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Molecular Techniques in Mycobacterial Detection.

The decades-long decline in tuberculosis (TB) in the United States ended in the mid-1980s. Between 1985 and 1992, the number of TB cases reported to the Centers for Disease Control and Prevention (CDC) increased by about 20%, and during this same period, outbreaks of multidrug-resistant TB occurred.[1-6] Since 1992, as a result of increased federal funding, enhanced TB control activities, and heightened TB awareness, the incidence of TB has resumed its downward trend. However, TB remains a public health problem, and the efforts directed toward its control and eventual elimination must continue.

Delayed diagnosis was one of the problems identified during investigations of outbreaks of multidrug-resistant TB. One reason for the delay was prolonged time to identification of Mycobacterium tuberculosis complex (MTBC) in clinical specimens. To correct this problem, experts at the CDC made recommendations concerning mycobacterial test methods and turnaround times for results.[7] They advocate use of both liquid and solid media for mycobacterial culture and a rapid method for identification of MTBC (eg, nucleic acid probe or chromatographic technique) and reporting of these results within 21 days of specimen receipt in the laboratory. Achieving this 21-day goal for identification of MTBC represented a marked improvement over the situation existing in many laboratories in the mid- to late-1980s. However, waiting 21 days or longer for a definitive diagnosis of TB is not optimal.

Results of a smear, prepared from a concentrated sputum and stained for acid-fast bacilli (AFB), should be reported within 24 hours of specimen receipt.[7] The AFB smear, however, is neither sensitive nor specific for TB. Thus, there is a need for a diagnostic test to confirm or exclude TB more reliably than the AFB smear, but with a similar turnaround time. In response to .this demand, manufacturers have developed nucleic acid amplification (NAA) tests, which theoretically have the potential to fulfill these criteria.

To date, the Food and Drug Administration (FDA) has cleared 2 NAA tests for direct detection of MTBC in respiratory specimens, the Amplified Mycobacterium Tuberculosis Direct Test (MTD) (Gen-Probe, Inc, San Diego, Calif) and the AMPLICOR Mycobacterium tuberculosis Test (Roche Diagnostic Systems, Inc, Indianapolis, Ind). Initially, the FDA limited the use of these NAA tests to AFB smear-positive respiratory specimens from patients who had not received antituberculous drugs for 7 days or within the previous year. This decision was based on the recommendation of the Advisory Panel, which reviewed the data from the clinical trials conducted to evaluate these NAA tests. In general, both NAA tests performed comparably in these trials, where they were evaluated as a screening test (ie, testing all respiratory specimens submitted for detection of mycobacteria, regardless of the suspected risk of TB).[8] The performance of the NAA tests was excellent when testing AFB smear-positive specimens (sensitivity, 95-96%, specificity, 100%), but was much lower when testing smear-negative specimens (sensitivity, 48-53%, specificity, 96-99%, depending on the NAA test). As a consequence, in a population where the prevalence of MTBC in AFB smear-negative specimens is low, NAA testing of smear-negative specimens would yield many false-positive results relative to additional cases of TB detected.

For the most part, early evaluations of the NAA tests conducted outside of the clinical trials yielded similar results.[9-17] An exception was a retrospective evaluation of the AMPLICOR test in prison inmates.[18] The sensitivity of the test in that study, which included 569 sputum specimens from 187 inmates with suspected TB in prison infirmaries or clinics, was higher than in the clinical trials (92.8% overall, 95.8% for AFB smear-positive specimens, and 87.5% for smear-negative samples). Although the reason for the greater sensitivity is not known, it is possible that the performance of the assay as a diagnostic test in a well-defined population at high risk for TB is different from its performance as a screening test, which occurred in the clinical trials.

