181: ANTIMYCOBACTERIAL AGENTS o 1-month daily rifapentine + isoniazid in HIV-
positive patients: noninferior to 9-month isoniazid
Overview regimen.
• Used to treat infections caused by:
Active TB Treatment
o Mycobacterium tuberculosis (TB)
o Mycobacterium leprae (leprosy) • Standard first-line regimen for drug-susceptible TB:
o Nontuberculous mycobacteria (NTM) 1. Intensive phase (2 months):
▪ Isoniazid (H)
• Administered as multi-drug regimens over prolonged
▪ Rifampin (R)
periods.
▪ Pyrazinamide (Z)
• Over 160 species of mycobacteria identified; most are
▪ Ethambutol (E)
nonpathogenic.
2. Continuation phase (4 months):
• TB: ▪ Isoniazid + Rifampin
o Declining in the U.S. but remains a major cause of
• Extended therapy (9 months):
morbidity/mortality in low- and middle-income
o Cavitary disease
countries (e.g., sub-Saharan Africa, Asia),
o Incomplete pyrazinamide course
especially with HIV co-epidemic.
o Delayed culture conversion (>2 months)
• NTM infections:
• HIV co-infection considerations:
o Increasing in developed countries.
o ART initiation: within 2 weeks if CD4 ≤50/μL, within
o Typically affect immunocompromised patients or
8–12 weeks if CD4 ≥50/μL.
those with structural lung disease.
o Rifampin interacts with protease inhibitors and
• Global TB control requires: NNRTIs → consider rifabutin.
o Early diagnosis o TB-IRIS may occur; mild cases: continue therapy;
o Effective drug regimens severe cases: glucocorticoids (e.g., prednisone 4
o Vaccination strategies weeks).
o Treatment of latent TB infection (LTBI) o Intermittent TB therapy not recommended in HIV
co-infection.
Tuberculosis (TB) Adherence Strategies
General Principles
• Directly observed therapy (DOT)
• Earliest human TB cases: ~9000 years ago.
• Patient education and counseling
• Historical treatment:
• Field/home visits
o Sanatorium movement: fresh air, nutrition, bed
• Mobile health technologies (video DOT, reminders, electronic
rest, isolation.
pillboxes)
• Streptomycin discovery (1943) started modern antibiotic
• Monthly monitoring for hepatotoxicity (symptoms + ALT/AST
therapy.
if risk factors present)
• Multiple-drug regimens shortened treatment from years → 6
• Monthly sputum cultures for active TB
months for drug-susceptible TB.
Treatment Failure
Diagnosis
• Causes:
• Latent TB Infection (LTBI) and active TB:
o Nonadherence
o History & physical examination
o Poor absorption
o Radiographic imaging
o Drug resistance
o Tuberculin skin test (TST)
o Interferon-γ release assays (IGRAs) • Repeat drug susceptibility testing.
o Acid-fast staining • Add ≥2 effective drugs if resistance suspected.
o Mycobacterial culture
o Molecular diagnostics Multidrug-Resistant TB (MDR-TB)
• Active TB: requires confirmation by culture or molecular • Defined: resistant to isoniazid and rifampin.
detection of M. tuberculosis. • Risk factors:
o Previous TB treatment
LTBI Treatment Regimens o High MDR-TB prevalence regions (≥5%)
• Isoniazid + Rifapentine: weekly for 3 months (preferred in • Treatment:
children >2 years and adults, including HIV-positive) o WHO 2019: all-oral bedaquiline-containing
• Rifampin: daily for 4 months regimen (9–11 months vs 18–20 months)
• Isoniazid + Rifampin: daily for 3 months o Bangladesh regimen (STREAM-1 trial):
▪ Intensive phase: kanamycin,
• Isoniazid: daily or twice weekly for 6–9 months
prothionamide, isoniazid, fluoroquinolone,
• Notes:
ethambutol, pyrazinamide, clofazimine (7
o Rifamycin-based regimens are preferred over 6–9
drugs)
month isoniazid due to effectiveness and
▪ Continuation phase: fluoroquinolone,
tolerability.
ethambutol, pyrazinamide, clofazimine (4
o Caution in HIV patients: drug interactions,
drugs)
subclinical TB, rifampin resistance risk.
▪ Duration: 9–12 months; favorable
o Completion rates of self-administered weekly
outcomes ~90%
isoniazid + rifapentine similar to DOT.
