Transcript Treatment of Tuberculosis

Treatment of TuberculosisNot just another pill
Karen Fitzmaurice, RN
Martha Ainslie, MD
Alfred Gin, PharmD
Objectives:
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By attending the session, the attendee will
be able to:
• Become familiar with the first and second line
anti-tuberculosis antibiotics and the standard
treatment regimes
• Identify the common adverse effects and drug
interactions associated with these antibiotics
• Describe problem-solving techniques that are
used to help identify and manage common
adverse effects
Outline
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Review the first line agents
Discuss duration of therapy
Review common side effects and
management
Review treatment of TB in special
populations
Briefly talk about drug resistance and
second line agents
The scope of the problem
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A 2 cm cavity contains 108 organisms
• A patient with active TB will have organisms
that are rapidly dividing as well as semidormant and dormant organisms
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There are naturally occurring mutations to
all our TB drugs
Use of monotherapy allows the selective
growth of the resistant organisms and
gives rise to drug resistance
A prolonged course of antibiotics is
required to kill the semi-dormant and
dormant organisms
In order to treat TB you must
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Take into consideration:
• Known or suspected drug resistance
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Hx of prior TB treatment
Country of origin
• Location of disease
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Standard tx is 6 months
TB meningitis: 9-12 months
• Likelihood of adherence and/or adverse
reactions
• Co morbidities and host immune status
Standard treatment regime:
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Intensive phase
• Goal is to quickly kill the rapidly dividing
organism to control disease and render
patient non-infectious and prevent
emergence of drug resistance
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Continuation phase
• Sterilize the lungs by killing dormant
and semi-dormant organisms to prevent
relapse
• DOT allows for intermittent therapy
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Give all meds together
as a single dose unless:
•Profound nausea, vomiting
•Swallowing issues
Standard treatment Regime:
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Intensive phase (first 8 weeks)
• 4 drugs X 8 weeks in the intensive phase
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INH/RMP/PZA/EMB daily X 14 doses
• If in hospital – daily until smear negative
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5/7 X 6 weeks (30 doses) WRHA
3/7 X 6 weeks (18 doses) FNIH, unless drug
resistance suspected, then 5/7
• Ethambutol can be dropped if organism
pansensitive
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Continuation phase
• Twice weekly INH and rifampin DOT
2HREZ/4HR2
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In intensive phase
• H,R: kill rapidly dividing TB
• Z: works to kill semi dormant TB in the acidic
environment of the cavity or in macrophages
• E: used to prevent the emergence of RIF
resistance when primary resistance to INH
may be present
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In continuation phase
• H,R: kill any remaining rapidly dividing cells as
well as sterilizing fibrotic areas
Rifampin
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Inhibits RNA polymerase
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The most important drug we use
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Bactericidal against rapidly dividing
agents, and penetrates into fibrotic areas
to kill semidormant organisms
• Without rifampin treatment course is 12-18
months
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Usual dose 10 mg/kg max 600mg
Rifampin side effects
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Change in colour of urine, sweat
Puritis with or without rash: 6%
Hepatotoxicity
• Significant transaminase elevation: rare
• Can be seen as part of hypersensitivity rx
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Dose dependent interference with bilirubin
uptake causing unconjugated
hyperbilirubinemia or jaundice without LFT
abnormalities
Thrombocytopenia
Hypersensitivity rx in 0.07-0.3%
Rifampin Drug Interactions
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Potent inducer of cytochrome P450
enzyme system
Rifampin decreases drug concentration of:
• alfentanil, amiodarone, anticoagulants (oral), atovaquone,
barbiturates, beta-blockers, buspirone, calcium channel
blockers, clarithromycin, oral contraceptives, corticosteroids,
cyclosporine, dapsone, digoxin, disopyramide, HMG-CoA
reductase inhibitors, azole antifungals, lamotrigine, losarten,
macrolides, methadone, morphine, NNRTIs, odansetron,
phenytoin, propafenone, protease inhibitors, quinidine,
sirolimus, sulfonylureas, tacrolimus, theophylline, tricyclic
antidepressants
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Rifampin concentration decreased by:
• protease inhibitors
eCPS accessed 4/2/12
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Isoniazid
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Usual dose 300 mg daily (5
mg/kg)
Inhibits mycolic acid synthesis
Profound early bactericidal
activity against rapidly dividing
cells
Isoniazid side effects
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Peripheral neuropathy
• Dose related side effect
• Vit B6 supplements to prevent
Rare: seizures
 +ANA antibodies in 20%, less than
1% develop lupus
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INH Hepatotoxicity
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Hepatitis
• Incidence increases
with age
• Generally occurs
within weeks to
months rather than
days
• Takes weeks to
regress, recovery is
complete in most
following drug
cessation
INH Drug Interactions
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INH inhibits cytochrome P450 system
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Increase concentrations of:
• carbamazepine, phenytoin,
cycloserine, theophylline, warfarin
• These effects are offset with
rifampin
• Check levels
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Also weak inhibitor of monoamine
oxidase
Pyrazinamide
Active against dormant and semidormant TB within macrophages or
in acidic environments
 No proven benefit extending PZA
beyond 2 months in pts with
pansensitive TB
 No PZA → minimum of 9 months of tx
 Dose is 25 mg/kg, requires renal dosing
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Pyrazinamide
side effects
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Hepatotoxicity
• Actual incidence hard to predict as PZA
always used with other TB meds, in one
study hepatotoxicity attributed to PZA in
1%
• In the RZ studies for LTBI incidence os
severe liver injury 5%
Rash
 Non gouty arthralgias
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• Seen in up to 40% of patients on daily Z
Ethambutol
Inhibits arabinosyl transferase
(synthesis of TB cell wall
component)
 Less bactericidal compared to
INH or RIF
 Dose: 15 mg/kg
 Requires renal dosing
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Ethambutol
side effects
• retrobulbar neuritis
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Manifests as decreased visual acuity or
decreased red-green colour discrimination in
one or both eyes
Risk higher in pts with renal failure
• Rarely used in children due to an
inability to monitor for symptoms
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Duration of therapy in patients with
pansensitive strain of TB
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Depends on location of TB
• CNS involvement
• Osteomyelitis
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Was PZA used in first 2 months
• No→9 months of tx
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What were the culture results at 2
months?