After the NAA tests were cleared by the FDA with the limitations described, Gen-Probe modified the MTD with the aim of increasing sensitivity and decreasing turnaround time. This enhanced MTD was approved by the FDA in September 1999 for testing respiratory specimens, regardless of the smear result. The clinical trial of the enhanced MTD was designed to evaluate the product as a diagnostic rather than a screening test. Patients with suspected TB (eg, hospitalized patients in airborne precautions) were prospectively enrolled at 7 sites, and at each site, a physician estimated the probability that the patient had TB.[19] In addition, 3 physician experts in diagnosis and management of TB reviewed cases that were not "proven TB" (defined as [is greater than] 80% chance of TB by the enrolling physician and [is greater than or equal to] 22 cultures positive for MTBC), or "TB excluded" (defined as [is less than] 10% likelihood of TB by enrolling physician and all cultures negative for MTBC). The combination of culture results and clinical diagnosis was considered the "gold standard" for TB. For the 339 patients enrolled, the overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively, of the enhanced MTD were 85.9%, 97.8%, 91.0%, and 96.3%. In patients infected with human immunodeficiency virus (HIV), these same values were 80.0%, 97.7%, 85.7%, and 96.6%. The overall sensitivity of culture (3 media combined) was 93.0%. For AFB smear, the sensitivity and specificity were 62.0% and 92.2% overall, and 40.0% and 85.2% in the HIV-infected patients.

In subsequent evaluations, the performance of the enhanced MTD has been better than in the clinical trial. Gamboa et al[20] tested 410 respiratory specimens by both the initial and enhanced MTD. Based on a combination of culture results and clinical data, the positivity rate for TB in this population was 23.2% (95 specimens from 65 patients). The overall sensitivity, specificity, PPV, and NPV, respectively, were 83%, 100%, 100%, and 96% for the initial MTD and 94.7%, 100%, 100%, and 98.4% for the enhanced version. Bergmann et al[21] evaluated the enhanced MTD in Texas prison inmates, testing 1004 respiratory specimens from 489 patients. In this population, 25 patients (5.1%) were diagnosed with TB, based on the results of culture, molecular fingerprinting of isolates in cases where laboratory cross-contamination was suspected, and clinical data. After resolution of discrepancies, the overall sensitivity, specificity, PPV, and NPV, respectively, of the enhanced MTD were 90.9%, 99.1%, 83.3%, and 99.6%, by patient. These same values were 100%, 100%, 100%, and 100% for AFB smear-positive patients and 83.3%, 99.1%, 71.4%, and 99.6% for smear-negative patients. Excluding the AFB smear-negative patient whose specimen contained inhibitory substances (because the MTD result truly cannot be interpreted), the sensitivity increased to 95.2% in all patients and to 90.9% in those with negative smears. Peirsimoni et al[22] evaluated the performance of the enhanced MTD in 273 pulmonary specimens (205 patients) and 184 extrapulmonary specimens (152 patients) at 4 sites in Italy. Ninety-eight specimens (21.4%) were determined to be from patients with TB, based on culture results plus a chart review by a TB expert. Excluding specimens from known TB patients receiving therapy, the overall sensitivity, specificity, PPV, and NPV of the MTD for diagnosis of pulmonary TB were 92.8%, 99.4%, 98.5%, and 97%, respectively. These same values were 100%, 100%, 100%, and 100%, respectively, in AFB smear-positive patients, and 85.3%, 99.4%, 96.7%, and 97.3%, respectively, in smear-negative patients. Data from these 3 studies support the use of the enhanced MTD as a rapid test for diagnosis of pulmonary TB in patients for whom there is a moderate to high suspicion of TB, regardless of the AFB smear result.

Both Gen-Probe and Roche NAA products have been used to test nonrespiratory specimens, although neither manufacturer states that their assay should be used for this purpose, nor do standardized methods for processing such specimens exist. The performance of both tests on nonrespiratory specimens has varied; in some studies, it was similar to the performance on respiratory specimens in the initial clinical trials, whereas in others, it was lower (Table).[20,22-25] One potential reason for this variation is the types of specimens evaluated. For example, pleural fluid contains substances that inhibit amplification with the MTD assay and therefore should not be tested by this method unless it is pretreated (ie, by extensive washing of the specimen) to remove inhibitors. Because neither NAA manufacturer makes that claim that nonrespiratory specimens can be tested with their assay, laboratories must validate either product in-house, including sufficient numbers of each type of specimen that are positive and negative for MTBC by culture.

