#Tuberculosis Treatment & Management

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Tuberculosis

Author: Thomas E Herchline, MD; Chief Editor: Michael Stuart Bronze, MD  more…

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Anteroposterior chest radiograph of a young patient who presented to the emergency department (ED) with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine (remotemedicine.org).

Practice Essentials
Tuberculosis (TB) (see the image below), a multisystemic disease with myriad presentations and manifestations, is the most common cause of infectious disease–related mortality worldwide. Although TB rates are decreasing in the United States, the disease is becoming more common in many parts of the world. In addition, the prevalence of drug-resistant TB is increasing worldwide.

Anteroposterior chest radiograph of a young patient who presented to the emergency department (ED) with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine (remotemedicine.org).
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See 11 Travel Diseases to Consider Before and After the Trip, a Critical Images slideshow, to help identify and manage infectious travel diseases.

Signs and symptoms

Classic clinical features associated with active pulmonary TB are as follows (elderly individuals with TB may not display typical signs and symptoms):
Cough
Weight loss/anorexia
Fever
Night sweats
Hemoptysis
Chest pain (can also result from tuberculous acute pericarditis)
Fatigue
Symptoms of tuberculous meningitis may include the following:
Headache that has been either intermittent or persistent for 2-3 weeks
Subtle mental status changes that may progress to coma over a period of days to weeks
Low-grade or absent fever
Symptoms of skeletal TB may include the following:
Back pain or stiffness
Lower-extremity paralysis, in as many as half of patients with undiagnosed Pott disease
Tuberculous arthritis, usually involving only 1 joint (most often the hip or knee, followed by the ankle, elbow, wrist, and shoulder)

Symptoms of genitourinary TB may include the following:
Flank pain
Dysuria
Frequent urination
In men, a painful scrotal mass, prostatitis, orchitis, or epididymitis
In women, symptoms mimicking pelvic inflammatory disease
Symptoms of gastrointestinal TB are referable to the infected site and may include the following:
Nonhealing ulcers of the mouth or anus
Difficulty swallowing (with esophageal disease)
Abdominal pain mimicking peptic ulcer disease (with gastric or duodenal infection)
Malabsorption (with infection of the small intestine)
Pain, diarrhea, or hematochezia (with infection of the colon)
Physical examination findings associated with TB depend on the organs involved. Patients with pulmonary TB may have the following:
Abnormal breath sounds, especially over the upper lobes or involved areas
Rales or bronchial breath signs, indicating lung consolidation
Signs of extrapulmonary TB differ according to the tissues involved and may include the following:
Confusion
Coma
Neurologic deficit
Chorioretinitis
Lymphadenopathy
Cutaneous lesions
The absence of any significant physical findings does not exclude active TB. Classic symptoms are often absent in high-risk patients, particularly those who are immunocompromised or elderly.
See Clinical Presentation for more detail.

