleural effusion
results from the penetration of bacilli into pleural space from an adjacent
subpleural focus. In severe cases, the primary site rapidly enlarges, its
central portion undergoes necrosis and cavitation develops. TB in young
children is almost invariably accompanied by hilar or mediastinal
lymphadenopathy due to spread of bacilli from the lung parenchyma through
lymphatic vessels. Enlarged lymph nodes may compress bronchi, causing obstruction
and subsequent segmental or lobar collapse. Partial obstruction may cause
obstructive emphysema, and bronchiectasis may also develop. Hematogenous
dissemination which is common and often asymptomatic may result in the most
severe manifestations of primary M.TB infection. Bacilli reach the bloodstream from
the pulmonary lesion or the lymph nodes and disseminate into various organs,
where they may produce granulomatous lesions. Immunocompromised persons may
develop military TB and /or tuberculous meningitis.
Post-primary disease
Also called adult-type, reactivation or secondary
tuberculosis, post-primary disease results from endogenous reactivation of
latent infection and is usually localized to the apical and posterior segments
of upper lobes, where the substantially higher mean oxygen tension favors
mycobacterial growth. In addition, the superior segments of the lower lobes
frequently involved. The extent of lung parenchymal involvement varies greatly,
from small infiltrates to extensive cavitary disease. With cavity formation, liquefied
necrotic contents are ultimately discharged into the airways, resulting in
satellite lesions within the lungs that may in turn undergo cavitation. Massive
involvement of pulmonary segments or lobes with coalescence of lesions produces
tuberculous pneumonia.
Early in the course of disease, symptoms and signs are often
nonspecific and insidious, consisting mainly of fever and night sweats, weight
loss, anorexia, general malaise and weakness. However, in majority cases, cough
eventually develops – often initially nonproductive and subsequently
accompanied by the production of purulent sputum, sometimes with blood
streaking. Massive hemoptysis may ensue as a consequence of the erosion of a
blood vessel in the wall of cavity. Hemoptysis, however may also resukt from
rupture of a dilated vessel in a cavity (Rasmussen’s aneurysm) or from
aspergilloma formation in an old cavity. Pleuritic chest pain sometimes
develops in patients with subpleural parenchymal lesions.
Physical findings are of limited use in pulmonary
tuberculosis. Many patients have no abnormalities detectable by chest
examination, whereas others have detectable rales in the involved areas during
inspiration, especially after coughing. Occasionally, shonchi due to partial
bronchial obstruction and classic amphoric breath sounds in areas with large
cavities may be heard. Systemic features include fever in up to 80% of cases
and wasting. Absence of fever, however does not exclude TB. The most common
hematologic findings are mild anemia and leukocytosis. Hyponatremia due to
SIADH has also been reported.
(2) Extrapulmonary TB
The extrapulmonary sites most
commonly involved in TB are the lymph nodes, pleura, genitourinary tract, bones
and joints, meninges, peritoneum and pericardium.
Lymph node TB (Tuberculous Lymphadenitis)
The most common presentation of extrapulmonary TB is
particularly frequent among HIV-infected patients. Once caused mainly by M.
bovis, tuberculous lymphadenitis is due to M.TB. the disease presents as
painless swelling of the lymph nodes, most commonly at posterior cervical and
supraclavicular sites. Lymph nodes usually discrete and nontender in early
disease but may be inflamed and have a fistulous ract draining caseous
material. Associated pulmonary disease is seen in >40% of cases. Systemic
symptoms are usually limited to HIV-infected patients. The diagnosis is
established only by fine-needle aspiration or surgical biopsy.
Pleural TB
This is common in primary TB and may result from either
contiguous spread of parenchymal inflammation or, as in many cases of pleurisy
accompanying postprimary disease, actual penetration by tubercle bacilli into
pleural space. The effusion may be small, remain unnoticed, and resolve
sponatenously or may be sufficiently large to cause symptoms such as fever,
peluritic chest pain, and dyspnea.