, o Drug prioritization (meta-analysis of >12,000 • Also active against gram-positive/negative bacteria,
patients): Legionella, M. kansasii, M. marinum
▪ Better outcomes: linezolid, bedaquiline, Mechanism of Action
clofazimine, carbapenems, later- • Inhibits mycobacterial DNA-dependent RNA polymerase
generation fluoroquinolones → blocks RNA synthesis
▪ Worse outcomes: kanamycin, • MIC for M. tuberculosis: 1 μg/mL
capreomycin Pharmacology
o BPaL regimen (Nix-TB study): • Lipophilic, oral absorption
▪ Bedaquiline, pretomanid, linezolid • Peak serum: 10–20 μg/mL in 2.5 h
▪ Duration: 6 months • Distributed widely, including CSF
▪ Highly drug-resistant TB • Excreted mainly via bile
▪ Favorable outcomes: 89%
• Induces CYP450 → many drug interactions
▪ Side effects mainly from linezolid
Dosing
▪ Recommended only under operational
• Adults: 10 mg/kg/day (max 600 mg)
research conditions
• Children: 10–20 mg/kg/day
First-Line Anti-TB Drugs • No renal adjustment required
Isoniazid (H) Resistance
• Critical drug for TB and LTBI. • rpoB gene mutations → altered RNA polymerase
• Bactericidal: active organisms; bacteriostatic: slow-dividing • NTM: intrinsic resistance common
organisms. Adverse Effects
• Administered daily (preferred) or intermittent (twice • Hepatotoxicity uncommon
weekly DOT) • Rash, pruritus, GI symptoms, pancytopenia
• Often combined with pyridoxine 25–50 mg/d to prevent • Rare hypersensitivity: fever, chills, renal/hepatic failure
neuropathy.
Mechanism of Action Pyrazinamide (Z)
• Prodrug activated by KatG catalase-peroxidase • Nicotinamide analog, bactericidal
• Forms isonicotinoyl-NADH complex → inhibits InhA → • Used in initial 2 months of TB treatment
blocks mycolic acid synthesis • Shortens treatment from 9 → 6 months
• Releases free radicals with antimycobacterial activity • Decreases relapse rates
Pharmacology Mechanism of Action
• Oral or IM administration; water-soluble • Prodrug → pyrazinoic acid (POA)
• Peak serum: 3–5 μg/mL within 0.5–2 h • Active in acidic environments (pH <6.0, e.g.,
• Distribution: excellent, including CSF phagocytes/granulomas)
• Metabolized: N-acetyltransferase 2 (NAT2) → acetylation • Likely target: fatty acid synthetase I
o Fast acetylators → lower serum levels • MIC: 16–50 μg/mL at pH 5.5
o Slow acetylators → higher serum levels, more Pharmacology & Dosing
toxicity • Oral absorption: peak 20–60 μg/mL at 1–2 h
• Interactions via CYP450: warfarin, carbamazepine, • Dose: 15–30 mg/kg/day (max 2 g)
phenytoin, etc. • Distributes widely, including CSF
Dosing • Half-life: 9–11 h
• Adults: 5 mg/kg/day (max 300 mg) • Metabolized in liver; ~70% excreted in urine
• Children: 10 mg/kg/day • Dose adjustment in renal impairment
• Intermittent: 15 mg/kg (max 900 mg) Adverse Effects
• LTBI 3-month regimen: 15 mg/kg weekly + rifapentine • Hepatotoxicity (risk factors: age, liver disease, HIV,
Resistance hypoalbuminemia)
• Mutations in katG, inhA, kasA, NADH dehydrogenase 2 • Hyperuricemia (gout rare)
• Efflux pump overexpression: efpA, mmpL7, mmr, p55, • Pregnancy: not recommended in U.S.; recommended
Rv1258c internationally
• ~7% M. tuberculosis isolates in the U.S. resistant Resistance
Adverse Effects • Mutations in pncA gene → loss of pyrazinamidase
• Hepatotoxicity (rare: fulminant) • Conventional susceptibility testing challenging
• Peripheral neuropathy (25–50 mg pyridoxine prophylaxis)
• Rash, fever, anemia, optic atrophy, seizures, psychiatric Ethambutol (E)
symptoms • Bacteriostatic
• Risk factors: age, alcohol, liver disease, postpartum, HIV • Used in standard first-line regimen; provides synergy
• Active against M. tuberculosis, M. marinum, M. kansasii,
Rifampin (R) MAC
• Semisynthetic rifamycin • Least potent first-line drug against M. tuberculosis
• Introduced 1968 → shortened TB treatment Mechanism of Action
• Sterilizing and bactericidal • Inhibits arabinosyltransferases → blocks arabinogalactan
and lipoarabinomannan synthesis
, • MIC: 0.5–2 μg/mL o Potential to shorten drug-susceptible TB treatment
Pharmacology & Dosing (e.g., TBTC Study 31: 4-month
• 75–80% absorbed in 2–4 h rifapentine+moxifloxacin regimen non-inferior to 6-
• Peak serum: 2–4 μg/mL after 15 mg/kg month standard)
