Roman Kozlov, MD, DSc, Professor, Director of Institute of Antimicrobial Chemotherapy, Smolensk State Medical Academy, Smolensk, Russian Federation
Patient A is a 30-year-old male who was admitted to the hospital from home after 1 week of cough, profuse nocturnal sweating, loss of appetite and hyposomnia. He was seen by an emergency room physician who noted signs of depression. The patient has a history of intravenous drug abuse and hepatitis B.
|Heart Rate||110 beats per minute
|Respiratory Rate||20 breaths per minute
98% on room air
||WBC: 9.48 x 109/L
||Hgb: 11.4 g/dL (114 g/L)
|Platelets: 149 109/L||HIV test: Negative
||Young male, looks older then stated age
|HEENT||Depressed, pupils equally round and reactive to light and accommodation
||Unilateral (left side) crepitation
Regular rate and rhythm, no murmurs, rubs, or gallops
|Skin||Excoriated, otherwise normal|
|Neuro||Slightly altered, but baseline|
||Chest X-ray showed infiltrate in the middle of left lung with diameter of 1.7 cm with signs of cavitation.
||No growth at 5 days
|4+ squamous epithelial cells,
1+ segmented neutrophils, no organisms
|AFS (acid fast stain)
||No growth at 48 hrs
|MGIT (mycobacteria growth indicator tube)||Negative|
Infiltrative TB of left lung with cavitation without MTB shedding.
Patient A was originally administered isoniazid, rifampin, pyrazinamide, and ethambutol for 7 days per week for 8 weeks, followed by isoniazid and rifampin 7 days per week for 24 weeks. After two months he returned to the hospital, concerned that he had been “coughing up blood” over the previous 3 days. In addition to hemoptysis, he revealed that, since his previous visit, he had continued to feel malaise, was continuing to lose weight, and had been experiencing night sweats.
The emergency room physician immediately transferred the patient for isolation in a local hospital. A repeat chest radiograph revealed progressive bilateral fibronodular disease with a “miliary” pattern. The patient was given a 20-month regimen of levofloxacin, kanamycin, cycloserine, pyrazinamide and prothionamide. Following completion of therapy, closure of the destruction cavity was found with local pneumofibrosis.
With 1.3 million deaths annually, tuberculosis remains one of the leading causes of mortality worldwide. The emergence of multidrug- and extensive drug resistance (MDR-TB and XDR-TB, respectively) is a major public health problem that threatens progress made in TB care and control. Drug resistance arises due to improper use of antibiotics in drug-susceptible TB patients, which includes administration of inappropriate treatment regimens and failure to ensure that patients complete the whole treatment course.
Essentially, drug resistance arises in geographic locales with weak TB control programs. A patient who develops active disease with a MDR-TB strain can transmit this form of TB to other individuals.1
Rapid diagnosis and proper disease control are crucial for preventing organism shedding and infection of new individuals, for curbing additional drug-resistant TB (as occurred in this clinical case) and for saving the lives of MDR-TB patients who have a short life expectancy if not treated properly. Therefore, use of the most rapid methods available for culture and identification of mycobacterium tuberculosis complex (MTBC) is advocated.
Traditional solid media alone can require 4-8 weeks for detection of growth. Thus, culture methods that utilize both a liquid and a solid medium are now recommended and should allow detection within as little as 10-14 days, and up to as much as 21 days from receipt of specimen. Although liquid systems are more sensitive and may increase the case yield by as much as 10%, they are also more prone to contamination.2-3
Fortunately, major advances in rapid diagnostics have revolutionized TB diagnosis in the past few years. In the particular worst-case scenario described here, no confirmation of TB was achieved through the customary sputum smear. The classic solid medium and newer liquid culture assays (typically incubated for 14 days) were negative at 48 hours—at which time the patient was treated on the suspicion of TB. Presented with an especially difficult conundrum, the physician and patient could have benefitted from the availability of newer rapid TB diagnostics, some of which are independent of sputum smear and culture results.
From multiple, commercially available nucleic acid amplification tests (NAAT), a new fully automated platform, endorsed by WHO in 2010, permits rapid detection (<2 hours) outside of the conventional laboratory and requires only minimal healthcare skills.4 The test also detects MDR-TB and TB cases complicated by HIV, which are more difficult to diagnose. NAAT identifies mutations in the rpoBgene which code for resistance to rifamycin and, because this most often coincides with isoniazid resistance, serves as a surrogate marker for MDR.5
A second-generation NAAT platform now enables detection of second-line drug resistance, i.e., fluoroquinolone and aminoglycosides/capreomycin.6
An alternative diagnostic (available outside the US) utilizes unprocessed urine to detect the LAM antigen (lipoarabinomannan)—an outer mycobacterial cell wall component that is shed into, and cleared by, the kidney.7
This point-of-care test, which requires less than 30 min, is particularly beneficial for detecting sputum smear-negative patients and for early rule-in of TB in patients who are co-infected with HIV, but does not indicate the presence of an impending resistance problem, as was eventually encountered in this case scenario. In patients with smear-positive sputum, rapid detection of MDR cases can also be achieved through line-probe assays, which are based on reverse hybridization technology.8
With the emergence of these and other user-friendly detection platforms,9 TB diagnosis is making significant strides forward. Nonetheless, it is unlikely that a single test will serve all clinical settings; thus, context-specific tests will remain necessary.