• positive→9 months of tx
Duration of therapy = number of
doses
Planned
duration
Doses of 2/7
INH/Rif in
continuation
Total Doses
3/7 intensive
Total Doses
5/7 intensive
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9
12
months months months
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Monitoring for side effects during
therapy
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Clinical
• Screen for common side effects
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Microbiological response
• Sputum at 2 months
• Sputum at completion of therapy
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Laboratory response
• First 2 weeks: twice weekly
• At 1 month then monthly
• Check: AST, ALT, Bilirubin, CBC
Adverse Effects
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Rifampin
Isoniazid
• flushing, rash
• increase in LFTs,
hepatitis
• flu-like syndrome
• hematologic
• body fluid
discoloration
• increase in LFTs,
hepatitis
• peripheral
neuropathy
Pyrazinamide
• hepatitis
• increased serum
uric acid
Ethambutol
• optic neuritis
Common problems during therapy
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Nausea and vomiting
Abnormal LFTs
Drowsiness
Rash/puritis
Missed doses
SYMPTOM MANAGEMENT:
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Drowsiness:
• HS dosing
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Nausea:
• Have light food 30 – 60 minutes prior to DOT
• Antiemetic 30 minutes prior to DOT
• Stronger antiemetic/ranitidine/PPI
Rash/Itch:
• Minor itch continue meds with antihistamine
(usually RMP)
• Major rash drug challenge after rest
• RMP/INH/EMB/PZA (usually PZA)
Hepatotoxicity
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Asymptomatic increases in LFTs occur in
20% of pts on tx for TB
Most common serious side effect
Defined as AST >5xULN or >3xULN with
symptoms
Incidence depends on
• Age
• Pre-existing liver disease
• ETOH: appears to more than double risk of
INH hepatotoxiticity
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INH more hepatotoxic than rifampin
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Nausea, vomiting, abdominal pain
seen in 50-75% of patients with
hepatotoxicity
Fever 10%, rash in 5%
Jaundice is a late finding
What to do if a patient develops
abnormal LFTs on therapy?
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AST/ALT 5X ULN asymptomatic or
AST/ALT 3X ULN symptomatic or
Jaundice
→ HOLD TB Meds
Once ALT returns to <2x ULN then
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Restart rifampin alone or with ethambutol, repeat ALT on day
3
IF ALT <2x ULN then add in INH and repeat ALT in 3 days
Rechallenge with PZA may be hazardous and consider D/C
and extending tx to 9 months
Rash
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If minor, consisting of mainly puritis or
affecting limited area
• → trial antihistamines
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Petechial rash
• Check platelet count
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Generalized rash especially with fever or
involving mucocutaneous areas
• → hold all TB meds
• Once rash subsides: restart drugs one by one
• Rif → INH→ethambutol or PZA. If no rash with 3rd
drug then assume it is the 4th drug that is the cause
Missed doses
Manitoba Communicable Disease Control – Tuberculosis Protocol 2009
Paradoxical Reactions:
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Worsening of TB adenitis with
development of new lymph nodes,
increasing lymph node size or sinus
drainage
• Seen in up to 20% of patients
• Median time to onset: 1.5 months
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Can present with new pleural
effusions during trt for Pulm TB
Mgmt of Paradoxical Reactions:
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Rule out drug resistant TB
Aspiration of lymph nodes, effusions
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Corticosteroids
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• Unproven benefit
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NSAIDS
Treatment of patients in special
populations
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Hepatic Disease
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Renal insufficiency/ESRD
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HIV infection
Pregnancy/breastfeeding
Treatment in patients with preexisting liver disease
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Remember ↑ AST/ALT may be secondary
to TB
If ALT more than 3xULN not related to TB
• Avoid PZA
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IF patient has cirrhosis
• Rifampin + ethambutol + fluoroquinolone
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Severe liver disease with encephalopathy
• Ethambutol, fluoroquinolone, aminoglycoside
(or capreomycin), cycloserine
Renal insufficiency/ESRD:
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Dose adjust Z and E if
CrCl<30ml/min or on PD or HD
Intensive:
• INH/RMP OD post HD
• PZA/EMB 3X per week post HD
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Continuation
• INH/RMP 3X per week post HD
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No data on peritoneal dialysis
HIV infection:
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CD4 count <200
