Tuberculosis (Cut Off for Exam 1) Flashcards
1
Q
Transmission
A
- Transmitted by “droplet nuclei”
- Dependent on source infectiousness, environment of exposure, closeness/duration, # inhaled of organisms, host immune status
- 1 “active” disease patients infects ~1 person/month
2
Q
Phases of Infection
A
- Primary
- LTBI (latent tuberculosis infection)
- Active (“re-activation”) tuberculosis disease
3
Q
Primary Infection
A
- Inhalation of bacilli
- Bacilli ingested by pulmonary macrophages and evade immune system and multiple within macrophages
- Release of bacilli causes tissue necrosis
- Body granulomas to contain and prevent further extension of the necrotic lesion
- “Latent” phase of infection has begun
4
Q
LTBI
A
- Bacteria live in body without making patient sick (dormant)
- Evidence of infection: TST (positive skin test), reactive IFN-gamma release assay (Quanti-FERON Gold, T-SPOT)
- Normal chest X-ray, negative sputum AFB smears, and negative culture
- Patients aren’t contagious
- Treatment is part of TB elimination strategy in US
- 5-10% will develop active TB
5
Q
Active TB Disease
A
- “Re-activation”
- Onset may be gradual
- Productive cough lasting >3 weeks, chills, fever, night sweats, etc.
- Patients become sick and are able to spread disease again
- Inflammatory response can result in necrosis and structural collapse
6
Q
Diagnosis
A
- Physical examination
- Positive TST or blood test (Quanti-FERON Gold)
- Abnormal chest radiograph - often seen in apical segments of upper lobes
- Positive sputum smear or culture
7
Q
Antituberculosis Drugs
A
- R: Rifampin (RIF), Rifabutin, Rifapentine
- I: Isoniazid (INH)
- P: Pyrazinamide (PCA)
- E: Ethambutol (EMB)
8
Q
Additional Antituberculosis Drugs
A
- Injectables: streptomycin, amikacin
- Quinolones: Moxifloxacin
- Cycloserine
- P-aminosalicylic acid
- Ethionamide
9
Q
Treatment Principles for LTBI
A
- Active disease should be ruled out FIRST
- Monotherapy may be used ONLY for LTBI
- Risk of isoniazid-resistance is low and low disease burden
- Delay treatment during pregnancy
10
Q
Treatment Regimens for LTBI
A
- Isoniazid & Rifapentine: once weekly for 3 months
- Rifampin: Daily for 4 months
- Isoniazid: daily for 9 or 6 months (latter used for HIV and children >= 2 y.o.)
11
Q
LTBI + INH
A
- Only 40-60% who initiate 9 month INH therapy complete it
- Poor adherence
- Long treatment duration
- Toxicity
12
Q
3HP + DOT Advantages
A
- Higher completion rates
- Shorter duration
- Less hepatotoxicity
- Given once weekly
- Newer studies shown effectiveness in patients 2-17 y.o., HIV on ART, not receiving DOT
13
Q
DOT
A
- Directly Observed Therapy
- Health care worker watches patient swallow each dose
- Consider for most patients
- Intermittent therapy: facilitates supervision, improves outcomes
- DOT can lead to reductions in relapse and drug resistance
- Use DOT with other measures to promote adherence
14
Q
Treatment Principles for Active Disease
A
- Patient should be isolated until no longer infectious
- Empiric therapy has multiple drugs: helps cover and prevent drug-resistant, de-escalate once susceptibilities are known
- Duration is dependent on: host factors, extent of disease, and presence of resistance
- Never add a single drug to a failing regimen
15
Q
Treatment Adherence
A
- Long treatment duration (6 mo to 2-3 years)
- Non-adherence is a major problem
- Single most important factor in treatment failure
- Leads to resistance
16
Q
Drug-Drug Interactions
A
- Rifamycins are common CYP450 Inducers: increases metabolism of other drugs like HIV protease inhibitors, oral contraceptives, antifungals, methadone
- Isoniazid is an inhibitor: decreases metabolism of other drugs like phenytoin, carbamazepine, warfarin, and benzodiazepines
17
Q
Mycobacterial Resistance
A
- Naturally occuring mutations can confer resistance