Treatment of MDR-TB
In general, treatment of MDR-TB is extended to 20 months and an individualized treatment regimen often is required. The principles of management include use of aggressive regimens with at least five drugs that are likely to be effective.10 Fluoroquinolones play a key role in resistant TB, and the later generation fluoroquinolones (e.g. levofloxacin or moxifloxacin) are considered to be the most effective ones.11-12 Use of an injectable agent, such as capreomycin or an aminoglycoside (e.g.kanamycin), have been shown to predict culture conversion and survival.13
However, resistance to aminoglycosides is becoming increasingly common. The regimens may be reinforced by pyrazinamide and ethambutol, as these contribute by increasing the regimen’s activity or by preventing resistance to more active agents.
The current WHO guidelines on treatment regimens for MDR-TB recommend an intensive phase of 8 months and total treatment duration of 20 months for most patients.14 The guidelines were developed following the GRADE process for guideline development that has been adopted by WHO, and recommendations were based on an analysis of more than 9,000 cases treated in observational studies.
The results from an observational study in Bangladesh showed much better rates of treatment success using regimens having duration of 12 months or less compared with those usually achieved when the longer regimens are used.15 However, there is much less evidence on the effectiveness and safety of these so-called “short-regimens” compared with regimens lasting 20 months.16
- World Health Organization (WHO), Multidrug-resistant Tuberculosis (MDR-TB) [Online] Accessed: 03 June 2014. Available at: http://www.who.int/tb/challenges/mdr/en/
- Tenover FC, Crawford JT, Huebner RE, et al. (1993) The resurgence of tuberculosis: is your laboratory ready? J Clin Microbiol 31:767–770.
- WHO, TB diagnostics and laboratory strengthening - WHO policy. The use of liquid medium for culture and DST, 2007. [Online] Accessed: 03 June 2014. Available at: http://www.who.int/tb/laboratory/policy_liquid_medium_for_culture_dst/en/index.html?utm_source=feedblitz&utm_medium=FeedBlitzEmail&utm_content=565123&utm_campaign=Twelve-hourly_%272011-08-10%2000%3A00%3A00%27
- WHO (2010) WHO endorses new rapid tuberculosis test. [Online] Accessed: 03 June 2014. Available at: http://www.who.int/mediacentre/news/releases/2010/tb_test_20101208/en/
- Boehme, C.C., Nabeta, P., Hilleman, D. et al. (2010) Rapid molecular detection of tuberculosis and rifampin resistance. New Eng J Med. 363:1005-15.
- Miotto, P., Cabibbe, A.M., Manteganai, P. et al. (2012) GenoType MTBDRsl performance on clinical samples with diverse genetic background. Eur Respir J. 40:690-8.
- Lawn, S.D., Kerkhoff, A.D., Vogt, M., Wood, R. (2008) Diagnostic accuracy of a low-cost urine antigen, point of care screening assay for HIV-associated pulmonary tuberculosis before antiretroviral therapy: a descriptive study. Lancet Infect Dis. 2012 1293): 201-97.
- Ling, D.I., Zwerling, A., Pai, M. (2008) GenoType MTBDR assays for the diagnosis of multidrug-resistant tuberculosis: a meta-analysis. Eur Respir J. 32:1165-74.
- Dheda, K,. Ruhwald, M., Theron, G. et al. (2013) Point-of-care diagnosis of tuberculosis: Past, present and future. Respirol. 18:217-232.
- Mitnick, C.D., Shin, S.S., Seung, K.J. et al. (2008) Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med. 359:563–74.
- Blumberg, H.M., Burman, W.J., Chaisson, R.E. et al. (2003) American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med. 167:603–662.
- Caminero, J.A., Sotgiu, G., Zumla, A., Migliori, G.B. (2010) Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis. 10:621–629.
- Frieden, T.R., Sherman, L.F., Maw, K.L. et al. (1996) A multi-institutional outbreak of highly drug-resistant tuberculosis: Epidemiology and clinical outcomes. JAMA. 276:1229–35.
- WHO (2011) Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 Update.
- Van Deun, A., Maug, A.K., Salim, M.A. et al. (2010) Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 182(5): 684–92.
- WHO. The use of short regimens for treatment of multidrug-resistant tuberculosis. [Online] Accessed: 03 June 2014. Available at: http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/short-regimens/en/
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