Diagnosis

Screening methods for TB include the following:
Mantoux tuberculin skin test with purified protein derivative (PPD) for active or latent infection (primary method)
In vitro blood test based on interferon gamma release assay (IGRA) with antigens specific for Mycobacterium tuberculosis for latent infection
Obtain the following laboratory tests for patients with suspected TB:
Acid-fast bacilli (AFB) smear and culture using sputum obtained from the patient: Absence of a positive smear result does not exclude active TB infection; AFB culture is the most specific test for TB
HIV serology in all patients with TB and unknown HIV status: Individuals infected with HIV are at increased risk for TB
Other diagnostic testing may warrant consideration, including the following:
Specific enzyme-linked immunospot (ELISpot)
Nucleic acid amplification tests
Blood culture
Positive cultures should be followed by drug susceptibility testing; symptoms and radiographic findings do not differentiate multidrug-resistant TB (MDR-TB) from fully susceptible TB. Such testing may include the following:
Direct DNA sequencing analysis
Automated molecular testing
Microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays
Additional rapid tests (eg, BACTEC-460, ligase chain reaction, luciferase reporter assays, FASTPlaque TB-RIF)
Obtain a chest radiograph to evaluate for possible associated pulmonary findings. The following patterns may be seen:
Cavity formation: Indicates advanced infection; associated with a high bacterial load
Noncalcified round infiltrates: May be confused with lung carcinoma
Homogeneously calcified nodules (usually 5-20 mm): Tuberculomas, representing old infection
Primary TB: Typically, pneumonialike picture of infiltrative process in middle or lower lung regions
Reactivation TB: Pulmonary lesions in posterior segment of right upper lobe, apicoposterior segment of left upper lobe, and apical segments of lower lobes
TB associated with HIV disease: Frequently atypical lesions or normal chest radiographic findings
Healed and latent TB: Dense pulmonary nodules in hilar or upper lobes; smaller nodules in upper lobes
Miliary TB: Numerous small, nodular lesions that resemble millet seeds
Pleural TB: Empyema may be present, with associated pleural effusions
Workup considerations for extrapulmonary TB include the following:
Biopsy of bone marrow, liver, or blood cultures
If tuberculous meningitis or tuberculoma is suspected, perform lumbar puncture
If vertebral ( Pott disease) or brain involvement is suspected, CT or MRI is necessary
If genitourinary complaints are reported, urinalysis and urine cultures can be obtained
See Workup for more detail.

Management

Physical measures (if possible or practical) include the following:
Isolate patients with possible TB in a private room with negative pressure
Have medical staff wear high-efficiency disposable masks sufficient to filter the bacillus
Continue isolation until sputum smears are negative for 3 consecutive determinations (usually after approximately 2-4 weeks of treatment)
Initial empiric pharmacologic therapy consists of the following 4-drug regimens:
Isoniazid
Rifampin
Pyrazinamide
Either ethambutol or streptomycin [1]
Special considerations for drug therapy in pregnant women include the following:
In the United States, pyrazinamide is reserved for women with suspected MDR-TB
Streptomycin should not be used
Preventive treatment is recommended during pregnancy
Pregnant women are at increased risk for isoniazid-induced hepatotoxicity
Breastfeeding can be continued during preventive therapy
Special considerations for drug therapy in children include the following:
Most children with TB can be treated with isoniazid and rifampin for 6 months, along with pyrazinamide for the first 2 months if the culture from the source case is fully susceptible.
For postnatal TB, the treatment duration may be increased to 9 or 12 months
Ethambutol is often avoided in young children
Special considerations for drug therapy in HIV-infected patients include the following:
Dose adjustments may be necessary [2, 3]
Rifampin must be avoided in patients receiving protease inhibitors; rifabutin may be substituted
Considerations in patients receiving antiretroviral therapy include the following:
Patients with HIV and TB may develop a paradoxical response when starting antiretroviral therapy
Starting antiretroviral therapy early (eg, < 4 weeks after the start of TB treatment) may reduce progression to AIDS and death [4]
In patients with higher CD4+ T-cell counts, it may be reasonable to defer antiretroviral therapy until the continuation phase of TB treatment [5]
Multidrug-resistant TB
When MDR-TB is suspected, start treatment empirically before culture results become available, then modify the regimen as necessary. Never add a single new drug to a failing regimen. Administer at least 3 (preferably 4-5) of the following medications, according to drug susceptibilities:
An aminoglycoside: Streptomycin, amikacin, capreomycin, kanamycin
A fluoroquinolone: Levofloxacin (best suited over the long term), ciprofloxacin, ofloxacin
A thioamide: Ethionamide, prothionamide
Pyrazinamide
Ethambutol
Cycloserine
Terizidone
Para-aminosalicylic acid
Rifabutin as a substitute for rifampin
A diarylquinoline: Bedaquiline
Surgical resection is recommended for patients with MDR-TB whose prognosis with medical treatment is poor. Procedures include the following:
Segmentectomy (rarely used)
Lobectomy
Pneumonectomy
Pleurectomy for thick pleural peel (rarely indicated)
Latent TB
Recommended regimens for isoniazid and rifampin for latent TB have been published by the US Centers for Disease Control and Prevention (CDC) [6] : An alternative regimen for latent TB is isoniazid plus rifapentine as directly observed therapy (DOT) once-weekly for 12 weeks [7, 8] ; it is not recommended for children under 2 years, pregnant women or women planning to become pregnant, or patients with TB infection presumed to result from exposure to a person with TB that is resistant to 1 of the 2 drugs.