• OD 7/7 X 2 months for intensive phase
• 3X per week for continuation phase
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Protease inhibitor interaction with
Rifampin Rifabutin in consultation with
HIV pharmacist
Starting of ART (on new HIV DX)
• Dependent on CD4 count
TB and HIV Drug Interactions
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Rifampin and Protease inhibitors (PI)
• Effect: Decreased PI serum levels
• Substitute Rifampin with Rifabutin 150 mg po
thrice weekly (may need to increase to 300 mg
thrice weekly or 150 mg po daily)
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Rifampin and Efavirenz
• Effect: Decreased efavirenz levels
• Increase efavirenz dose to 800 mg po daily
(usual 600 mg daily)
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Rifampin and Raltegravir
• Effect: Decreased raltegravir levels
• Increase raltegravir to 800 mg po BID (usual
dose 400 mg po BID and continue higher dose
for at least 2 weeks post completion of
Rifampin)
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Pregnancy:
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TB not an indication for pregnancy
termination
First line drugs safe in pregnancy (H,R,E)
• PZA: limited data with respect to teratogenic
effects. Recommended by WHO and IUATLD
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Fluoroquinolones and aminoglycosides
contraindicated while pregnant
Breastfeeding Moms:
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1st line drugs
• Very small concentrations in breast milk
• Encourage breast feeding
• Have not shown to produce toxic effects in
newborn
• Mum should be on pyridoxine supplements
• Drugs level in breast milk not sufficiently high
to be considered effective tx for infant
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Certain 2nd line drugs not recommended data unknown
Concerns re poor absorption:
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Consider if significant malnutrition, diabetic gastroparesis,
HIV, underlying GI disease, treatment failure
INH/RMP serum levels:
• Usually 2 hours (+/- 6 hours) post oral drug admin
• Special lab handling
• Done in Mayo Clinic (Rif) and in Ontario Lab (INH) results take
~ 2-3 weeks
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Available IV drugs include INH, RIF, fluoroquinolones,
aminoglycocides
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Recommendations-Parental route (delays discharge)
• Only select drugs via Home Care/Mount Carmel Clinic/Lions
Place in WRHA
Drug resistance
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Primary versus acquired
PZA resistance: treat for 9 months
INH monoresistance
• 6 month R,Z,E
• 12 months of 2RZE/10RE
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MDR= resistance to INH and RIF
MDR =failure of public health
Second Line*
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Fluoroquinolones
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• Ciprofloxacin
• Levofloxacin
• Moxifloxacin
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Aminoglycosides
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• Amikacin
• Streptomycin
• Capreomycin
• Kanamycin
Rifamycins
• Rifabutin
• Rifapentine**
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Ethionamide
Cycloserine
Para-aminosalicyclic acid
(PAS)
Clofazimine
**not commercially available
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Third Line
Amoxicillin/clavulanate
 Imipenem/cilastatin
 Linezolid
 Clarithromycin
 Thiacetazone
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Management of MDR-TB
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Individual regimes guided by DST
• Ask yourself: could the DST pattern have changed due
to tx during the interval from sputum collection to
obtaining DST?
Management of MDR-TB
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Injectable: used daily for first 2-6
months then can be stepped down to
3x/week, ideally for >6 months
Must have daily directly observed
therapy for the duration of therapy
Duration: 18-24 months after
sputum conversion
Surgery in MDR TB-it’s back
Objectives:
• Become familiar with the first and
second line anti-tuberculosis antibiotics
and the standard treatment regimes
• Identify the common adverse effects
and drug interactions associated with
these antibiotics
• Describe problem-solving techniques
that are used to help identify and
manage common adverse effects
Take home points
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Duration of tx depends on results of 2
month cultures and the inclusion of PZA
Treatment completion depends on the
number of doses taken not duration of tx
Many side effects do not require
discontinuation of tx
Beware of drug-drug interactions
Hepatotoxicity is the most common
serious side effect requiring
discontinuation of drug
• Introduce Rif then INH once LFTs return to
normal
Questions or Comments?
References:
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Manitoba Health(Dec 2009)Tuberculosis
Protocol
Public Health Agency of Canada (2007)
Canadian TB Standards 6th Edn p.117 –
p.119, p.122 – p.128, p.130, p.161 –
p.163, p.206 – p.209
MMWR June 20, 2003
WHO guidelines 2009
Saukkonen et al. Am J Resp Crit Care Med 2006
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