Tuberculosis in Pregnant Patients
Tuberculosis that is discovered during pregnancy should be treated without delay. Because tuberculosis can spread to the fetus, treatment in pregnant women should be initiated whenever the probability of maternal disease is moderate to high.
The initial treatment regimen in pregnant patients consists of isoniazid, rifampin, and ethambutol. Consideration should be given to including PZA in the initial regimen as well: PZA has not been widely used in the United States to treat pregnant women with tuberculosis, but it is recommended for use in this setting by the WHO and the International Union Against Tuberculosis and Lung Disease, as well as some public health agencies in the United States.3,87 PZA is recommended for use in all HIV-infected pregnant patients and in pregnant patients who are thought to be at high risk for drug-resistant tuberculosis (pending susceptibility test results). If PZA is not included in the regimen, the minimum duration of treatment is 9 months. Supplemental pyridoxine (vitamin B6), 25 to 50 mg a day, is indicated for all pregnant women taking isoniazid, to prevent peripheral neuropathy. Aminoglyco-sides and fluoroquinolones should be avoided in pregnancy because of potential adverse effects on the fetus.
Drug-Resistant Tuberculosis
Treatment of drug-resistant tuberculosis, especially MDR-TB, is quite challenging and should be done by, or in close consultation with, an expert in this subject. Recommendations for the treatment of drug-resistant tuberculosis have been developed [see Table 5]. Treatment of isolated isoniazid resistance can be accomplished with a 6-month regimen of daily rifampin, PZA, and ethambutol. Treatment of isolated rifampin resistance requires a minimum of 12 months of therapy with a regimen such as isoni-azid, PZA, ethambutol, and a fluoroquinolone. Treatment of MDR-TB (resistance to both isoniazid and rifampin) requires 18 to 24 months, depending on the full resistance pattern, and is associated with significantly higher morbidity and mortality than drug-susceptible disease. Treatment of MDR-TB requires the use of second-line drugs, which have less in vitro activity and significantly more toxicity than first-line drugs [see Table 2].
Common errors that lead to the emergence of drug resistance include the addition of a single drug to a failing regimen, failure to identify preexisting or acquired drug resistance, initiation of an inadequate primary regimen, failure to identify and address noncompliance, and use of monotherapy for active disease (in cases in which therapy for latent tuberculosis was prescribed but active disease was present).88
Table 4 Evidence-Based Guidelines for Duration of Therapy for Drug-Susceptible Extrapulmonary Tuberculosis and Adjunctive Use of Corticosteroids*3,85
|
Site |
Duration of Antimicrobial Therapy (Rating) |
Adjunctive Corticosteroids (Rating) |
Corticosteroid Regimens |
|
Lymph node |
6 mo (A/I) |
Not recommended (D/III) |
Pericarditis: prednisone, 60 mg/day, wk 1-4; 30 mg/day, wk 5-8; 15 mg/day, wk 9-10; 5 mg/day, wk 11 |
|
Bone and joint |
6-9 mo (A/I) |
Not recommended (D/III) |
|
|
Pleural disease |
6 mo (A/II) |
Not recommended (D/III) |
|
|
Pericarditis |
6 mo (A/II) |
Strongly recommended (A/I) |
|
|
CNS, including meningitis |
9-12 mo (B/II) |
Strongly recommended (A/I) |
Meningitis: dexamethasone for 6 wk; in children < 25 kg, 8 mg/day x 3 wk; in children > 25 kg and in adults, 12 mg/day x 3 wk; in all patients, dose is tapered over the next 3 wk |
|
Disseminated disease |
6 mo (A/II) |
Not recommended (D/III) |
|
|
Genitourinary |
6 mo (A/II) |
Not recommended (D/III) |
|
|
Peritoneal |
6 mo (A/II) |
Not recommended (D/III) |
*Preferred duration of therapy for extrapulmonary tuberculosis caused by drug-resistant organisms is unknown. CNS—central nervous system
Table 5 Potential Regimens for the Treatment of Drug-Resistant Tuberculosis3
|
Pattern of Drug Resistance |
Suggested Regimen (Alternative Choice) |
Duration of Treatment (mo) |
Comments |
|
Isoniazid (± streptomycin) |
Rifampin, pyrazinamide, ethambutol; addition of a fluoroquinolone* may strengthen regimen for patients with extensive disease |
6 |
Use at least three other drugs; include rifampin, pyrazin-amide, and ethambutol or streptomycin |
|
Rifampin |
Isoniazid, ethambutol, and a fluoro-quinolone,* plus pyrazinamide for the first 2 mo; an injectable agent+ may be included for the first 2-3 mo for patients with extensive disease |
12-18 |