[TABULAR DATA NOT REPRODUCIBLE IN ASCII]

Thorough evaluations of the use of commercial NAA tests with a single type of nonrespiratory specimen are limited. The few that have been published involve testing cerebrospinal fluid (CSF) for the diagnosis of meningeal TB. Lang et al[26] used the original MTD assay to test 84 CSF specimens, all of which were AFB smear-negative. Five specimens were MTBC culture-positive, and 19 were from patients with probable TB meningitis, based on strict clinical, radiographic, and laboratory criteria. Specimens were processed according to the manufacturer's recommendations for respiratory specimens, with modifications suggested by Pfyffer et al[27]: the volume of CSF tested was increased 10-fold, CSF was pretreated with a denaturation agent, and amplification time was increased. The sensitivity, specificity, PPV, and NPV of the MTD assay for diagnosis of meningeal TB were 33%, 100%, 100%, and 79%, respectively. Sensitivity was increased to 83% without compromising specificity by lowering the cutoff for a positive MTD result from [is greater than or equal to] 30000 relative light units (RLU) to [is greater than or equal to] 11 000 RLU. Bonington et al[28] tested 83 CSF specimens from 69 patients with the Roche AMPLICOR assay. Forty patients in their study were treated for TB meningitis, 8 of whom had definite meningeal TB, based on a positive CSF AFB smear and culture (3/8) alone or a positive CSF AFB smear alone (5/8). The diagnosis was considered probable in 10 patients, possible in 15, and uncertain in 7, based on predetermined clinical, radiographic, and laboratory criteria. Excluding 5 patients whose first CSF sample was obtained more than 9 days after antituberculous therapy was initiated, the sensitivity of the AMPLICOR test was 28.6% overall and 60.0% for those with definite or probable TB meningitis; specificity was 100% in all patient groups.

In addition to their intended use as tools for direct detection of MTBC in clinical specimens, the NAA tests may be used for rapid identification of MTBC in broth cultures of all specimen types (except blood, depending on the product and the methods of collecting and processing the specimen). In one evaluation, broth from 249 BACTEC 12B cultures with a growth index [is greater than or equal to] 20 was tested by the AMPLICOR MTB Test.[29] Of these, 142 contained mycobacteria, including 44 MTBC. Excluding blood specimens (collected in Isolator tubes [Wampole Laboratories, Cranbury, NJ], which contain sodium polyanetholsulfonate, a substance that inhibits the polymerase chain reaction), both the sensitivity and specificity of the NAA test were 100%. The time to identification of MTBC by AMPLICOR (mean, 16 days; range, 4 to 26 days) was significantly shorter than by nucleic acid probe (mean, 28 days; range 13 to 43 days) (P [is less than or equal to] .0001). In a comparable study, broth from signal-positive ESP II bottles was tested by the AMPLICOR MTB Test.[30] Of the 242 signal-positive cultures evaluated, 98 contained mycobacteria, of which 26 were MTBC. After resolution of discrepancies and exclusion of blood specimens, the sensitivity and specificity of the NAA test were 92.0% and 97.6%, respectively. The time to identification of MTBC was significantly shorter by AMPLICOR (mean, 19 days; range, 6 to 39 days) than by nucleic acid probe (mean, 25 days; range, 8 to 42 days) (P [is less than] .05). In similarly designed evaluations, the sensitivity and specificity, respectively, of the enhanced MTD were 100% and 100% when used to test 12B cultures of respiratory specimens with a growth index [is greater than or equal to] 50[31] and 94,1% and 100% with signal-positive ESP II cultures of nonrespiratory specimens (excluding blood, which was associated with readings in the equivocal range).[32] As with the nonrespiratory specimens, neither Roche Diagnostic Systems nor Gen-Probe claims that their product should be used to test broth cultures; therefore, laboratories must validate the method in-house.