• Poor CSF penetration (requires 25 mg/kg for 50% serum • Common drugs:
CSF levels) o Levofloxacin: 750 mg/day commonly used for
• Intermittent therapy: 25–35 mg/kg 3×/week MDR-TB
• Dose adjustment: renal insufficiency o Moxifloxacin: High dose 800 mg/day
Adverse Effects recommended for shorter MDR-TB regimens
• Optic neuritis: decreased visual acuity, central scotoma, o Avoided: Ciprofloxacin, ofloxacin (poor efficacy);
green color blindness gatifloxacin (dysglycemia)
• Risk: dose-dependent (1–5%), increased in renal • Pharmacokinetics:
insufficiency o Well absorbed orally
• Monitoring: baseline and monthly visual acuity, color vision, o Distribution: high tissue penetration
optic fundus o Reduced absorption with multivalent cations (e.g.,
antacids)
• Recovery usually months; some deficits permanent in elderly
• Adverse effects:
• Peripheral neuropathy: rare
o GI intolerance, rash, dizziness, headache
Resistance
o QTc prolongation (rarely requiring cessation)
• Mutations in embB gene, especially codon 306
o Pediatric use limited due to tendon/cartilage risks
• Resistance: Mutations in gyrA and gyrB genes
Other Rifamycin Drugs
Diarylquinolines – Bedaquiline
Rifabutin
• Mechanism: Inhibits mycobacterial ATP synthase →
• Semisynthetic rifamycin S derivative
bactericidal
• Inhibits DNA-dependent RNA polymerase
• Resistance:
• Used instead of rifampin in HIV patients on PIs or NNRTIs
o atpE gene mutations
• More active in vitro against MAC and NTM o Non-target mutations: Rv0678, PepQ → cross-
• Half-life: 45 h (longer than rifampin) resistance to clofazimine
• Adverse effects: GI, rash, headache, myalgia, uveitis, lab • Pharmacokinetics:
abnormalities o Oral bioavailability excellent
• Resistance: rpoB mutations o Long half-life (>14 days)
Rifapentine o Dosage: 400 mg/day for 2 weeks, then 200 mg
• Semisynthetic cyclopentyl rifamycin 3x/week (total 6 months)
• Mechanism: same as rifampin • Drug interactions:
• Lipophilic, prolonged half-life → weekly/twice-weekly o CYP3A4 metabolism
dosing o Rifampin decreases levels by 50%
• Used in continuation phase of noncavitary, drug- o Efavirenz may reduce levels (~50% in chronic use)
susceptible TB in HIV-seronegative patients • Adverse effects: QT prolongation; FDA black box warning
• Peak serum: 5–6 h, steady state: 10 days (initial trial higher mortality)
• Half-life: 13 h • Use: Integral to WHO-endorsed shorter oral MDR-TB
• Adverse effects: similar to other rifamycins; teratogenic in regimens
animal models Oxazolidinones – Linezolid
• Resistance: mutations in rpoB (cross-resistant with rifampin) • Mechanism: Binds 50S ribosomal subunit → inhibits protein
SECOND-LINE ANTITUBERCULOSIS DRUGS synthesis
Indications • Pharmacokinetics:
• Treatment of drug-resistant TB (MDR-TB, XDR-TB) o Nearly 100% oral bioavailability
• Patients intolerant or allergic to first-line agents o Good tissue & CSF penetration
• Situations where first-line supplemental agents are • Resistance: Mutations in 23S rRNA, L3 (rplC), L4 (rplD)
unavailable • Adverse effects:
WHO Classification o Optic/peripheral neuropathy, pancytopenia, lactic
• Group A: Fluoroquinolones, Diarylquinolines, Oxazolidinones acidosis
• Group B: Clofazimine, Cycloserine o Serotonin syndrome with serotonergic drugs
• Group C: Nitroimidazoles, Amoxicillin-clavulanate, • Use: MDR-TB (~80% success with individualized regimens)
Carbapenems, Aminoglycosides, Ethionamide, Para- • Dosing: 600 mg daily preferred; single dose better tolerated
aminosalicylic acid (PAS) • Emerging agents: Sutezolid (higher early bactericidal
activity, fewer side effects; phase 2A trials)
Group A Drugs
Fluoroquinolones Group B Drugs
• Mechanism: Inhibit DNA gyrase & topoisomerase IV → Clofazimine
prevent replication & protein synthesis; bactericidal. • Mechanism: Increases reactive oxidant species, destabilizes
• Use: membranes; kills “persister” organisms
o MDR-TB and drug-resistant TB • Pharmacokinetics:
, o Fat-soluble, half-life ~70 days • Opportunistic infections in:
o Absorption improved with fatty meals o Preexisting lung disease
• Adverse effects: GI intolerance, reversible orange-brown o Immunocompromised hosts
discoloration of skin/fluids o Otherwise healthy individuals
• Use: MDR-TB regimens; low cost; studied for treatment (nodular/bronchiectatic disease)