Isoniazid, pyrazinamide, and streptomycin for 9 mo is an alternative regimen; however, prolonged therapy with an injectable agent may not be feasible or desirable, and an all-oral regimen should be as effective; some experts continue pyrazinamide throughout the course of therapy |
|
Isoniazid and rifampin (± streptomycin) |
A fluoroquinolone,* pyrazinamide, etham-butol, and an injectable agent,+ ± an alternative agentt |
18-24 |
Extended treatment is needed to lessen the risk of relapse; in patients with extensive disease, the addition of an alternative agent may be prudent to lessen the risk of failure and additional acquired drug resistance; consider resectional surgery as adjunct to chemotherapy |
|
Isoniazid, rifampin (± streptomycin), and ethambutol or pyrazinamide |
A fluoroquinolone* (ethambutol or pyrazin-amide, if active), injectable agent,+ and two alternative agentst |
24 |
Use the first-line agents to which the strain is susceptible; add two or more alternative agents in patients with extensive disease; consider resectional surgery as adjunct to chemotherapy |
Note: treatment of drug-resistant tuberculosis should be carried out by, or in consultation with, a physician with expertise and experience in treating drug-resistant disease [see Table 2 for dosages].
*For example, levofloxacin, moxifloxacin, gatifloxacin.
+Injectable agents may include aminoglycosides (streptomycin, amikacin, or kanamycin) or the polypeptide capreomycin. {Alternative agents are ethionamide, cycloserine, para-aminosalicylic acid, clarithromycin, amoxicillin-clavulanate, and linezolid.
In patients suspected of having MDR-TB (e.g., those who failed to complete an earlier regimen or who followed their therapy erratically, those with recent exposure to an MDR-TB case, or those from extremely high-risk areas), the physician should consider initiating therapy with extended empirical regimens, pending culture results. This is especially the case for patients with extensive pulmonary disease or extrapulmonary disease such as tuberculous meningitis or mil-iary disease. Documented MDR-TB requires treatment with at least four drugs (and more if possible) to which the organisms are susceptible, such as three oral drugs and one injectable agent [see Table 5].
The role of surgery in MDR-TB has not been examined in randomized studies but is thought by some experts to be beneficial in selected cases. In one case series, surgical resection in conjunction with fluoroquinolone therapy was associated with improved microbiologic and clinical outcomes in 205 patients with MDR-TB.89 Surgery should be deferred until the patient has completed several months of intensive chemotherapy, and it should be performed by an experienced surgeon.3
Monitoring Response to Treatment
For patients undergoing treatment of pulmonary tuberculosis, a sputum specimen for AFB smear and culture should be obtained at least monthly until two consecutive specimens are culture negative.3 It is essential to obtain an AFB sputum smear and culture after 2 months of therapy, because of their value in predicting risk of relapse. Drug susceptibility tests should be repeated on M. tuberculosis isolates from patients whose cultures are positive after 3 months of treatment.
In patients with pulmonary tuberculosis, a repeat chest radiograph should be taken after 2 months of therapy; more frequent chest radiographs are not indicated. However, a chest radiograph taken at the completion of therapy can be useful for providing a baseline against which subsequent films can be compared.
Bacteriologic monitoring is more difficult in patients with ex-trapulmonary disease. In these cases, the response to treatment often must be assessed clinically because it is not feasible to obtain follow-up cultures.
All patients undergoing treatment of tuberculosis should be seen on a monthly basis; at each visit, they should undergo a clinical evaluation to identify possible adverse effects of the anti-tuberculosis medications and to assess adherence. Baseline liver function tests, creatinine level, and platelet count should be obtained on all patients. In patients taking first-line antituberculosis drugs, ATS/CDC/IDSA guidelines do not recommend monthly liver or renal function tests during treatment unless baseline abnormalities were present or there are clinical reasons to obtain the tests.3 Patients taking ethambutol should be questioned monthly regarding visual disturbances; monthly testing of visual acuity and color vision is recommended for those treated with dosages higher than 20 mg/kg/day or for those who require ethambutol for more than 2 months.