The BDProbeTec ET system (BD Biosciences, Sparks, Md), although not presently available in the United States, offers a distinct advantage over the Gen-Probe and Roche assays: inclusion of an internal amplification control in the specimen well. Data from a preclinical evaluation of the BDProbeTec ET system for rapid diagnosis of pulmonary TB suggest that it has promise[33]; however, additional studies including more AFB smear-negative patients are needed. Of 600 evaluable respiratory specimens, 16 were culture-positive for MTBC; 12 were AFB smear-positive and 4 were smear negative. After initial testing, the overall sensitivity, specificity, PPV, and NPV of the BDProbeTec ET were 87.5%, 99.0%, 70.0%, and 99.7%, respectively. These same values were 100%, 100%, 100%, and 100% for the 23 smear-positive specimens and 50.0%, 99.0%, 25.0%, and 99.6% for the smear-negative samples.

An issue with regard to the use of commercial NAA tests that has yet to be systematically evaluated is cost-effectiveness. Currently, NAA tests cannot replace traditional methods for diagnosis and management of TB.[34] The AFB smear is used to assess infectiousness and the need for airborne precautions. Culture is essential for drug susceptibility testing, for identification to the species level, and if indicated, strain identification. Thus, the NAA test is an additional test associated with added costs, predominantly laboratory expenses for reagents and technical time. However, the increase in laboratory costs may be offset by savings elsewhere in the hospital or in the Public Health Department and/or by improved patient care.

Data concerning the impact of the MTBC NAA tests on patient outcome are anecdotal, rather than based on results of well-designed clinical trials. In general, the influence of these NAA tests on patient outcome varies based on the AFB smear result. In AFB smear-positive patients, antituberculous therapy is generally begun after the smear result is reported. For this reason, the NAA tests are most beneficial in smear-positive patient populations in which a reasonable proportion of the specimens contains a nontuberculous mycobacterium. In smear-positive patients, NAA testing has the greatest impact on resources associated with infection control practices but can also influence patient management. For smear-positive patients whose specimens are NAA-negative and do not contain substances that inhibit amplification, initiation of a contact investigation is unnecessary. Hospitalized smear-positive patients could be released from airborne precautions (for which room charges typically are higher than for regular rooms), based on a negative NAA result (provided that the sample contains no inhibitory substances), rather than waiting for 3 consecutive negative AFB smears, as is the current CDC recommendation. With regard to patient management, a negative NAA result on a smear-positive specimen that contains no inhibitors allows modification of therapy, directing it toward the most frequently encountered nontuberculous mycobacteria. However, if the smear-positive sample with a negative NAA result contains inhibitors, a second specimen must be evaluated before concluding that the patient does not have TB.

Patients who will benefit most from the NAA test results are those whose respiratory specimens are AFB smear negative. In smear-negative patients for whom the suspicion of TB is high, the NAA test can confirm or exclude the diagnosis much sooner in the course of their illness than is possible based on results of traditional smear and culture. Earlier diagnosis allows more rapid initiation of antituberculous therapy. This benefits the ill patient and his/her close contacts, because although smear-negative patients are less infectious than those who are smear-positive, transmission of TB from a smear-negative source can occur.[35] In addition to beginning therapy more quickly, NAA testing of smear-negative specimens could, in some cases, eliminate the need for invasive diagnostic procedures, which are both costly and pose an added risk to the patient, and shorten the length of stay for hospitalized patients.