- Develops during treatment due to poor prescribing practices, poor supervision of regimes, PK/PD issues, poor infection ontrol
- Drug-susceptible oragnisms are killed which selects for drug-resistant mutants
- Consider in patients who are culture positive 2-4mo into treatment, patients who previously been treated for TB, contact with drug-resistant TB, patients born in countries where drug resistant TB is prevalent
18
Q
Mono-resistant
A
Resistant to one TB treatment drug
19
Q
Poly-resistant
A
Resistant to at least any 2 TB drugs (excluding the combination of isoniazid and rifampin)
20
Q
MDR
A
- Multidrug resistant
- Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugs
21
Q
XDR
A
- Extensively drug resistant
- Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs
22
Q
TB + HIV
A
- HIV most important factor for TB progression
- HIV is driving global resurgence of TB
- Test ALL HIV-positive patients for TB
23
Q
Treatment TB + HIV
A
- Consult experts in management of both
- Consider pill burden/adherence, overlapping toxicities, DDI, IRIS
- 4-drug regimen, treatment often extended to 9 months
- Recommend daily regimens
- Rifabutin (may still need to dose adjust) often used instead of rifampin in patients receiving HAART
24
Q
Liver Disease + TB
A
- Use INH and RIF if possible
- If Avoiding INH: Rifampin, ethambutol, and pyrazinamide for 6 months
- If Avoiding PZA: Isoniazid, rifampin for 9 months and add EMB if susceptibility is available
25
Isoniazid
-INH
-MoA: Inhibits mycolic acid synthesis, prodrug requiring alteration by catalase
-Resistance: alteration in catalase gene
-Only available by mouth, separate from antacids by 2 hours
-AE: GI intolerance, peripheral neuropathy, elevated LFTs and hepatitis
Monitor: LFTs and signs of neuropathy
26
INH Hepatotoxicity
- Transient elevation occurs in up to 15% patients
- Overt hepatotoxicty occurs in <1%
- Monitor LFTs monthly
- Risk increases with age
27
Rifamycins
- MoA: inhibits protein synthesis
- Resistance: alteration in binding site, cross-resistance within class
- Take on empty stomach, separate by antacids by 2 hours
- Rifampin usually preferred but Rifabutin has less DDI and Rifapentine has a long duration (dosed once weekly)
28
Rifamycin AE
- GI Intolerance
- Elevated LFTs and hepatitis
- Leukopenia, thrombocytopenia, hemolytic anemia
- Red/orange secretions
- Monitoring: LFTs and CBC
29
PZA
- MoA: unclear, bactericidal for semi-dormant M. tuberculosis, prodrug activated by pncA
- Resistance: alterations in genes that code for pncA
- Only available PO
- AE: GI intolerance, elevated LFTs and hepatitis, arthralgias, elevations in uric acid, photosensitivty
- Monitoring: LFTs, SCr (renal adjustment)
30
Ethambutol
- EMB
- MoA: inhibitor of cell wall synthesis
- Bactericidal at high end of dosing
- Protects against further development of resistance when primary INH resistance is present
- AE: neuritis, eye damage
- Renal adjustment!!
31
Pyridoxine
- Vitamin B6
- INH interferes competitively with pyroxidine metabolism
- INH use may result in neuropathy
- Risks for vitamin B6 deficiency: alcoholism, >= 65 y.o., pregnancy, diabetes, CKD, autoimmune disease
32
Non-TB Mycobacteria
- Ubiquitous in the environment
- No human-human transmission
- Disease rare in immunocompetent
- Usually seen in HIV, elderly, and patients with cystic fibrosis
- Results in pneumonia and disseminated infections
- Diagnose by culture from sterile site and imaging
33
Non-TB Infection Symptoms
- Fever
- Night sweats
- Weight loss (>25%)
- Fatigue
- Malaise
- Anorexia
- Diarrhea
- Abdominal pain
34
Non-TB MAC Treatment
- At least 2 effective drugs to prevent resistance
- Preferred: Clarithromycin + Ethambutol +/- Rifabutin
- Alt: Sub azithromycin for clarithomycin
35
MAC Treatment Adjustments
- Macrolides cause GI symptoms, metallic taste, QTc prolongation
- Rifabutin dose adjustment due to DDI (450 mg with inducers, 150 mg with inhibitors)
