Patient

Background:
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.

Radiology: Chest X-ray showed infiltrate in the middle of left lung with diameter of 1.7 cm
with signs of cavitation.

Diagnosis
Infiltrative TB of left lung with cavitation without MTB shedding.
Treatment
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.
Discussion
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 XDRTB, 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.
TB Diagnostics
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.
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 hoursat 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. 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.
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.
With the emergence of these and other user-friendly detection platforms, 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. 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. Use of an injectable agent, such
as capreomycin or an aminoglycoside (e.g.kanamycin), have been shown to predict culture
conversion and survival. However, resistance to aminoglycosides is becoming increasingly
common. The regimens may be reinforced by pyrazinamide and ethambutol, as these
contribute by increasing the regimens 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.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. However, there is much less evidence on the effectiveness and safety of
these so-called short-regimens compared with regimens lasting 20 months.