shortening • Disseminated infections in immunocompromised patients
Cycloserine • Skin and soft tissue infections in surgical settings
• Mechanism: D-alanine analog; inhibits peptidoglycan Classification
synthesis (alanine racemase) • Slow-growing NTM: >1 week to subculture
• Pharmacokinetics: Well absorbed orally; good CSF • Rapid-growing NTM: <1 week to subculture
penetration • Growth rate helps distinguish NTM from M. tuberculosis
• Dosage: 250 mg 2–3x/day Diagnosis
• Adverse effects: Seizures, psychosis, peripheral • Pulmonary NTM: Clinical symptoms + radiographic evidence
neuropathy, headache, somnolence + reproducible culture or bronchoscopy
• Monitoring: Required in epilepsy, renal insufficiency, alcohol • Disseminated or extrapulmonary: Culture from blood, soft
use, depression history tissue, or bone
Group C Drugs Therapeutic Considerations
Nitroimidazoles – Delamanid & Pretomanid Slowly Growing NTM
• Mechanism: Inhibit mycolic acid biosynthesis after activation • Photochromogens: M. marinum, M. kansasii (pigment only
by M. tuberculosis nitroreductases in light)
• Delamanid: • Scotochromogens: M. gordonae, M. scrofulaceum (pigment
o Adult dose: 100 mg BID independent of light)
o QT prolongation noted; part of ongoing trials • Nonchromogens: MAC, M. ulcerans
(including with bedaquiline) Mycobacterium avium complex (MAC)
• Pretomanid: • Common in underlying lung disease
o Adult dose: 200 mg daily • Nodular/bronchiectatic disease:
o Used in BPaL regimen for highly resistant TB (FDA- Clarithromycin/azithromycin + rifampin/rifabutin + ethambutol,
approved) 3x/week for ≥12 months post-culture conversion
o Hepatotoxicity concerns in some trials • Fibrocavitary or severe disease: Daily regimen; consider
β-Lactams – Amoxicillin-Clavulanate & Carbapenems amikacin/streptomycin
• Mechanism: Carbapenems poor substrate of BlaC; • Inhaled liposomal amikacin: Approved for refractory MAC
clavulanate inhibits β-lactamase (persistent positive cultures ≥6 months)
• Usage: IV meropenem+clavulanate or imipenem-cilastatin for • HIV patients: ART interactions considered; low CD4 may
severe resistant TB require lifelong therapy
• Limitation: IV administration; limited long-term safety data Mycobacterium kansasii
Aminoglycosides – Amikacin, Streptomycin • Treatment: Rifampin + ethambutol + isoniazid or macrolide
• Mechanism: Bind 16S rRNA → inhibit protein synthesis; • Duration: ≥18 months or 12 months post-culture conversion
bactericidal • Rifampin resistance: Treated with multi-drug regimen guided
• Usage: Severe NTM or drug-resistant TB; kanamycin and by susceptibility
capreomycin no longer recommended Mycobacterium marinum
• Dosing: • Source: Fresh/saltwater, fish tanks
o Streptomycin: 15 mg/kg/day IM (max 1 g) • Treatment: Clarithromycin + ethambutol or rifampin;
o Amikacin: 15–30 mg/kg/day IM/IV (max 1 g) alternatives: doxycycline, minocycline, TMP-SMX
• Adverse effects: Ototoxicity, nephrotoxicity, neurotoxicity • Drug susceptibility testing if culture persists >3 months
• Resistance: Mutations in 16S rRNA gene (rrs) Rapidly Growing NTM
Ethionamide • Includes M. abscessus, M. fortuitum, M. chelonae
• Mechanism: Inhibits InhA → blocks mycolic acid synthesis • Treatment: Complex; requires expert consultation
• Use: Drug-resistant TB • M. abscessus: Macrolide + parenteral agent (amikacin,
• Adverse effects: GI intolerance, hepatotoxicity, neurologic cefoxitin, imipenem) for ≥4 months (skin/soft tissue), ≥6
side effects, hypothyroidism months (bone)
• Dosing: With food + pyridoxine (50–100 mg/day) • Surgical resection considered if localized infection
Para-aminosalicylic acid (PAS)
• Mechanism: Inhibits folate synthesis & iron uptake; Drugs for NTM Treatment
bacteriostatic Macrolides
• Adverse effects: Nausea, vomiting, diarrhea, hemolysis in • Clarithromycin:
G6PD deficiency o Inhibits 50S ribosome
• Dosing: Enteric-coated granules 4 g orally every 8 h o Resistance via ermB or inducible erm41 (M.
abscessus)
NONTUBERCULOUS MYCOBACTERIA (NTM) o Dosage: 500 mg 3x/week (mild), 500–1000 mg
Epidemiology daily (severe)
• 150 species identified; only a minority are pathogenic
positive patients: noninferior to 9-month isoniazid
Overview regimen.