Data from a retrospective evaluation of the AMPLICOR MTB assay (as a screening tool, testing 956 respiratory specimens from 502 patients) conducted at our institution suggest that NAA tests may be particularly useful in patients infected with HIV. In that study, performance characteristics of the NAA test were similar to those of the initial clinical trials[9]; in smear-negative patients, the sensitivity was 40% and the specificity was 99.5%. To examine the potential impact of the NAA test results on clinical outcome of AFB smear-negative patients, we reviewed medical records of those with specimens positive for MTBC by NAA and culture. Four of these 7 patients had recently been diagnosed with TB and were receiving antituberculous therapy; therefore, based on current data, they would have been excluded from analysis. The other 3 patients were HIV-positive and had noncavitary pulmonary and extrapulmonary TB, although the diagnosis had not been made at the time, a positive NAA test result could have been available. Two of these 3 patients were hospitalized, and for both, antituberculous therapy would have been started 1 week earlier on the basis of a positive NAA result. In both patients, needle aspiration of a lymph node was required for diagnosis and probably would have been avoided had the NAA test result been available. One patient died from disseminated TB 3 days after appropriate therapy was begun; but the effect of an earlier diagnosis on the outcome cannot be determined. In the third patient, who was managed as an outpatient, antituberculous therapy could have been initiated 3 weeks earlier had the positive NAA test result been known.

In our evaluation of the enhanced MTD in prison inmates, the clinical course of 2 AFB smear-negative patients, both HIV-positive, could have been altered based on the positive NAA test result.[21] For both patients, the hospital stay would have been shortened (by at least 7 days in one case, and 14 days in the other), and one or more invasive procedures probably would have been avoided. In the first patient, who had a 4-month history of fever, anorexia, weakness, and weight loss and a chest radiograph "consistent with miliary tuberculosis," anti-tuberculous therapy was begun after 2 sputum specimens were submitted for mycobacterial smear and culture. The second sputum was MTD-positive and grew MTBC 1 month later. Because of the desire for a definitive diagnosis, video-assisted thoracotomy and lung biopsy were performed 4 days after the second sputum was collected. The tissue obtained was AFB smear-negative; MTBC grew in the culture 36 days later. The second patient had fever, malaise, and night sweats; chest radiograph showed a right upper-lobe infiltrate, a loculated right pleural effusion, and calcified granulomas throughout both lung fields. Two sputum specimens for mycobacterial smear and culture were collected; the first was MTD-positive and 22 days later grew MTBC, and the second was negative for MTBC by both MTD and culture. A chest tube was placed the day after the first sputum specimen was obtained. Pleural TB was considered the most likely diagnosis, but physicians caring for this patient preferred not to begin antituberculous therapy until a diagnostic specimen was procured. Thoracotomy with pleural biopsy was performed 2 weeks after the first sputum specimen was obtained (which was MTD positive). Histopathologic examination of the pleural tissue showed caseating granulomas, and 4-drug therapy was begun.

In summary, it appears that the predominant effect of the MTBC NAA tests in AFB smear-positive patients is on public health and hospital infection-control practices. Patient management is affected only in those cases in which the NAA test is negative and inhibitory substances are not detected. Patients with the greatest potential to benefit from the NAA tests are those who are AFB smear-negative. In these patients, the NAA test may result in earlier diagnosis and initiation of therapy, earlier discharge from the hospital, and/or fewer invasive procedures (eg, bronchoscopy, needle aspiration, and lung biopsy), radiographic studies, and/or laboratory tests.

References

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[2.] Centers for Disease Control and Prevention. Nosocomial transmission of multidrug-resistant tuberculosis to health-care workers and HW-infected patients in an urban hospital--Florida. MMWR Morb Mortal Wkly Rep. 1991;40:718-722.

[3.] Centers for Disease Control and Prevention. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons--Florida and New York, 1988-1991. MMWR Morb Mortal Wkly Rep. 1991 ;40:585-591.

[4.] Centers for Disease Control and Prevention. Transmission of multidrug-resistant tuberculosis among immunocomprornised persons in a correctional system--New York. MMWR Morb Mortal Wkly Rep. 1992;41:507-509.

[5.] Fischl MA, Daikos GL, Utamchandani RB, et al. Clinical presentation and outcome of patients with HIV infection and tuberculosis caused by multiple-drugresistant bacilli. Ann Intern Med. 1992;117:184-190.

[6.] Edlin BR, Tokars JI, Grieco MH, et al. An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome. N Engl J Med. 1992 ;326:1414-1521.

