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Tuberculosis continued
First-line drugs
isoniazid (INH), rifampin (RIF), pyrazinamide (PZA),
and ethambutol (EMB) are used together in initial treatment
INH is given orally once/day, has good tissue penetration (including
CSF), and is highly bactericidal. It remains the single most useful and
least expensive drug for TB treatment. INH resistant about 10% .INH is
safe during pregnancy.
Adverse reactions include:
1- General: rash, fever, and, rarely, anemia and agranulocytosis.
2- Liver disease INH causes asymptomatic, transient
aminotransferase elevations & clinical (usually reversible)
hepatitis occurs more often in patients> 35 yr, alcoholics,
postpartum women, and patients with chronic liver disease.
3- Peripheral neuropathy can result from INH-induced pyridoxine
(vitamin B
6
) deficiency, most likely in pregnant or breastfeeding
women, undernourished patients, patients with diabetes mellitus or
HIV infection, alcoholics, patients with cancer or uremia, and the
elderly. A daily dose of pyridoxine 25 to 50 mg can prevent this
complication.
RIF it is an oral bactericidal, is well-absorbed, penetrates well into
cells and CSF, and acts rapidly. It also eliminates dormant organisms
in macrophages or caseous lesions that can cause late relapse. Thus,
RIF should be used throughout the course of therapy. Adverse effects
include cholestatic jaundice (rare), fever, thrombocytopenia, renal
failure & drugs interaction. RIF is safe during pregnancy.
PZA is an oral bactericidal drug. When used during the intensive
initial 2 mo of treatment, it shortens the duration of therapy to 6 mo
and prevents development of resistance to RIF.
Its major adverse effects are GI upset and hepatitis. It often causes
hyperuricemia, which is generally mild and only rarely induces gout.
PZA safety in pregnancy has not been confirmed.
EMB is given orally and is the best tolerated of the first-line drugs. Its
main toxicity is optic neuritis, which is more common at higher doses
and with impaired renal function. Patients with optic neuritis present
initially with an inability to distinguish blue from green, followed by
impairment of visual acuity which is reversible if detected early,
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patients should have a baseline test of visual acuity and color vision
and should be questioned monthly regarding their vision. Caution is
warranted if communication is limited by language and cultural
barriers, in young children who cannot read eye charts or unconscious
patients ,when these symptoms develop it should be stopped &
another drug is substituted . EMB can be used safely during
pregnancy.
Second-line drugs
Other antibiotics are active against TB and are used primarily when
patients have drug-resistant TB (DR-TB) or do not tolerate one of the
first-line drugs.
Group 1 aminoglycosides & related drugs: for parenteral use only
Streptomycin is very effective and bactericidal. Resistance is still
relatively uncommon.dose-related adverse effects include renal
tubular damage, vestibular damage, and ototoxicity. In patients with
renal insufficiency, dosing frequency should be reduced
Streptomycin is contraindicated during pregnancy because it may
cause vestibular toxicity and ototoxicity in the fetus.
Kanamycin and amikacin Their renal and neural toxicities are
similar to those of streptomycin. Kanamycin is the most widely used
injectable for MDR-TB.
Capreomycin, a related non-aminoglycoside parenteral bactericidal
drug, has dosage, effectiveness, and adverse effects similar to those of
aminoglycosides.
Group 2 fluoroquinolones as levofloxacin & moxifloxacin are the
most active and safest TB drugs after INH and RIF.
Group 3 rifamycins derivatives as:
•
Rifabutin is used for patients taking drugs (particularly
antiretroviral drugs) that have unacceptable interactions with RIF.
Its action is similar to RIF, rifabutin has been associated with
uveitis.
•
Rifapentine is used in one dose/wk regimens but is not used in
children or patients with HIV (because of unacceptable treatment
failure rates) or extrapulmonary TB.
Group 4 Other 2nd-line drugs include ethionamide, cycloserine, and
para-aminosalicylic acid (PAS). These drugs are less effective and
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more toxic than the first-line drugs but are essential in treatment of
MDR-TB.
Group 5 new drugs Bedaquiline, delamanid, and sutezolid are new
anti-TB drugs that are typically reserved for highly resistant TB
(precise indications are not yet fully defined) or for patients who
cannot tolerate other 2nd-line drugs.