Physical findings are those of pleural effusion (dullness to percussion & absence of
breath sound). A CXR reveals the effusion and, in up to 1/3 of cases, also
shows a parenchymal lesion. Thoracocentesis is acquired to ascertain the nature
of effusion and to differentiate it from manifestations of other etiologies.
The fluid is straw colored and at times hemorrhagic. Neutrophils may
predominate in the early stage while mononuclear cells are the typical finding
later. Mesothelial cells are generally rare or absent. Needle biopsy of plerua
often required for diagnosis and reveals granulomas and/or yields a positive
culture in up to 80% of cases. This form of pleural TB responds well to
chemotherapy and may resolve sponatenously.
Tuberculous empyema is a less common complication of
pulmonary TB. It is usually the result of the rupture cavity with spillage of a
large number or organisms into pleural spaces. This process may create a
bronchoplerual fistula with evident air in the pleural space. A CXR shows
hydropneumothroax with an air-fluid level. The pleural fluid is purulent and
thick and contains large numbers of lymphocytes. Acid-fast smears and
mycobacterial cultures are often positive. Surgical drainage is required as an
adjunct to chemotherapy.
Tuberculous of upper airways
Nearly always a complication of advanced cavitary pulmonary
Tb may involve the larynx, pharynx and epiglottis. Symptoms include hoarseness,
dysphonia, and dysphagia in addition to chronic productive cough. Ulcerations
may be seen on laryngoscopy. Acid-fast smear of the sputum is often positive
but biopsy may be necessary in some cases to establish the diagnosis. Carcinoma
of the larynx may have similar features but is usually painless.
Skeletal tuberculosis
In bone & joint disease, pathogenesis is related to
reactivation of hematogenous foci or to spread from adjacent paravertebral
lymph nodes. Weight bearing joints are most commonly affected. Spinal TB often
involves two or more adjacent vertebral bodies. While the upper thoracic spine
is the most common site of spinal TB in children, the lower thoracic and upper
lumbar vertebrae are usually affected in adults. From the anterior superior or
inferior angle of the vertebral body, the lesion slowly reaches the adjacent
body, later affecting the intervertebral disk. With advanced of disease,
collapse of vertebral bodies results in kyphosis (gibbus). A paravertebral cold
abscess may also form. In the upper spine, this abscess may track to and
penetrate chest wall, presenting as a soft tissue mass, in the lower spine it
may reach the inguinal ligaments or present as psoas abscess.
Aspiration of the abscess or bone biopsy confirms the
tuberculous etiology, as cultures are usually positive and histologic findings
highly typical. TB of hip joints usually involving the head of femur, causes
pain; TB of knee produces pain & swelling. If the disease goes
unrecognized, the joints may be destroyed. Diagnosis requires examination of
the synovial fluid, which is thick in appearance, with a high protein
concentration and a variable cell count. Synovial biopsy and tissue culture may
be necessary to establish the diagnosis.
Tuberculous Meningitis and Tuberculoma
It is seen most often in young children but also develop in
adults, especially those infected with HIV. Tuberculous meningitis results from
the Hematogenous spread of primary or postprimary pulmonary disease or from the
rupture of a subependymal tubercle into the subarachnoid space. In more than
half cases, evidence of old pulmonary lesions or a military pattern is found on
chest radiography. The disease often presents subtly as headache and slight
mental changes after a prodrome of weeks of low grade fever, malaise, anorexia
and irritability. If not recognized, tuberculous meningitis may evolve acutely
with severe headache, confusion, lethargy altered sensorium and neck rigidity.
Typically, the disease evolves over 1-2 weeks, a course longer than that of
bacterial meningitis. Paresis of cranial nerves is a frequent finding and the
involvement of cerebral arteries may produce focal ischemia.
Lumbar puncture is the cornerstone of diagnosis. CSF reveals
a high leukocyte counts, usually with predominance of lymphocytes but sometomes
with a presdominance of neutrophils in the early stage; a protein content of
1-8g/L; and a low glucose concentration. Culture of CSF is diagnostic in up to
80% of cases and remains the gold standard. Imaging studies (CT and MRI) may
show hydrocephalus and abnormal enhancement of basal cisterns or ependyma.