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[8.] American Thoracic Society Workshop. Rapid diagnostic tests for tuberculosis. What is the appropriate use? Am J Respir Crit Care Med. 1997;155:1804-1814.

[9.] Bergmann JS, Woods GL. Clinical evaluation of the Roche Amplicor PCR Mycobacteriurn tuberculosis test for detection of M. tuberculosis in respiratory specimens. J Clin Microbiol. 1996;34:1083-1085.

[10.] Moore DF, Curry JI. Detection and identification of Mycobacterium tuberculosis directly from sputum sediments by Amplicor PCR. J Clin MicrobioL 1995; 33:2686-2691.

[11.] Abe C, Hirano K, Wada M, et al. Detection of Mycobacterium tuberculosis in clinical specimens by polymerase chain reaction and Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test. J Clin Microbiol. 1993;31:3270-3274.

[12.] Bodmer T, Mockl E, Michlemann K, Matter L. Improved performance of Gen-Probe Amplified Mycobacterium Direct Test when 500 instead of 50 microliters of decontaminated sediment is used. J Clin Microbiol. 1996;34:222-223.

[13.] Bodmer T, Gunner A, Schopfer K, Matter L. Screening of respiratory tract specimens for .the presence of Mycobacterium tuberculosis by using the GenProbe Amplified MTD test. J Clin Microbiol. 1994;32:1483-1487.

[14.] Bradley SR Reed SL, Catanzaro A. Clinical efficacy of the Amplified Mycobacterium Tuberculosis Direct Test for the diagnosis of pulmonary tuberculosis. Am J Respir Crit Care Med. 1996; 153:1606-1610.

[15.] Daloviso JR, Montenegro-James S, Kennedy SA, et al. Comparison of the Amplified Mycobacterium Tuberculosis (MTB) Direct Test, Amplicor MTB PCR, and IS6110-PCR for detection of MTB in respiratory specimens. Clin Infect Dis. 1996;23:1099-1106.

[16.] Beavis KG, Lichty MB, Jungkind DL, Giger O. Evaluation of AMPLICOR PCR for direct detection of Mycobacterium tuberculosis from sputum specimens. J Clin MicrobioL 1995;33:2582-2586.

[17.] D'Amato RF, Wallman AA, Hochstein LH, et al. Rapid diagnosis of pulmonary tuberculosis by using Roche AMPLICOR Mycobacterium tuberculosis test. J Clin Microbiol. 1995;34:1832-1834.

[18.] Smith MB, Bergmann JS, Harris SL, Woods GL. Evaluation of the Roche [Amplicor.sup.(tm)] MTB assay for the detection of Mycobacterium tuberculosis in sputum specimens from prison inmates. Diagn Microbiol Infect Dis. 1997;27:113-116.

[19.] Jonas V, Acedo M, Clarridge JE, et al. A multi-center evaluation of MTD and culture compared to clinical diagnosis. In: Abstracts of the 98th General Meeting of the American Society for Microbiology; May 17-21, 1998; Atlanta, Ga. Abstract L-31.

[20.] Gamboa F, Fernandez G, Padilla E, et al. Comparative evaluation of initial and new versions of the Gen-Probe Amplified MycobacteriumTuberculosis Direct Test for direct detection of Mycobacterium tuberculosis in respiratory and nonrespiratory specimens. J Clin MicrobioL 1998;36:684-689.

[21.] Bergmann JS, Yuoh G, Fish G, Woods GL. Clinical evaluation of the enhanced Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for rapid diagnosis of tuberculosis in prison inmates. J Clin Microbiol. 1999;37:1419-1425.

[22.] Piersimoni C, Callegaro A, Scarparo C, et al. Comparative evaluation of the new Gen-Probe Mycobacteriurn tuberculosis Amplified Direct Test and the semiautomated Abbott LCx Mycobacterium tuberculosis assay for direct detection of Mycobacteriurn tuberculosis complex in respiratory and extrapulmonary specimens. J Clin Microbiol. 1998;36:3601-3604.