Contact Investigation and Reporting of Tuberculosis Cases
Physicians are required by law to report tuberculosis cases to their local public health agency. In some hospitals, this is handled by the infection control department, but the physician should ensure that the case has been reported expeditiously, so that the local health department can contact the patient while he or she is still hospitalized. This will help to ensure that the patient is not lost to follow-up after discharge. Discharge planning should be carried out in a collaborative fashion with the involvement of the public health department, which should have the resources and the ability to provide DOT to patients with tuberculosis in the outpatient setting. The local public health agency is responsible for conducting a contact investigation to identify others who have been exposed to an infectious patient (e.g., in the home, at work, and in other social settings). This can lead to the identification of newly infected contacts, for whom treatment of latent tuberculosis is a priority, and it can lead to other potential cases. In addition, when the patient is a child, the contact investigation can lead to the identification of the source case. Priority for contact investigations should be given to instances in which infants or HIV-infected persons (or other highly immuno-compromised persons) have been exposed, given the rapid progression from infection to active disease in these settings.
LTBI
Therapy for latent tuberculosis can markedly reduce the risk of progression to active disease and is recommended for patients who are at increased risk for disease progression. Patients with LTBI (i.e., those who test positive on tuberculin skin testing or other diagnostic tests but whose chest radiograph is negative and who have no signs or symptoms of tuberculosis) who are at increased risk for progression to active disease should be encouraged to undergo therapy.
The CDC and ATS have issued guidelines on the treatment of latent tuberculosis [see Table 6]. The preferred regimen is a 9-month course of isoniazid; 6 months of isoniazid is an alternative in HIV-seronegative adults. The recommendation for this duration of therapy comes from reanalysis of data from older trials.90 Rifampin taken for 4 months is an alternative for the treatment of LTBI and is recommended for adults suspected of harboring an isoniazid-resistant strain of M. tuberculosis.
A 2-month regimen of rifampin plus PZA for the treatment of LTBI is not recommended, because of its unacceptably high rate of hepatotoxicity in these patients. A CDC survey suggests that the risk of death with this regimen is nearly 1 in 1,000 persons, and the rate of hospitalization is 3 in 1,000 persons.91 Rifampin and PZA, however, remain an important component of a mul-tidrug regimen for patients with active tuberculosis. Isoniazid may also be given twice weekly in DOT to facilitate adherence in institutional settings or when resources are available.
Patients receiving therapy for LTBI should have an initial clinical evaluation, followed by follow-up evaluations at least monthly; no more than 1 month’s supply of medication should be dispensed at a time. The monthly clinical evaluation should include questioning about side effects and a brief clinical assessment for signs of hepatitis. Although adverse reactions to isoni-azid are not common, they can be serious. Hepatotoxicity is the most important side effect. However, at a tuberculosis clinic in Seattle, hepatotoxicity occurred in only 0.15% of patients who completed isoniazid monotherapy for LTBI—a rate much lower than those reported in earlier studies.92 The rate of isoniazid-re-lated hepatotoxicity has been estimated to be 1 to 3 per 1,000 patients. Age is a risk factor: isoniazid-induced hepatotoxicity is rare in patients younger than 20 years, but the rate increases with advancing age. Risk may also be higher in patients with underlying liver disease (including hepatitis C), in those with a history of heavy alcohol consumption, and in the postpartum period (especially for Hispanic women). Asymptomatic, and generally transient, elevations of the aminotransferase level can occur in 10% to 20% of patients taking isoniazid for LTBI. The risk of fatal hepatitis from isoniazid is currently reported to range from 0 to 0.3 (median, 0.04) per 1,000 patients.91,92 Death has been associated with continued administration of isoniazid despite onset of hepatitis symptoms. The drug should be discontinued when levels of alanine aminotransferase (ALT) or aspartate aminotrans-ferase (AST) exceed five times normal in asymptomatic patients or three times normal in those with symptoms.
Patients should be advised to discontinue isoniazid at the onset of symptoms that are consistent with hepatitis (e.g., nausea, loss of appetite, and dull midabdominal pain) and to immediately seek medical evaluation should these symptoms occur. Liver function tests should be obtained for any patient who develops symptoms suggestive of hepatitis. We recommend baseline liver function tests for all adult patients at the start of therapy for LTBI. However, ATS/CDC guidelines recommend baseline laboratory testing only for patients whose initial evaluation suggests a liver disorder and for those at increased risk for hepato-toxicity, including HIV-infected patients, pregnant women,women in the immediate postpartum period (i.e., within 3 months after delivery), patients with a history of chronic liver disease (e.g., hepatitis B, hepatitis C, alcoholic hepatitis, or cirrhosis), regular users of alcohol, and patients at risk for chronic liver disease.1 Baseline laboratory tests should also be obtained in patients who are taking other potentially hepatotoxic medications for chronic medical conditions. Active hepatitis and end-stage liver disease are relative contraindications to the use of iso-niazid for treatment of latent tuberculosis. Routine laboratory monitoring (e.g., monthly AST or ALT measurement) during treatment of latent tuberculosis is recommended for persons whose baseline liver function test results are abnormal and for other patients at risk for hepatic disease (see above).
