ANTI TUBERCULAR AGENT 1.

ISONIAZID

Adult Dosing & Uses

Dosing Forms & Strengths
tablets
y y y

50mg 100mg 300mg

oral syrup
y

50mg/5mL

injectable solution
y

100mg/mL

Latent Tuberculosis Infection

Treatment of latent TB infection greatly reduces the risk that TB infection will progress to acitve disease >30 kg: 300 mg PO qDay x9 months Countries with low-to-medium incidence of TB (mostly US and Canada): May consider shorter regimen (3 months) of supervised once weekly treatment that includes isoniazid and rifapentine (new CDC guidelines for this regimen currently in progress)

Active Tuberculosis Disease

5 mg/kg PO/IM qDay, not to exceed 300 mg qDay 15 mg/kg PO/IM up; not to exceed 900 mg 1-3 times/week Used in multi-drug regimen containing rifampin (or ribabutin or rifapentin), pyrazinamide, and ethambutol Duration of treatment dependent on regimen consisting of an initial phase of treatment and a continutation phase of treatment Note: Daily treatment has best results for HIV positive individuals

See Also Combos

With rifampin (Rifamate) With rifampin & pyrizinamide (Rifater)

Other Indications & Uses

Newly infected patients Household members & close associates of people recently diagnosed w/ TB +ve TB skin test with +ve non-progressive CXR +ve TB skin test with underlying disease or immunosuppression +ve TB skin test, <35 years old; >35 years old weigh use against risk of hepatitis

Adverse Effects
>10%
Mild incr LFTs (10-20%) Peripheral neuropathy (dose-related incidence, 10-20% incidence with 10 mg/kg/d) Loss of appetite Nausea Vomiting Stomach pain Weakness

1-10%
Dizziness Slurred speech Lethargy Progressive liver damage (increases with age; 2.3% in pts > 50 yo) Hyperreflexia

<1%
Agranulocytosis

Anemia Megaloblastic anemia Thrombocytopenia Systemic lupus erythematosus Seizure

Contraindications & Cautions

Black Box Warnings
Severe and sometimes fatal hepatitis may occur within the first 3 months of treatment and many months after treatment. Risk is related to age and increased with daily alcohol consumption. Patients should be instructed about signs and symptoms of hepatitis.

Contraindications
Prev INH hepatic injury or reaction; acute liver dz Hypersensitivity

Cautions
Alcohol or illicit injectable drug use, predisposition to neuropathy, malnourished, severe renal impairment, chronic liver dz Use w/ other anti-TB agents Give pyridoxine (B6) concurrently for pregnant women, malnourished pts. or those with neuropathic diathesis Alcohol use, renal or hepatic dysfunction will affect serum levels

Pharmacology
Absorption: rapid & complete; rate can be slowed with food Distribution: all body tissues and fluids including CSF; crosses placenta; enters breast milk Protein Bound: 10-15%

Half-life elimination: fast acetylators: 30-100 min; slow acetylators: 2-5 hr; may be prolonged with hepatic or severe renal impairment Peak Plasma Time: 1-2 hr Metabolism: hepatic with decay rate determined genetically by acetylation phenotype Excretion: urine (75-95%); feces

Mechanism of Action
Unknown: prob. inhibits cell-wall biosynthesis by interfering w/ lipid & DNA synthesis (bactericidal)
2. RIFAMPIN

Adult Dosing & Uses

Dosing Forms & Strengths
capsule
y y

150mg 300mg

injectable powder
y

600mg

Tuberculosis (TB)
Daily dose: 10 mg/kg PO qD 2x/week: 10 mg/kg PO 2x/week No more than 600mg/d

Neisseria Meningitidis Carrier

600 mg BID x2 d

Haemophilus Carriers
600 mg qD x4 d

See Also Combos

with isoniazid with isoniazid & pyrazinamide

Other Information
No more than 600 mg/d Take on empty stomach

Other Indications & Uses

N. meningitidis (asymptomatic carriers only) Off-label: H. influenzae (type B); combo Rx: group A beta-hemolytic strep, aspergillosis, Bartonella henselae, C. jeikeium, Chlamydia trachomatis, L. monocytogenes, leprosy, N. gonorrhoeae, M. catarrhalis, F. tularensis, Brucella spp., N. meningitides, S. pneumoniae, S. aureus, Staphylococcus epidermidis

Adverse Effects
1-10%
Increased LFTs (up to 14%) Rash (1-5%) Epigastric distress (1-2%) Anorexia Nausea Vomiting Diarrhea Cramps Pseudomembranous colitis Pancreatitis

Frequency Not Defined

Muscular weakness

Contraindications & Cautions

Contraindications
Hypersensitivity to rifamycins Concomitant live bacterial vaccines Contraindicated in patients receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity Contraindicated in patients receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance

Cautions
May decrease the effectiveness of OCPs Do not administer parenteral IM or SC History of diabetes mellitus (may make diabetes management more difficult) Rifampin is not recommended for intermittent therapy; caution patient against intentional or accidental interruption of daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D

Pharmacology
Absorption: oral: well absorbed; food may delay or slightly reduce peak Distribution: highly lipophilic; crosses blood-brain barrier well, relative diffusion from blood into CSF: adequate with or without inflammation (exceeds usual MICs), CSF: blood level ratio: inflamed meninges: 25% Protein Bound: 80% Half-life elimination: 3-4 hr; prolonged with hepatic impairment; end-stage renal disease: 1.8-11 hr Peak Plasma Time: Oral: 2-4 hr Metabolism: hepatic; undergoes enterohepatic recirculation Excretion: feces (60-65%) and urine (~30%) as unchanged drug

Mechanism of Action
Inhibits DNA-dependent RNA polymerase; potent enzyme inducer (see Enzyme Induction and Inhibition: General Principles)
3. RIFAPENTIN

Adult Dosing & Uses

Dosing Forms & Strengths
tablet
y

150mg

Tuberculosis
600 mg PO 2x/week for 2 months; interval between doses not <3 d THEN 600 mg PO qWeek for 4 months Used in combo with other antitubercular agents Administration: take with meal

Adverse Effects
>10%
Hyperuricemia (most likely d/t pyrazinamide from initial phase combo Tx)

1-10%
Hypertension Headache Dizziness Rash Pruritus Acne Anorexia

Nausea/vomiting Dyspepsia Diarrhea Neutropenia Lymphopenia Anemia Leukopenia Thrombocytosis Increased ALT/AST Arthralgia Pain Pyuria Proteinuria Hematuria Urinary casts Hemoptysis

Contraindications & Cautions

Contraindications
Hypersensitivity to rifamycins Monotherapy Porphyria

Cautions
Pyridoxine supplementation recommended for ts predisposed to neuropathy Hepatic disease HIV+ pts: do not use w/ INH during continuous phase; not studied in initial phase

May render hormonal contraceptives ineffective May tint body tissues, fluids & even contact lenses & dentures

Pharmacology
Half-Life: 13 hr Protein Bound: 98% Peak Plasma Time: 5-6 hr Excretion: feces (70%) & urine Enzymes induced: CYP3A4, CYP2C9/10

Mechanism of Action
Inhibits RNA polymerase in M. tuberculosis
4. PZA

Adult Dosing & Uses

Dosing Forms & Strengths
tablet
y

500mg

Tuberculosis Treatment For HIV Negative

Daily therapy
y

15-30 mg/kg PO qDay; not to exceed 2 g/day

Twice weekly therapy

y

50 mg/kg PO twice weekly; not to exceed 2 g/dose

Tuberculosis Treatment For HIV Exposed/Infected

20-40 mg/kg/dose PO qDay; not to exceed 2 g/day

See Also Combo

With isoniazid & rifampin

Other Indications & Uses

Tuberculosis; should always be admin with other anti-TB drugs

Adverse Effects
1-10%
Malaise Nausea Vomiting Anorexia Arthralgia Myalgia

<1%
Fever Rash Itching Acne Photosensitivity Gout Dysuria Porphyria Thrombocytopenia Hepatotoxicity Interstitial nephritis

Contraindications & Cautions

Contraindications

Severe hepatic damage, acute gout, hypersensitivity

Cautions
See pkg insert for complete dosage info

Pharmacology
Absorption: well absorbed Distribution: widely into body tissues and fluids including liver, lung, and CSF Relative diffusion from blood into CSF: adequate with or without inflammation (exceeds usual MICs) CSF:blood level ratio: inflamed meninges: 100% Protein binding: 50% Metabolism: hepatic Half-life elimination: 9-10 hr Time to peak, serum: within 2 hr Excretion: urine (4% as unchanged drug)

Mechanism of Action
Unknown; bacteriostatic or -cidal for Mycobacterium
5. ETHAMBUTOL

Adult Dosing & Uses

Dosing Forms & Strengths
tablet
y y

100mg 400mg

Mfr Recommendation
Initial TB Treatment: 15 mg/kg PO qD Prior TB Treatment: 25 mg/kg PO qD; after 60 d, decrease to 15 mg/kg PO qD

ATS, CDC, IDSA Recommendation

TB, Daily Administration
y y y

40-55 kg: 800 mg PO 56-75 kg: 1.2 g PO >75 kg: 1.6 g PO

TB, Twice-Weekly
y y y

40-55 kg: 2 g PO 56-75 kg: 2.8 g PO >75 kg: 4 g PO

TB, 3x-Weekly
y y y

40-55 kg: 1.2 g PO 56-75 kg: 2 g PO >75 kg: 2.4 g PO

Disseminated MAC (Off-label)