[23.] Chedore P, Jamieson FB. Routine use of the Gen-Probe MTD2 amplification test for detection of Mycobacteriurn tuberculosis in clinical specimens in a large public health mycobacteriology laboratory. Diagn Microbiol Infect Dis. 1999:35:185-191.

[24.] Reischl U, Lehn N, Wolf H, Naumann L. Clinical evaluation of the automated COBAS AMPLICOR MTB assay for testing respiratory and nonrespiratory specimens. J Clin MicrobioL 1998;36:2853-2860.

[25.] Tortoli E, Tronci M, Tose CP, et al. Multicenter evaluation of two commercial amplification kits (Amplicor, Roche and LCs, Abbott) for direct detection of Mycobacterium tuberculosis in pulmonary and extrapulmonary specimens. Diagn Microbiol Infect Dis. 1999;33:173-179.

[26.] Lang AM, Feris-lglesias J, Pena C, et al. Clinical evaluation of the GenProbe Amplified Direct Test for detection of Mycobacterium tuberculosis complex organisms in cerebrospinal fluid. J Clin Microbiol. 1998;36:2191-2194.

[27.] Pfyffer GE, Kissling P, Jahn EMI, Wetscher HM, Salfinger M, Weber R. Diagnostic performance of Amplified Mycobacterium tuberculosis Direct Test with cerebrospinal fluid, other nonrespiratory, and respiratory specimens. J Clin Microbiol. 1996;34:834-841.

[28.] Bonington A, Strang JIS, Klapper PE, et al. Use of Roche AMPLICOR Mycobacterium tuberculosis PCR in early diagnosis of tuberculous meningitis. J Clin Microbiol. 1998;36:1251-1254.

[29.] Smith MB, Bergmann JS, Woods GL. Detection of Mycobacterium tuberculosis in Bactec 12B broth cultures by the Roche Amplicor PCR assay. J Clin Microbiol. 1997;35:900-902.

[30.] Hernandez A, Bergmann JS, Woods GL. Amplicor[TM] MTB polymerase chain reaction test for identification of Mycobacterium tuberculosis in positive Difco ESP II broth cultures. Diagn Microbiol Infect Dis. 1997;27:17-20.

[31.] Bergmann JS, Woods GL. Enhanced Amplified Mycobacterium Tuberculosis Direct Test for detection of Mycobacterium tuberculosis complex in positive BACTEC 12B broth cultures of respiratory specimens. J Clin Microbiol. 1999;37: 2099-2101.

[32.] Bergmann JS, Woods GL. Enhanced Amplified Mycobacterium Tuberculosis Direct Test for detection of Mycobacterium tuberculosis complex in positive ESP II broth cultures of nortrespiratory specimens. Diagn Microbiol Infect Dis. 1999;35:245-248.

[33.] Bergmann JS, Keating WE, Woods GL. Clinical evaluation of the BDProbeTec ET system for rapid detection of Mycobacterium tuberculosis. J Clin Microbiol. 2000;38:863-865.

[34.] Centers for Disease Control and Prevention. Nucleic acid amplification tests for tuberculosis. MMWR Morbid Mortal Wkly Rep. 1996;45:950-951.

[35.] Sepkowitz KA. How contagious is tuberculosis? Clin Infect Dis. 1996;23: 954-962.

Accepte for publication August 11, 2000.

From the Deaprtment of Pathology, University of Texas Medical Branch-Galveston, Tex.

Presented at the Ninth Annual William Beauont Hospital DNA Technology Symposium, DNA Technology in the Clinical Laboratory, Royal Oak, Mich, April 13-15, 2000.

Dr Woods is a speaker on the Gen-Probe speaker's bureau.

Reprints: Gail L. Woods, MD, Department of Pathology, 301 University Blvd, University of Texas Medical Branch-Galveston, Galveston, TX 77555-0740 (e-mail: gwoos@utmb.edu).
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Author:Woods, Gail L.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jan 1, 2001
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