Gastrointestinal tuberculosis
GI TB is uncommon. Various pathogenetic mechanism are
involved: swallowing of sputum with direct seeding, Hematogenous spread or
ingestion of milk from cows affected by bovine TB. The terminal ileum and the
cecum are the most commonly involved. Abdominal pain and swelling, obstruction,
hematochezia and a palpable mass in the abdomen are common findings at
presentation. Fever, weight loss, anorexia and night sweats are also common. With
intestinal wall involvement, ulceration and fistulae may stimulate Crohn’s
disease.
Tuberculous peritonitis follows either the direct spread of
tubercle bacilli from ruptured lymph nodes and intraabdominal organs or hematogenous
seeding. Nonspecific abdominal pain, fever and ascites should raise the
suspicion of tuberculous peritonitis. Paracentesis reveals an exudative fluid
with a high protein content and leukocytosis that is usually lymphocytic. Peritoneal
biopsy is often needed to establish the diagnosis.
Pericardial Tuberculosis
The onset may be subacute, although an acute presentation
with dyspnea, fever, dull retrosternal pain and a pericardial friction rub is
possible. An effusion eventually develops in many cases; cardiovascular
symptoms and signs of cardiac tamponade may ultimately appear. A definitive
diagnosis can be obtained by pericardiocentesis under echocardiographic
guidance. The effusion is exudative in nature, with a high count of leukocytes.
Hemorrhagic effusion is frequent. Culture of pericardial fluid reveals M.TB in
up 2/3 cases while pericardial biopsy has a higher yield.
Without treatment, pericardial TB is usually fatal. Even
with treatment, complications may develop, including chronic constrictive
pericarditis with thickening of the pericardium, fibrosis and sometimes
calcification which may be visible on CXR. A course of glucocorticoid treatment
(prednisone 20-60mg/d for up to 6wks) is useful in the management of acute
disease, reducing effusion, facilitating hemodynamic recovery and thus
decreasing mortality rates.
Miliary or Disseminated Tuberculosis
This is due to hematogenous spread of tubercle bacillia. In
children is is often the consequence of primary infection, in adults it may be
due to either recent infection or reactivation of old disseminated foci. The
lesions are usually yellowish granulomas 1-2mm in diameter that resemble millet
seeds.
Clinical manifestations are nonspecific and protean,
depending on the predominant site of involvement. Fever, night sweats, anorexia,
weakness and weight loss are presenting symptoms in the majority cases. At
times, patient has cough and other respiratory symptoms due to pulmonary
involvement as well as abdominal symptoms. Physical findings include
hepatomegaly, splenomegaly and lymohadenopathy. Eye examination may reveal
choroidal tubercles, which are pathognomonic of military TB.
CXR reveals a military reticulonodular pattern, although no
radiographic abnormality may be evident early in the course and among
HIV-infected patients. Other radiologic findings include large infiltrates,
interstitial infiltrates and pleural effusion. Sputum smear microscopy is
negative in 80% of cases.
Various hematologic abnormalities may be seen, including
anemia with leukopenia, lymphopenia, neutrophilic leukocytosis and leukemoid
reactions, and polycythemia. Disseminated intravascular coagulation has been
reported. Elevation of alkaline phosphatase levels and other abnormal values in
liver function tests are detected in patients with severe hepatic involvement.
The TST may be negative in up to half of cases, but reactivity may be restored
during chemotherapy. Bronchoalveolar lavage and transbronchial biopsy are more
likely to provide bacteriologic confirmation, and granulomas are evident in
liver or bone-marrow biopsy specimens from many patients. If it goes
unrecognized, miliary tuberculosis is lethal; with proper early treatment,
however, it is amenable to cure. Glucocorticoid therapy has not proved
beneficial.
A rare presentation seen in the elderly is cryptic miliary
tuberculosis, which has a chronic course characterized by mild intermittent
fever, anemia, and—ultimately—meningeal involvement preceding death. An acute
septicemic form, nonreactive miliary tuberculosis, occurs very rarely and is
due to massive hematogenous dissemination of tubercle bacilli. Pancytopenia is
common in this form of disease, which is rapidly fatal. At postmortem
examination, multiple necrotic but nongranulomatous ("nonreactive")
lesions are detected.