Approach Considerations
Isolate patients with possible tuberculosis (TB) infection in a private room with negative pressure (air exhausted to outside or through a high-efficiency particulate air filter). Medical staff must wear high-efficiency disposable masks sufficient to filter the tubercle bacillus. Continue isolation until sputum smears are negative for 3 consecutive determinations (usually after approximately 2-4 wk of treatment). Unfortunately, these measures are neither possible nor practical in countries where TB is a public health problem.
Drug therapy

For initial empiric treatment of TB, start patients on a 4-drug regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin, if it is used as a fourth drug) can be discontinued. [1]
Patients with TB who are receiving pyrazinamide should undergo baseline and periodic serum uric acid assessments, and patients with TB who are receiving long-term ethambutol therapy should undergo baseline and periodic visual acuity and red-green color perception testing. The latter can be performed with a standard test, such as the Ishihara test for color blindness.
After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can be stopped. Isoniazid plus rifampin are continued as daily or intermittent therapy for 4 more months. If isolated isoniazid resistance is documented, discontinue isoniazid and continue treatment with rifampin, pyrazinamide, and ethambutol for the entire 6 months. Therapy must be extended if the patient has cavitary disease and remains culture-positive after 2 months of treatment.
Directly observed therapy (DOT) is recommended for all patients. With DOT, patients on the above regimens can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing. Patients on twice-weekly dosing must not miss any doses. Prescribe daily therapy for patients on self-administered medication.
Monitoring

Patients diagnosed with active TB should undergo sputum analysis for Mycobacterium tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity includes baseline and periodic liver enzymes, complete blood cell (CBC) count, and serum creatinine.

Treatment in Children
Most children with TB can be treated with isoniazid and rifampin for 6 months, along with pyrazinamide for the first 2 months if the culture from the source case is fully susceptible.
For postnatal TB, many experts increase the treatment duration to 9 or 12 months because of the possible impaired immune system in children younger than 12 months. Bacillus Calmette-Guérin (BCG) vaccine is not recommended in infants in the United States but is commonly used around the world.
Isoniazid tablets may be crushed and added to food. Isoniazid liquid without sorbitol should be used to avoid osmotic diarrhea, which can cause decreased absorption.
Rifampin capsules may be opened and the powder added to food. If rifampin is not tolerated, it may be taken in divided doses 20 minutes after light meals.
Ethambutol is often avoided in young children because of difficulties monitoring visual acuity and color perception. However, studies show that ethambutol (15 mg/kg) is well tolerated and can prevent further resistance if the child is infected with a resistant strain. Go to Pediatric Tuberculosis for complete information on treatment of children.

Treatment in HIV-Infected Patients
Treatment regimens for active or latent TB in patients with HIV infection are similar to those used in HIV-negative patients, but dose adjustments may be necessary. [2, 3] The most significant differences involve the avoidance of rifampin in patients who are on protease inhibitors. Rifabutin may be used in place of rifampin in such patients.
Antiretroviral therapy