Treatment of LTBI
Treatment is indicated principally for
•
documented TST conversion within the previous 2 yr.
•
CXR changes consistent with old TB but no evidence of active TB
•
People who, if infected, are at high risk of developing active TB
(eg, HIV-infected & drug-induced immunosuppression)
•
Any child < 5 yr who is a close contact of a person with smear-
positive TB, regardless of whether there was TST conversion
Treatment generally consists of:
1- INH unless resistance is suspected , 300 mg /day
(10mg/kg)for 9 mo
2- RIF 600 mg /day for 6 mo.:if INH resistance or intolerance.
3- combination of INH & RIF for 3 months if no time
available but higher side effects.
Prevention:General preventive measures as staying at home, avoiding
visitors, covering coughs with a tissue or hand are followed.
Vaccination
The BCG vaccine is made from an attenuated strain of M. bovis . BCG
clearly reduces the rate of extrathoracic TB in children, especially TB
meningitis, and may prevent TB infection.
Although BCG vaccination often converts the TST, the reaction is
usually smaller than the response to natural TB infection, and it
usually wanes more quickly. IGRAs are not influenced by BCG
vaccination and should ideally be used in patients who have received
BCG to be sure that the TST response is due to infection with M.
tuberculosis.
Special Populations
Children
Children infected with tuberculosis are more likely than adults to
develop active disease, extrapulmonary disease mostly Lymphadenitis
and meninges.
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The elderly
Reactivated disease can involve any organ, but particularly the lungs,
reactivation may cause few symptoms and can be overlooked for
weeks or months, delaying appropriate evaluation
INH causes hepatotoxicity in up to 4 to 5% of patients > 65 yr
compared with < 1% of patients < 65 yr.
HIV-infected patients
TST sensitivity is generally poor here due to anergy.
Dissemination of bacilli during primary infection is usually much
more extensive in patients with HIV infection. Consequently, a larger
proportion of TB is extra-pulmonary & the NTM infection is common
especially if CD4 <50. Tuberculomas (mass lesions in the lungs or
CNS due to TB) are more common and more destructive. HIV
infection reduces both inflammatory reaction and cavitation of
pulmonary lesions. As a result, a chest x-ray may show a nonspecific
pneumonia or even be normal. Smear-negative TB is more common
when HIV co-infection is present.
Treatment of TB should started 2 weeks before starting HAART & the
courses as classical TB unless DR TB is there .
TB in pregnancy
No harmful effect of TB on pregnancy & vise verse
Treatment should avoid PYZ * STP & include RIF,INH&E MB for 9
months .
TB & hepatitis
In hepatic patient caution is needed as TB &anti-TB can injure the
liver.
Anti-TB induced hepatitis : manifested as malaise ,N&V with clinical
jaundice + 3 folds elevation of liver enzymes or asymptomatic 5 folds
elevation of enzymes, the management:
4- Stop all drugs if the patients toxic give streptomycin + one
from the 2
nd
line , if not toxic keep him without treatment
5- Do investigations to exclude accidental cause
6- After full recovery start gradual half dose re-introduction of
RIF then EMB then INH
7- Not to re-introduce PYZ as it can be fatal
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TB lymphadenitis
Tuberculous lymphadenitis typically involves the lymph nodes in the
posterior cervical and supraclavicular chains or Mediastinal lymph
nodes as a part of primary pulmonary diseases
tuberculous lymphadenitis is characterized by progressive swelling of
the affected nodes to become inflamed matted together and tender
with +ve fluctuation & the overlying skin may break down, resulting
in a draining fistula. treatment with classical anti-TB plus surgical
excision the treatment should continue for 6 months regardless the
nodes increased or disappeared
Miliary TB
miliary TB occurs when a tuberculous lesion erodes into a blood
vessel, disseminating millions of tubercle bacilli into the bloodstream
and throughout the body. The lungs and bone marrow are most often
affected, but any site may be involved. Miliary TB is most common
among children < 4 yr, immunocompromised people, and the elderly.
Symptoms include fever, chills, weakness, malaise, and often
progressive dyspnea. Intermittent dissemination of tubercle bacilli
may lead to a prolonged FUO. Bone marrow involvement may cause
anemia, thrombocytopenia, or a leukemoid reaction.