• Used to treat infections caused by:
Active TB Treatment
o Mycobacterium tuberculosis (TB)
o Mycobacterium leprae (leprosy) • Standard first-line regimen for drug-susceptible TB:
o Nontuberculous mycobacteria (NTM) 1. Intensive phase (2 months):
▪ Isoniazid (H)
• Administered as multi-drug regimens over prolonged
▪ Rifampin (R)
periods.
▪ Pyrazinamide (Z)
• Over 160 species of mycobacteria identified; most are
▪ Ethambutol (E)
nonpathogenic.
2. Continuation phase (4 months):
• TB: ▪ Isoniazid + Rifampin
o Declining in the U.S. but remains a major cause of
• Extended therapy (9 months):
morbidity/mortality in low- and middle-income
o Cavitary disease
countries (e.g., sub-Saharan Africa, Asia),
o Incomplete pyrazinamide course
especially with HIV co-epidemic.
o Delayed culture conversion (>2 months)
• NTM infections:
• HIV co-infection considerations:
o Increasing in developed countries.
o ART initiation: within 2 weeks if CD4 ≤50/μL, within
o Typically affect immunocompromised patients or
8–12 weeks if CD4 ≥50/μL.
those with structural lung disease.
o Rifampin interacts with protease inhibitors and
• Global TB control requires: NNRTIs → consider rifabutin.
o Early diagnosis o TB-IRIS may occur; mild cases: continue therapy;
o Effective drug regimens severe cases: glucocorticoids (e.g., prednisone 4
o Vaccination strategies weeks).
o Treatment of latent TB infection (LTBI) o Intermittent TB therapy not recommended in HIV
co-infection.
Tuberculosis (TB) Adherence Strategies
General Principles
• Directly observed therapy (DOT)
• Earliest human TB cases: ~9000 years ago.
• Patient education and counseling
• Historical treatment:
• Field/home visits
o Sanatorium movement: fresh air, nutrition, bed
• Mobile health technologies (video DOT, reminders, electronic
rest, isolation.
pillboxes)
• Streptomycin discovery (1943) started modern antibiotic
• Monthly monitoring for hepatotoxicity (symptoms + ALT/AST
therapy.
if risk factors present)
• Multiple-drug regimens shortened treatment from years → 6
• Monthly sputum cultures for active TB
months for drug-susceptible TB.
Treatment Failure
Diagnosis
• Causes:
• Latent TB Infection (LTBI) and active TB:
o Nonadherence
o History & physical examination
o Poor absorption
o Radiographic imaging
o Drug resistance
o Tuberculin skin test (TST)
o Interferon-γ release assays (IGRAs) • Repeat drug susceptibility testing.
o Acid-fast staining • Add ≥2 effective drugs if resistance suspected.
o Mycobacterial culture
o Molecular diagnostics Multidrug-Resistant TB (MDR-TB)
• Active TB: requires confirmation by culture or molecular • Defined: resistant to isoniazid and rifampin.
detection of M. tuberculosis. • Risk factors:
o Previous TB treatment
LTBI Treatment Regimens o High MDR-TB prevalence regions (≥5%)
• Isoniazid + Rifapentine: weekly for 3 months (preferred in • Treatment:
children >2 years and adults, including HIV-positive) o WHO 2019: all-oral bedaquiline-containing
• Rifampin: daily for 4 months regimen (9–11 months vs 18–20 months)
• Isoniazid + Rifampin: daily for 3 months o Bangladesh regimen (STREAM-1 trial):
▪ Intensive phase: kanamycin,
• Isoniazid: daily or twice weekly for 6–9 months
prothionamide, isoniazid, fluoroquinolone,
• Notes:
ethambutol, pyrazinamide, clofazimine (7
o Rifamycin-based regimens are preferred over 6–9
drugs)
month isoniazid due to effectiveness and
▪ Continuation phase: fluoroquinolone,
tolerability.
ethambutol, pyrazinamide, clofazimine (4
o Caution in HIV patients: drug interactions,
drugs)
subclinical TB, rifampin resistance risk.
▪ Duration: 9–12 months; favorable
o Completion rates of self-administered weekly
outcomes ~90%
isoniazid + rifapentine similar to DOT.