DIAGNOSIS
AFB microscopy
Although rapid and inexpensive, AFB microscopy has a relatively low sensitivity in confirmed
cases of pulmonary TB. Most modern laboratories processing large numbers of
diagnostic specimens use auramine-rhodamine staining and fluorescence
microscopy. The more traditional method—light microscopy of specimens stained
with Kinyoun or Ziehl-Neelsen basic fuchsin dyes—is satisfactory, although more
time-consuming. For patients with suspected pulmonary tuberculosis, three
sputum specimens, preferably collected early in the morning, should be
submitted to the laboratory for AFB smear and mycobacterial culture. If tissue
is obtained, it is critical that the portion of the specimen intended for
culture not be put in formaldehyde. The use of AFB microscopy on urine or
gastric lavage fluid is limited by the presence of commensal mycobacteria that
can cause false-positive results.
Mycobacterial Culture
Specimens may be inoculated onto egg- or agar-based medium
(e.g., Löwenstein-Jensen or Middlebrook 7H10) and incubated at 37°C (under 5%
CO2 for Middlebrook medium). Because most species of mycobacteria, including M.
tuberculosis, grow slowly, 4–8 weeks may be required before growth is detected.
Although M. tuberculosis may be presumptively identified on the basis of growth
time and colony pigmentation and morphology, a variety of biochemical tests
have traditionally been used to speciate mycobacterial isolates.
Nucleic acid amplification
These systems permit the diagnosis of tuberculosis in as
little as several hours, with high specificity and sensitivity approaching that
of culture. These tests are most useful for the rapid confirmation of
tuberculosis in persons with AFB-positive specimens but also have utility for
the diagnosis of AFB-negative pulmonary and extrapulmonary tuberculosis.
Drug susceptibility testing
In general, the initial isolate of M. tuberculosis should be
tested for susceptibility to isoniazid, rifampin, and ethambutol. In addition,
expanded susceptibility testing is mandatory when resistance to one or more of
these drugs is found or the patient either fails to respond to initial therapy
or has a relapse after the completion of treatment.
Susceptibility testing may be conducted directly (with the
clinical specimen) or indirectly (with mycobacterial cultures) on solid or
liquid medium. Results are obtained most rapidly by direct susceptibility
testing on liquid medium, with an average reporting time of 3 weeks. With indirect
testing on solid medium, results may be unavailable for 8 weeks. Molecular
methods for the rapid identification of genetic mutations known to be
associated with resistance to rifampin and isoniazid have been developed but
are not marketed in the United States.
Radiographic Procedures
The initial suspicion of pulmonary tuberculosis is often
based on abnormal chest radiographic findings in a patient with respiratory
symptoms. Although the "classic" picture is that of upper-lobe
disease with infiltrates and cavities, virtually any radiographic pattern—from
a normal film or a solitary pulmonary nodule to diffuse alveolar infiltrates in
a patient with ARDS—may be seen. MRI is useful in the diagnosis of intracranial
tuberculosis.
DIAGNOSIS OF LATENT
TB INFECTION
Tuberculin Skin Testing
Skin testing with tuberculin purified protein derivative
(PPD) is most widely used in screening for latent M. TB infection. The test is
limited value in the diagnosis of active TB because of its relatively low
sensitivity & specificity and its inability to discriminate between latent
infection and active disease. False-negative reactions are common in
immunosuppressed patients and in those with overwhelming TB. False-positive
reactions may be caused by infections with nontuberculous mycobacteria and by
bacilli Calmette-Guerin vaccination (BCG).
TREATMENT
Two aims of TB treatment are to interrupt TB transmission
and to prevent morbidity and death by curing patients with TB. Randomized
clinical trials clearly indicated that the administartaion of streptomysin to
patients with chronic TB reduced mortality rates and led to cure in majority
cases. With the discovery of para-aminosalicylic acis (PAS) and isoniazid, it
became axiomatic that cure of TB require concomitant administration of at least
two agents to which the organism was susceptible. Early clinical trials
demonstrated that a long period of treatment was required to prevent
recurrence.