Treatment: 15 mg/kg PO qD Prophylaxis: use same dose with other antibiotics

Pulmonary M. Avium Complex (MAC) without HIV (Off-label)

25 mg/kg PO qD; after 60 d, decrease to 15 mg/kg PO qD

Other Indications & Uses

Tuberculosis: intended to be used concomitantly with other anti-TB drugs; usually isoniazid initially; subsequently, use second-line anti-TB drugs Off-label: MAC infections

Adverse Effects
Frequency Not Defined
Acute gout or hyperuricemia Abdominal pain Anaphylaxis Anorexia

Confusion, disorientation Fever Headache LFT abnormalities Malaise Nausea Optic neuritis; symptoms may include decreased acuity, color blindness or visual defects (usually revrsible with discontinuation, though irreversible blindness has been reported) Peripheral neuritis Pruritis Rash Vomiting

Contraindications & Cautions

Contraindications
Optic neuritis Hypersensitivity

Cautions
See pkg insert for complete dosage info < 5 yo: may be difficult to monitor visual acuity

Pharmacology
Absorption: ~80% Distribution: widely throughout body; concentrated in kidneys, lungs, saliva, and red blood cells Relative diffusion from blood into CSF: adequate with or without inflammation (exceeds usual MICs) CSF:blood level ratio: normal meninges: 0%; inflamed meninges: 25%

Protein binding: 20-30% Metabolism: hepatic (20%) to inactive metabolite Half-life elimination: 2.5-3.6 hr; end-stage renal disease: 7-15 hr Time to peak, serum: 2-4 hr Excretion: urine (~50%) and feces (20%) as unchanged drug

Mechanism of Action
Interferes with metabolite production in Mycobacterium
6. STREPTOMYCIN

Adult Dosing & Uses

Dosing Forms & Strengths
powder for injection
y

1g

injectable solution
y

400mg/mL

Moderate-Severe Infections
1-2 g/day divided q6-12hr IM; no more than 2 g/day

Tuberculosis
Daily therapy: 15 mg/kg IM qD; no more than 1 g/day 2x/week therapy: 25-30 mg/kg IM 2x/week; no more than 1.5 g/day

Tularemia
1-2 g IM in divided doses for 7-14 days until patient is afebrile for 5-7 days

Plague
15 mg/kg IM BID for minimum 10 days

Strep Endocarditis

1 g IM BID for 7 days, THEN 500 mg BID for 7 days, concomitant with penicillin If >60 years old, 500 mg BID for entire 14 days

Entero. Endocarditis
1 g IM BID x2 weeks, THEN 500 mg BID x4 weeks, concomitant with penicillin

Brucellosis
1 g IM qD/BID x1 week, THEN qD x1 week in conjunction with doxycycline or tetracycline

Renal Impairment
Load: 1 g IM, THEN CrCl: 50-80 mL/min: 7.5 mg/kg IM q24hr CrCl: 10-50 mL/min: 7.5 mg/kg IM q24-72hr CrCl <10 mL/min: 7.5 mg/kg IM q72-96hr Hemodialysis: 50-75% of initial loading dose at end of dialysis period

Adverse Effects
Frequency Not Defined
Hypotension Neurotoxicity Drowsiness Headache Drug fever Paresthesia Skin rash Nausea Vomiting Eosinophilia Anemia

Arthralgia Weakness Tremor Ototoxicity (auditory) Ototoxicity (vestibular) Nephrotoxicity Difficulty in breathing

Contraindications & Cautions

Black Box Warnings
May cause nephrotoxicity and neurotoxicity. Avoid concurrent use of nephrotoxic/neurotoxic drugs. May cause neuromuscular blockade and respiratory paralysis, especially when given after anesthesia or muscle relaxants. Use the parenteral form only where appropriate audiometric and laboratory testing facilities are available.

Contraindications
Hypersensitivity to streptomycin or other aminoglycosides; severe hypersensitivity to sulfites Concomitant live bacterial vaccines

Cautions
For tuberculosis, do not exceed 120 g total over course of Tx; discontinue in case of toxicity or organism resistance For endocarditis, discontinue in case of ototoxicity Reduce dosage in case of renal impairment: serum conc. should not exceed 20-25 mcg/mL

Pharmacology
Absorption: IM: well absorbed; not absorbed from gut Distribution: to extracellular fluid including serum, abscesses, ascitic, pericardial, pleural, synovial, lymphatic, & peritoneal fluids; crosses placenta; small amounts enter breast milk Protein Bound: 34%

Half-life elimination: newborns: 4-10 hr; adults: 2-4.7 hr, prolonged with renal impairment Peak Plasma Time: within 1 hr Excretion: urine (90% as unchanged drug); feces, saliva, sweat, & tears (<1%)

Mechanism of Action
Interferes with normal bacterial protein synthesis