, o Drug prioritization (meta-analysis of >12,000 • Also active against gram-positive/negative bacteria,
patients): Legionella, M. kansasii, M. marinum
▪ Better outcomes: linezolid, bedaquiline, Mechanism of Action
clofazimine, carbapenems, later- • Inhibits mycobacterial DNA-dependent RNA polymerase
generation fluoroquinolones → blocks RNA synthesis
▪ Worse outcomes: kanamycin, • MIC for M. tuberculosis: 1 μg/mL
capreomycin Pharmacology
o BPaL regimen (Nix-TB study): • Lipophilic, oral absorption
▪ Bedaquiline, pretomanid, linezolid • Peak serum: 10–20 μg/mL in 2.5 h
▪ Duration: 6 months • Distributed widely, including CSF
▪ Highly drug-resistant TB • Excreted mainly via bile
▪ Favorable outcomes: 89%
• Induces CYP450 → many drug interactions
▪ Side effects mainly from linezolid
Dosing
▪ Recommended only under operational
• Adults: 10 mg/kg/day (max 600 mg)
research conditions
• Children: 10–20 mg/kg/day
First-Line Anti-TB Drugs • No renal adjustment required
Isoniazid (H) Resistance
• Critical drug for TB and LTBI. • rpoB gene mutations → altered RNA polymerase
• Bactericidal: active organisms; bacteriostatic: slow-dividing • NTM: intrinsic resistance common
organisms. Adverse Effects
• Administered daily (preferred) or intermittent (twice • Hepatotoxicity uncommon
weekly DOT) • Rash, pruritus, GI symptoms, pancytopenia
• Often combined with pyridoxine 25–50 mg/d to prevent • Rare hypersensitivity: fever, chills, renal/hepatic failure
neuropathy.
Mechanism of Action Pyrazinamide (Z)
• Prodrug activated by KatG catalase-peroxidase • Nicotinamide analog, bactericidal
• Forms isonicotinoyl-NADH complex → inhibits InhA → • Used in initial 2 months of TB treatment
blocks mycolic acid synthesis • Shortens treatment from 9 → 6 months
• Releases free radicals with antimycobacterial activity • Decreases relapse rates
Pharmacology Mechanism of Action
• Oral or IM administration; water-soluble • Prodrug → pyrazinoic acid (POA)
• Peak serum: 3–5 μg/mL within 0.5–2 h • Active in acidic environments (pH <6.0, e.g.,
• Distribution: excellent, including CSF phagocytes/granulomas)
• Metabolized: N-acetyltransferase 2 (NAT2) → acetylation • Likely target: fatty acid synthetase I
o Fast acetylators → lower serum levels • MIC: 16–50 μg/mL at pH 5.5
o Slow acetylators → higher serum levels, more Pharmacology & Dosing
toxicity • Oral absorption: peak 20–60 μg/mL at 1–2 h
• Interactions via CYP450: warfarin, carbamazepine, • Dose: 15–30 mg/kg/day (max 2 g)
phenytoin, etc. • Distributes widely, including CSF
Dosing • Half-life: 9–11 h
• Adults: 5 mg/kg/day (max 300 mg) • Metabolized in liver; ~70% excreted in urine
• Children: 10 mg/kg/day • Dose adjustment in renal impairment
• Intermittent: 15 mg/kg (max 900 mg) Adverse Effects
• LTBI 3-month regimen: 15 mg/kg weekly + rifapentine • Hepatotoxicity (risk factors: age, liver disease, HIV,
Resistance hypoalbuminemia)
• Mutations in katG, inhA, kasA, NADH dehydrogenase 2 • Hyperuricemia (gout rare)
• Efflux pump overexpression: efpA, mmpL7, mmr, p55, • Pregnancy: not recommended in U.S.; recommended
Rv1258c internationally
• ~7% M. tuberculosis isolates in the U.S. resistant Resistance
Adverse Effects • Mutations in pncA gene → loss of pyrazinamidase
• Hepatotoxicity (rare: fulminant) • Conventional susceptibility testing challenging
• Peripheral neuropathy (25–50 mg pyridoxine prophylaxis)
• Rash, fever, anemia, optic atrophy, seizures, psychiatric Ethambutol (E)
symptoms • Bacteriostatic
• Risk factors: age, alcohol, liver disease, postpartum, HIV • Used in standard first-line regimen; provides synergy
• Active against M. tuberculosis, M. marinum, M. kansasii,
Rifampin (R) MAC
• Semisynthetic rifamycin • Least potent first-line drug against M. tuberculosis
• Introduced 1968 → shortened TB treatment Mechanism of Action
• Sterilizing and bactericidal • Inhibits arabinosyltransferases → blocks arabinogalactan
and lipoarabinomannan synthesis
, • MIC: 0.5–2 μg/mL o Potential to shorten drug-susceptible TB treatment
Pharmacology & Dosing (e.g., TBTC Study 31: 4-month
• 75–80% absorbed in 2–4 h rifapentine+moxifloxacin regimen non-inferior to 6-
• Peak serum: 2–4 μg/mL after 15 mg/kg month standard)