Drugs
4 major drugs are considered the first-line agents for the
treatment of TB: isoniazid, rifampin,
pyrazinamide and ethambutol.
These drugs are well absorbed after oral administration, with peak serum
levels at 2-4hrs and nearly complete elimination within 24h. these agents are
recommended on the basis of their bactericidal activity, their sterilizing
activity and their low rate of induction
of drug resistance.
Regimens
Standard short-course regimens are divided into an initial,
or bactericidal, phase and a continuation, or sterilizing, phase. During the
initial phase, the majority of the tubercle bacilli are killed, symptoms
resolve, and usually the patient becomes noninfectious. The continuation phase
is required to eliminate persisting mycobacteria and prevent relapse.
The treatment regimen of choice for virtually all forms of
TB in both adults and children consists of a 2-month initial phase of isoniazid, rifampin, pyrazinamide and ethambutol followed
by a 4-month continuation phase of
isoniazid and rifampin.
Treatment may be given daily throughout the course or
intermittently (3x/week OR 2x/week
after an initial phase of daily therapy). Continuation phase of once-weekly
rifapentine and isoniazid is equally effective for HIV-seronegative patients
with noncavitary pulmonary tuberculosis who have negative sputum cultures at 2
months. Intermittent treatment is especially useful for patients whose therapy
is being directly observed. Patinets with cavitary pulmonary TB and delayed
sputum-culture onversion should have the continuation phase extended by 3
months, for a total course of 9months.
For patients with sputum culture–negative pulmonary
tuberculosis, the duration of treatment may be reduced to a total of 4 months.
To prevent isoniazid-related neuropathy, pyridoxine (10–25 mg/d) should be
added to the regimen given to persons at high risk of vitamin B6 deficiency.
H: isoniazid; R=rifampin; Z=pyrazinamide;
E=ethambutol; S=streptomycin; Q=quinolone; PAS=para-aminosalicylic acid
|
Monitoring Treatment Response & Drug Toxicity
Patients with pulmonary disease should have their sputum
examined monthly until cultures become negative. >80% of patients will have
negative sputum cultures at the end of second month of treatment. By the end of
third month, virtually all patients should be culture-negative. In some
patients, especially those with extensive cavitary disease and large numbers of
organisms, AFB smear conversion may lag behind culture conversion. This
phenomenon is presumably due to the expectoration and microscopic visualization
of dead bacilli. As noted above, patients with cavitary disease who do not
achieve sputum culture conversion by 2 months require extended treatment.
When a patient's sputum cultures remain positive at 3
months, treatment failure and drug resistance or poor adherence with the
regimen should be suspected. A sputum specimen should be collected by the end
of treatment to document cure. If mycobacterial cultures are not practical,
then monitoring by AFB smear examination should be undertaken at 2, 5, and 6
months. Smears that are positive after 5 months of treatment in a patient known
to be adherent are indicative of treatment failure.
The most common adverse reaction of significance is
hepatitis. Patients should be carefully educated about the signs and symptoms
of drug-induced hepatitis (e.g., dark urine, loss of appetite) and should be
instructed to discontinue treatment promptly and see their health care provider
should these symptoms occur.
Hypersensitivity reactions usually require the
discontinuation of all drugs and rechallenge to determine which agent is the
culprit. Hyperuricemia and arthralgia caused
by pyrazinamide can usually be managed by the administration of
acetylsalicylic acid; however, pyrazinamide
treatment should be stopped if the patient develops gouty arthritis.
Individuals who develop autoimmune
thrombocytopenia secondary to rifampin therapy should not receive
the drug thereafter. Similarly, the occurrence of optic neuritis with ethambutol is an indication for
permanent discontinuation of this drug.
Other common manifestations of drug intolerance, such as pruritus and gastrointestinal upset, can generally be managed without
the interruption of therapy.
Ref: Harrison's Principal of Internal Medicine