The work up as pulmonary TB but If all tests are negative and miliary
TB is still a concern, biopsies of the bone marrow and the liver are
done. If TB is highly suspected ,treatment should usually proceed
despite inability to demonstrate TB organisms.
CXR in miliary TB shows thousands of 2-3mm interstitial nodules
evenly distributed through both lungs. Treatment as standard TB
pneumonia in immune-compromised patients
caused by unusual pathogens or by the same pathogens as those that
cause community-acquired pneumonia
clinical presentations
Symptoms and signs are same but here the Symptoms may be mild or
absent as no fever especially in neutropenic patients . In some patients
they show non-responding pneumonia or asymptomatic changes in
CXR .
Diagnosis
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Chest x-ray: may be normal
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Assessment of oxygenation
•
Induction or bronchoscopy to obtain sputum
•
Blood cultures
Treatment
1- Broad-spectrum antimicrobial therapy
that are effective against
gram-negative bacilli, Staphylococcus aureus, and anaerobes are
needed, If patients with conditions other than HIV infection do not
improve with 5 days of antibiotic therapy, antifungal therapy is
frequently added empirically.
2- therapies to enhance immune system function: as reduced or stop
the drugs or give CSF for neutropenic patients or IG to IG
deficient patients.
Prevention: as vaccination, post-exposure Ig or chemoprophylaxis
P. jirovecii pneumonia
is a ubiquitous organism transmitted by aerosol route and causes no
disease in immunocompetent patients, risk factor for P.j pneumonia:
•
Patients with HIV infection and CD4+ counts < 200/μL
•
Organ transplant recipients
•
Patients with hematologic cancers
•
Patients taking corticosteroids
Most patients have fever& dry cough evolves over several days to weeks(
in HIV infection less flared features) with dyspnea mostly on exercise.
Diagnosis
Chest x-ray characteristically shows diffuse, bilateral perihilar infiltrates,
but can be normal x-rays.
Histopathologic demonstration of the organism is needed for
confirmation of the diagnosis. Methenamine silver, Giemsa, Wright-
Giemsa, modified Grocott, Weigert-Gram, or monoclonal antibody stain
is used. Sputum specimens are usually obtained by induced sputum or
bronchoscopy.
Treatment
•
Trimethoprim/sulfamethoxazole
•
Corticosteroids if Pao
2
< 70 mm Hg
Treatment is with trimethoprim/sulfamethoxazole (TMP/SMX) 4 to 5
mg/kg IV or po tid for 14 to 21 days. Treatment can be started before
diagnosis is confirmed because P. jirovecii cysts persist in the lungs for
weeks. Alternative regimens, which are also given for 21 days, are
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Pentamidine ,Atovaquone ,Trimethoprim
with dapsone ,Clindamycin with primaquine
Adjunctive therapy with corticosteroids is recommended for patients with
a Pao
2
< 70 mm Hg.
Prevention
HIV-infected patients who have had P. jirovecii pneumonia or who have
a CD4+ count < 200/μL should receive prophylaxis with TMP/SMX
80/400 mg once/day
Aspergillosis
is an opportunistic infection caused by inhaling spores of the
mold Aspergillus, commonly present in the environment; the spores
invade blood vessels, causing hemorrhagic necrosis and infarction.
Symptoms may be those of :
• asthma related : either exacerbate asthma as any irritant or
colonization of the airway with antigenic stimulation causing
refractory asthma called allergic bronchopulmonary aspergillosis
• invasive pneumonia seen as acute fulminant disease in
immunodeficient patients ,toxic with imaging show air cresent sign
(air around a consolidation ) need immediate antifungal treatment
systemically
• mycetoma colonization of the fungi in any cavities as old TB or
CF lead to a ball like lesion on imaging show ball in cavity that
change in position can cause hemoptysis no need to antifungal
treatment may need surgical treatment
Diagnosis is primarily clinical but may be aided by imaging,
histopathology, and specimen staining and culture ,Galactomannan
antigen test on serum and bronchoalveolar lavage fluid can be useful.
Antifungal drugs voriconazole, amphotericin B (or its lipid
formulations), caspofungin, or itraconazole.