• Poor CSF penetration (requires 25 mg/kg for 50% serum • Common drugs:
CSF levels) o Levofloxacin: 750 mg/day commonly used for
• Intermittent therapy: 25–35 mg/kg 3×/week MDR-TB
• Dose adjustment: renal insufficiency o Moxifloxacin: High dose 800 mg/day
Adverse Effects recommended for shorter MDR-TB regimens
• Optic neuritis: decreased visual acuity, central scotoma, o Avoided: Ciprofloxacin, ofloxacin (poor efficacy);
green color blindness gatifloxacin (dysglycemia)
• Risk: dose-dependent (1–5%), increased in renal • Pharmacokinetics:
insufficiency o Well absorbed orally
• Monitoring: baseline and monthly visual acuity, color vision, o Distribution: high tissue penetration
optic fundus o Reduced absorption with multivalent cations (e.g.,
antacids)
• Recovery usually months; some deficits permanent in elderly
• Adverse effects:
• Peripheral neuropathy: rare
o GI intolerance, rash, dizziness, headache
Resistance
o QTc prolongation (rarely requiring cessation)
• Mutations in embB gene, especially codon 306
o Pediatric use limited due to tendon/cartilage risks
• Resistance: Mutations in gyrA and gyrB genes
Other Rifamycin Drugs
Diarylquinolines – Bedaquiline
Rifabutin
• Mechanism: Inhibits mycobacterial ATP synthase →
• Semisynthetic rifamycin S derivative
bactericidal
• Inhibits DNA-dependent RNA polymerase
• Resistance:
• Used instead of rifampin in HIV patients on PIs or NNRTIs
o atpE gene mutations
• More active in vitro against MAC and NTM o Non-target mutations: Rv0678, PepQ → cross-
• Half-life: 45 h (longer than rifampin) resistance to clofazimine
• Adverse effects: GI, rash, headache, myalgia, uveitis, lab • Pharmacokinetics:
abnormalities o Oral bioavailability excellent
• Resistance: rpoB mutations o Long half-life (>14 days)
Rifapentine o Dosage: 400 mg/day for 2 weeks, then 200 mg
• Semisynthetic cyclopentyl rifamycin 3x/week (total 6 months)
• Mechanism: same as rifampin • Drug interactions:
• Lipophilic, prolonged half-life → weekly/twice-weekly o CYP3A4 metabolism
dosing o Rifampin decreases levels by 50%
• Used in continuation phase of noncavitary, drug- o Efavirenz may reduce levels (~50% in chronic use)
susceptible TB in HIV-seronegative patients • Adverse effects: QT prolongation; FDA black box warning
• Peak serum: 5–6 h, steady state: 10 days (initial trial higher mortality)
• Half-life: 13 h • Use: Integral to WHO-endorsed shorter oral MDR-TB
• Adverse effects: similar to other rifamycins; teratogenic in regimens
animal models Oxazolidinones – Linezolid
• Resistance: mutations in rpoB (cross-resistant with rifampin) • Mechanism: Binds 50S ribosomal subunit → inhibits protein
SECOND-LINE ANTITUBERCULOSIS DRUGS synthesis
Indications • Pharmacokinetics:
• Treatment of drug-resistant TB (MDR-TB, XDR-TB) o Nearly 100% oral bioavailability
• Patients intolerant or allergic to first-line agents o Good tissue & CSF penetration
• Situations where first-line supplemental agents are • Resistance: Mutations in 23S rRNA, L3 (rplC), L4 (rplD)
unavailable • Adverse effects:
WHO Classification o Optic/peripheral neuropathy, pancytopenia, lactic
• Group A: Fluoroquinolones, Diarylquinolines, Oxazolidinones acidosis
• Group B: Clofazimine, Cycloserine o Serotonin syndrome with serotonergic drugs
• Group C: Nitroimidazoles, Amoxicillin-clavulanate, • Use: MDR-TB (~80% success with individualized regimens)
Carbapenems, Aminoglycosides, Ethionamide, Para- • Dosing: 600 mg daily preferred; single dose better tolerated
aminosalicylic acid (PAS) • Emerging agents: Sutezolid (higher early bactericidal
activity, fewer side effects; phase 2A trials)
Group A Drugs
Fluoroquinolones Group B Drugs
• Mechanism: Inhibit DNA gyrase & topoisomerase IV → Clofazimine
prevent replication & protein synthesis; bactericidal. • Mechanism: Increases reactive oxidant species, destabilizes
• Use: membranes; kills “persister” organisms
o MDR-TB and drug-resistant TB • Pharmacokinetics:
, o Fat-soluble, half-life ~70 days • Opportunistic infections in:
o Absorption improved with fatty meals o Preexisting lung disease
• Adverse effects: GI intolerance, reversible orange-brown o Immunocompromised hosts
discoloration of skin/fluids o Otherwise healthy individuals