Patients with HIV and TB may develop a paradoxical response (immune reconstitution inflammatory syndrome [IRIS]) when starting antiretroviral therapy. This response has been attributed to a stronger immune response to M tuberculosis. Clinical findings include fever, worsening pulmonary infiltrates, and lymphadenopathy.
However, in an open-label, randomized trial, Abdool Karim et al concluded that the initiation of antiretroviral therapy during TB therapy significantly improved patient survival. In this study, the mortality rate with simultaneous initiation of antiretroviral therapy and TB therapy was 5.4 deaths per 100 person-years (25 deaths in 429 patients), compared with 12.1 deaths per 100 person-years (27 deaths in 213 patients) with antiretroviral therapy started after the completion of TB therapy, a relative reduction of 56%. [4]
Subsequent studies by these and other researchers found that starting antiretroviral therapy early (eg, within 4 weeks after the start of TB treatment) reduced progression to AIDS and death. In patients with higher CD4+ T-cell counts, however, deferring initiation of antiretroviral therapy until the continuation phase of TB treatment may be a reasonable strategy, because the risks of IRIS and of adverse events that necessitate switching of antiretroviral drugs are lower with later initiation of antiretroviral therapy. [5]
Treatment length and recurrence rate

Swaminathan et al reported a significantly lower bacteriologic recurrence rate with 9 months, instead of 6 months, of an intermittent (3 times/wk) 4-drug regimen in patients with HIV infection and newly diagnosed TB. Mortality was similar in both groups. The rate of acquired rifampin resistance was high in both groups and was not altered by the longer TB treatment. [2]
Tuberculous meningitis

In patients with tuberculous meningitis, dexamethasone added to routine 4-drug therapy reduces complications.

Treatment of Multidrug-Resistant TB
When MDR-TB is suspected, because of a relevant history or epidemiologic information, treatment is initiated after sputum specimens are drawn for culture and sensitivity testing; however, treatment must be started empirically before culture results become available. Once results are known, the regimen is modified according to susceptibilities. (Costs are many times higher for the treatment of MDR-TB.)
The complexity of MDR-TB treatment lies in the futility of using isoniazid and rifampin. Isoniazid has the strongest antibactericidal action and significantly contributes to making patients rapidly noninfectious; rifampin has unique antibacterial properties against dormant bacilli that are no longer in the active phase of replication.
When initiating treatment, utilize at least 3-5 previously unused drugs for which there is in vitro susceptibility. Levofloxacin, which is a fluoroquinolone, has been shown to be best suited long-term and should be included in the regimen.
Never add a single new drug to a failing regimen. Administer at least 3 (preferably 4-5) of the following medications, according to drug susceptibilities:
An aminoglycoside – Ie, streptomycin, amikacin, capreomycin, kanamycin
A fluoroquinolone – Ie, levofloxacin, ciprofloxacin, ofloxacin
A thioamide – Eg, ethionamide, prothionamide
Pyrazinamide
Ethambutol
Cycloserine
Terizidone
Para-aminosalicylic acid
A diarylquinoline: Bedaquiline
Consider rifabutin as a substitute for rifampin, as approximately 15% of rifampin-resistant strains are rifabutin sensitive.
Successful MDR-TB treatment is more likely in association with such factors as lower prior patient exposure to anti-TB drugs, a higher number of anti-TB drugs to which the infection is still susceptible, and a shorter time since the first TB diagnosis (indicating less advanced disease).
Continue treatment for MDR-TB for 18-24 months after sputum culture conversion. The drugs should be prescribed daily (no intermittent therapy), and the patient should always be on DOT. Weekend DOT may not be possible; therefore, giving self-administered oral drugs on Saturdays and Sundays may be reasonable. All patients should be closely observed for 2 years after completion of treatment, with a low threshold for referral to TB centers.
Novel drugs for TB are currently under development and may prove valuable for treatment of MDR-TB. The diarylquinoline antimycobacterial, bedaquiline (Sirturo), was approved by the FDA in December 2012 as part of a 22-week multidrug regimen for pulmonary MDR-TB. Approval was based on phase 2 data that showed bedaquiline significantly improved time to sputum culture conversion and included 2 consecutive negative sputum cultures collected at least 25 days apart during treatment. At week 24, sputum culture conversion was observed in 77.6% of patients in the bedaquiline treatment group compared with 57.6% of patients in the placebo treatment group (p = 0.014). [73, 74]