Table 6 CDC Guidelines for the Treatment of Latent Tuberculosis in Adults97
|
Drug |
Dosage and Duration (Maximum Dose) |
Rating/Evidence Level |
Comments |
|
|
HIV-Negative Patients |
HIV-Positive Patients* |
|||
|
Isoniazid |
5 mg/kg (300 mg) daily for 9 mo 900 mg twice weekly for 9 mo |
A/II B/II |
A/II B/II |
Preferred for adults and children; indicated for HIV-infected patients and those with fibrotic lesions on chest x-ray; in HIV-infected patients, may be given concurrently with antiretroviral treatment; DOT must be used with twice-weekly dosing |
|
Isoniazid |
5 mg/kg (300 mg) daily for 6 mo 900 mg twice weekly for 6 mo |
B/II B/II |
C/I C/I |
Alternative for HIV-negative patients; DOT must be used with twice-weekly dosing |
|
Rifampin |
10 mg/kg (600 mg) daily for 4 mo |
B/II |
B/III |
Alternative regimen; for contacts of patients with isoniazid-resis-tant, rifampin-susceptible TB; HIV-infected patients taking protease inhibitors or certain NNRTIs cannot take rifampin and must instead use rifabutin; the combination of rifampin and pyrazinamide is not recommended (D/II) for treatment of latent TB infection because of high risk of hepatotoxicity |
*Current data on interactions with HIV-related drugs are available at http://www.aidsinfo.nih.gov/guidelines.
CDC—Centers for Disease Control and Prevention
DOT—directly observed therapy
NNRTI—nonnucleoside reverse transcriptase inhibitor
Peripheral neuropathy is also a side effect of isoniazid. It is relatively uncommon, but the risk is increased in persons with a nutritional deficiency, as well as those with diabetes mellitus, HIV infection, renal failure, or alcoholism, and in women who are pregnant or breast-feeding. Pyridoxine (25 to 50 mg a day) is recommended for patients with these risk factors to help prevent neuropathy. Some clinicians routinely give supplemental pyri-doxine to all patients taking isoniazid.
Vaccines
BCG vaccination involves use of a live attenuated strain of M. bovis. The primary benefit of BCG administration appears to be in preventing disseminated tuberculosis and tuberculous meningitis in young children; variable efficacy has been reported in adults. BCG has had little effect on the global epidemiology of tuberculosis. BCG is not recommended for use in the United States but is widely used outside of the United States, especially in developing countries. Interestingly, in the tropics, administration of BCG has been associated with a decreased risk of lep-rosy.93 The vaccine can produce a positive tuberculin test in recipients, and because of the low incidence of new tuberculous infections in the United States, case finding and treatment of latent tuberculous infection are considered more efficient and effective strategies. Interpretation of a tuberculin skin test reaction is not changed for patients who have received BCG,1 because tuberculin sensitivity tends to wane considerably after BCG vaccination, and BCG is often given in areas where tuberculosis is endemic. Given that many BCG-vaccinated persons come from areas with a high prevalence of tuberculosis, it is important that those who have significant reactions to the tuberculin skin test be evaluated for the presence of disease and managed accordingly. Appropriate follow-up includes a careful medical history, a chest x-ray to rule out disease, and evaluation for treatment of latent tuberculosis. Newer diagnostic tests are needed for distinguishing between infection with M. tuberculosis and immunization with BCG.
Hospital-Based Prevention
Tuberculosis infection control efforts, utilizing a hierarchy of measures recommended by the CDC, have proved effective in preventing nosocomial transmission of tuberculosis.22,93,94 Atop this hierarchy are administrative controls, which include high suspicion for tuberculosis, careful screening of patients, precautions against airborne infection for patients suspected of having tuberculosis, and prompt diagnosis and initiation of effective therapy. Engineering controls and respiratory protection constitute the second and third tiers of the hierarchy of control measures. Guidelines for implementing a tuberculosis infection control program in health care facilities have been published.