• Use: MDR-TB regimens; low cost; studied for treatment (nodular/bronchiectatic disease)
shortening • Disseminated infections in immunocompromised patients
Cycloserine • Skin and soft tissue infections in surgical settings
• Mechanism: D-alanine analog; inhibits peptidoglycan Classification
synthesis (alanine racemase) • Slow-growing NTM: >1 week to subculture
• Pharmacokinetics: Well absorbed orally; good CSF • Rapid-growing NTM: <1 week to subculture
penetration • Growth rate helps distinguish NTM from M. tuberculosis
• Dosage: 250 mg 2–3x/day Diagnosis
• Adverse effects: Seizures, psychosis, peripheral • Pulmonary NTM: Clinical symptoms + radiographic evidence
neuropathy, headache, somnolence + reproducible culture or bronchoscopy
• Monitoring: Required in epilepsy, renal insufficiency, alcohol • Disseminated or extrapulmonary: Culture from blood, soft
use, depression history tissue, or bone
Group C Drugs Therapeutic Considerations
Nitroimidazoles – Delamanid & Pretomanid Slowly Growing NTM
• Mechanism: Inhibit mycolic acid biosynthesis after activation • Photochromogens: M. marinum, M. kansasii (pigment only
by M. tuberculosis nitroreductases in light)
• Delamanid: • Scotochromogens: M. gordonae, M. scrofulaceum (pigment
o Adult dose: 100 mg BID independent of light)
o QT prolongation noted; part of ongoing trials • Nonchromogens: MAC, M. ulcerans
(including with bedaquiline) Mycobacterium avium complex (MAC)
• Pretomanid: • Common in underlying lung disease
o Adult dose: 200 mg daily • Nodular/bronchiectatic disease:
o Used in BPaL regimen for highly resistant TB (FDA- Clarithromycin/azithromycin + rifampin/rifabutin + ethambutol,
approved) 3x/week for ≥12 months post-culture conversion
o Hepatotoxicity concerns in some trials • Fibrocavitary or severe disease: Daily regimen; consider
β-Lactams – Amoxicillin-Clavulanate & Carbapenems amikacin/streptomycin
• Mechanism: Carbapenems poor substrate of BlaC; • Inhaled liposomal amikacin: Approved for refractory MAC
clavulanate inhibits β-lactamase (persistent positive cultures ≥6 months)
• Usage: IV meropenem+clavulanate or imipenem-cilastatin for • HIV patients: ART interactions considered; low CD4 may
severe resistant TB require lifelong therapy
• Limitation: IV administration; limited long-term safety data Mycobacterium kansasii
Aminoglycosides – Amikacin, Streptomycin • Treatment: Rifampin + ethambutol + isoniazid or macrolide
• Mechanism: Bind 16S rRNA → inhibit protein synthesis; • Duration: ≥18 months or 12 months post-culture conversion
bactericidal • Rifampin resistance: Treated with multi-drug regimen guided
• Usage: Severe NTM or drug-resistant TB; kanamycin and by susceptibility
capreomycin no longer recommended Mycobacterium marinum
• Dosing: • Source: Fresh/saltwater, fish tanks
o Streptomycin: 15 mg/kg/day IM (max 1 g) • Treatment: Clarithromycin + ethambutol or rifampin;
o Amikacin: 15–30 mg/kg/day IM/IV (max 1 g) alternatives: doxycycline, minocycline, TMP-SMX
• Adverse effects: Ototoxicity, nephrotoxicity, neurotoxicity • Drug susceptibility testing if culture persists >3 months
• Resistance: Mutations in 16S rRNA gene (rrs) Rapidly Growing NTM
Ethionamide • Includes M. abscessus, M. fortuitum, M. chelonae
• Mechanism: Inhibits InhA → blocks mycolic acid synthesis • Treatment: Complex; requires expert consultation
• Use: Drug-resistant TB • M. abscessus: Macrolide + parenteral agent (amikacin,
• Adverse effects: GI intolerance, hepatotoxicity, neurologic cefoxitin, imipenem) for ≥4 months (skin/soft tissue), ≥6
side effects, hypothyroidism months (bone)
• Dosing: With food + pyridoxine (50–100 mg/day) • Surgical resection considered if localized infection
Para-aminosalicylic acid (PAS)
• Mechanism: Inhibits folate synthesis & iron uptake; Drugs for NTM Treatment
bacteriostatic Macrolides
• Adverse effects: Nausea, vomiting, diarrhea, hemolysis in • Clarithromycin:
G6PD deficiency o Inhibits 50S ribosome
• Dosing: Enteric-coated granules 4 g orally every 8 h o Resistance via ermB or inducible erm41 (M.
abscessus)
NONTUBERCULOUS MYCOBACTERIA (NTM) o Dosage: 500 mg 3x/week (mild), 500–1000 mg
Epidemiology daily (severe)
• 150 species identified; only a minority are pathogenic