In another phase II study by Diacon et al, bedaquiline (TMC207) added to standard therapy for MDR-TB reduced the time to conversion to a negative sputum culture compared with placebo and increased the proportion of patients with conversion of sputum culture (48% vs 9%). [75]
Provisional guidelines from the Centers for Disease Control and Prevention (CDC) include use of bedaquiline for FDA-approved and off-label uses. In addition to the approved indication as part of at least a 4-drug regimen for treatment multidrug-resistant tuberculosis, the guidelines include use on a case-by-case basis for children, HIV-infected persons, pregnant women, persons with extrapulmonary MDR TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided. [76, 77]
The diagnosis of extensively drug-resistant TB (XDR-TB) is established with an isolate that is resistant to isoniazid, rifampin, at least 1 of the quinolones, and at least 1 injectable drug. Treatment options for XDR-TB are very limited, and XDR-TB carries a very high mortality rate.
A CDC analysis of the prevalence, trends, and risk factors for initial resistance to pyrazinamide in Mycobacterium tuberculosis complex (MTBC) cases in the United States showed that such resistance increased from 2% in 1999 to 3.3% in 2009. Pyrazinamide monoresistance was associated with younger age, Hispanic ethnicity, HIV infection, extrapulmonary disease, and normal chest radiograph and inversely associated with Asian and Black race, substance use, homelessness, and residence in a correctional facility. [78, 79]
In the same CDC analysis, pyrazinamide polyresistance was associated with Hispanic ethnicity, Asian race, previous TB diagnosis, and normal chest x-ray and inversely associated with age 45 years and older. Pyrazinamide resistance in multidrug-resistant cases was associated with female sex and previous TB diagnosis. Bacterial lineage, rather than host characteristics, was the primary predictor of pyrazinamide resistance ijn M tuberculosis cases. [78, 79]
Surgical resection

Surgical resection of an infected lung may be considered to reduce the bacillary burden in patients with MDR-TB. Surgery is recommended for patients with MDR-TB whose prognosis with medical treatment is poor. Surgery can be performed with a low mortality rate (< 3%), with prolonged periods of a chemotherapeutic regimen used for more than 1 year after surgery.
Procedures include segmentectomy (rarely used), lobectomy, and pneumonectomy. Pleurectomies for thick pleural peel are rarely indicated.
Intraoperative infection of uninvolved lung tissue has been observed in resections. Complications include the usual perioperative complications, recurrent disease, and bronchopleural fistulas.

Prevention and Consultations
The BCG vaccine continues to be used throughout much of the world and usually provides protection until early childhood. Immunity begins to wane, however, as early as 3 months after administration. [82] As previously noted, use of the BCG vaccine is not recommended in infants in the United States.
In a meta-analysis of eight randomized controlled studies involving a total of 10,320 patients aged 15 years or younger, Ayieko et al found that isoniazid prophylaxis reduced the risk of developing TB, with a pooled risk ratio (RR) of 0.65 (P  = 0.004). However, isoniazid had no effect in children who initiated treatment at 4 months of age or earlier. When those patients were excluded, isoniazid prophylaxis reduced the risk of developing TB by 59% (RR, 0.41; P < 0.001). [83]
The public health sector should be notified and involved in cases of TB. Local county health departments are expert and funded in the care of TB infection. Consultation with a primary care, pulmonology, internal medicine, or infectious disease specialist prior to initiating therapy is helpful, and it may be appropriate for this consultant to manage the antituberculous chemotherapy. Consult an expert on MDR-TB in cases of multidrug resistance.

*Extracts from Medscape

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Um comentário em “#Tuberculosis Treatment & Management

    Anônimo disse:
    08/05/2017 às 09:53

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