Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 56.

Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy

Mechanism of Action Absorption & Distribution Metabolism & Excretion Therapeutic Use Effects
Rifamycins (Rifampin, Rifapentine, and Rifabutin)
• Macrocyclic antibiotics characterized by a chromophoric naphthohydroquinone group that is spanned by a long aliphatic bridge, with an acetyl group at C25.
• Rifapentine and rifabutin are derivatives of rifampin
• Typified by rifampin's action against M. • After oral administration, • Metabolized by microsomal Rifampin Rifampin
tuberculosis absorbed to variable B-esterases and • Oral admin is available alone • Generally well-tolerated
extents. cholinesterases -> remove and as a fixed-dose • Fewer than 4%: rash, fever, nausea, vomiting
Rifampin the acetyl group at position 25 combination with:
• Enters bacilli in a concentration dependent Rifampin -> 25-O-desacetyl rifamycins INH (150 mg of INH + 300 mg • Rarely, hepatitis and deaths due to liver failure
manner, achieving steady-state concentrations • Food decreases CPmax • Rifampin also metabolized of R), OR have been observed in patients who received
within 15 minutes. • Should be taken on an by hydrolysis to 3-formyl INH and PZA (50 mg of INH + other hepatotoxic agents in addition to rifampin
• Binds to the subunit of DNA-dependent RNA empty stomach rifampin 120 mg of R + 300 mg PZA) or who had preexisting liver disease.
polymerase (rpoB) -> forms a stable drug– • Rifapentine is metabolized to • Parenteral form also available • Chronic liver disease, alcoholism, and old age
enzyme complex -> suppresses chain formation Rifapentine 3-formyl rifapentine and 3- • Dose for TB: appear to increase the incidence of severe
in RNA synthesis. • High-fat meal increases the formyl-25-O-desacetyl- Adults: 600mg OD, 1hr before or hepatic problems.
• In increased conc., inhibits RNA synthesis in AUC by 50% rifapentine 2hrs after a meal
mammalian mitochondria, viral DNA-dependent • Should be taken with food, • Rifabutin: a major pathway Children: 10-20mg/kg in the • GI disturbances have occasionally required
RNA polymerases, and reverse transcriptases if possible for elimination is CYP3A. same way. discontinuation of the drug.
• Inhibits the growth of most gram (+) bacteria & • Should never be given alone • Various nonspecific symptoms related to the
many gram (-) microorganisms Rifabutin • Drugs and metabolites are due to rapid dev’t of resistance nervous system also have been noted.
• Inhibits the growth of many M. tuberculosis • Food has no effect excreted by bile and • Prophylaxis of meningococcal
clinical isolates in vitro at concentrations of eliminated via feces. disease and H. influenzae • Hypersensitivity reactions may be encountered.
0.06-0.25 mg/L • Due to autoinduction, • Urine elimination accounts for meningitis. • Rare: hemolysis, hemoglobinuria, hematuria,
• Bactericidal against M. leprae. rifamycins reduce their own only one-third and less of • Combined with a B-lactam renal insufficiency, and acute renal failure
• Inhibits M. kansasii at 0.25 to1 mg/L AUCs with repeated metabolites antibiotic or vancomycin, useful
• Suppresses most strains of M. scrofulaceum, administration. • Dosage adjustment not for therapy in selected cases of • Adverse effects with high-dose rifampin more
M. intracellulare, and M. avium at 4mg/L • Good penetration into necessary in patients w/ renal staphylococcal endocarditis or common when time between doses is long
• M. fortuitum is highly resistant many tissues insufficiency osteomyelitis, especially those • High-dose rifampin should not be administered
• Activity is best optimized by a high AUC/MIC • Levels in the CNS reach caused by staphylococci on a dosing schedule of less than twice weekly -
ratio only ~5% of those in • May impart orange-red color "tolerant" to penicillin > associated with a flu-like syndrome of fever,
• Resistance suppression & enduring post- plasma, due to the activity to bodily fluids chills, and myalgias in 20% of patients
antibiotic effect: best optimized by high of P-glycoprotein. • Dose for TB:
Cmax/MIC Rifabutin: 5 mg/kg/day • Eosinophilia, interstitial nephritis, acute tubular
• Duration of time above MIC is of less Rifapentine: 10 mg/kg once a necrosis, thrombocytopenia, hemolytic anemia,
importance week and shock.
• If patients can tolerate it, higher doses -> higher • Light chain proteinuria
bactericidal activities & suppression of • Thrombocytopenia, transient leukopenia, and
resistance anemia

Rifabutin • Potential teratogenicity is unknown

• Inhibits the growth of most MAC isolates at • Crosses placenta
conc from 0.25 to 1mg/L - avoid use during pregnancy
• Inhibits many strains of M. tuberculosis at conc
of ≤ 0.125 mg/L • Decreases t1/2 for compounds that are
metabolized by CYPs
Resistance:
• The prevalence of rifampin-resistant isolates
are 1 in every 107 to 108 bacilli
• Due to an alteration of the target of this drug,
rpoB. In 86% of cases, due to mutations at
codons 526 and 531 of the rpoB gene
• Inducible or environment-dependent mutators
• Antibitiocs, endogenous oxidative, metabolic
stressors -> DNA damage -> induces dnaE2 ->
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy

assoc with error-prone DNA repair -> leads to

higher rates of rifampin resistance
Pharmacokinetic Parameters of Rifampin, Rifabutin, and Rifapentine
RIFABUTIN RIFAMPIN RIFAPENTINE
Protein binding (%) 71 85 97
Oral bioavailability (%) 20 68 --
Tmax (hours) 2.5-4.0 1.5-2.0 5.0-6.0
Cmax (total (ug/mL) 0.2-0.6 8-20 8-30
Cmax (free drug (ug/mL) 0.1 1.5 0.5
Half-life (hours) 32-67 2-5 14-18
IC/EC penetration 9 5 24-60
Autoinduction (AUC decrease) 40% 38% 20%
CYP3A induction Weak Pronounced Moderate
CYP3A substrate Yes No No
Isoniazid (NYDRAZID, others)
• A primary drug for the chemotherapy of tuberculosis. All patients infected with isoniazid-sensitive strains of the tubercle bacillus should receive the drug if they can tolerate it.
• Combination “short-course” therapy: INH + PZA + R -> improved remission rates
• (Isonicotinic acid hydrazide), also called INH, is a small water-soluble molecule that is structurally related to pyrazinamide
• Enters bacilli by passive diffusion. • Bioavailability of orally • Metabolized by hepatic • Available as a pill, as an elixir, • Acetylisoniazid -> rapidly acetylated by NAT-2 -
• Not directly toxic to the bacillus administered isoniazid is arylamine N-acetyltransferase and for parenteral > diacetylhydrazine (nontoxic)
• Must be activated to its toxic form within the ~100% for the 300 mg type 2 (NAT2), encoded by a administration • Acetylisoniazid -> acetylhydrazine -> slowly
bacillus by KatG, a multifunctional catalase- dose. variety of NAT2* alleles • Commonly used total daily converted to hepatotoxic metabolites by
peroxidase -> catalyzes the production of an • Pharmacokinetics of • Isoniazid is N-acetylated to N- dose: 5 mg/kg (max 300mg) CYP2E1
isonicotinoyl radical that -> interacts with isoniazid are described by a acetylisoniazid, using acetyl- • Oral and intramuscular doses • Rifampin -> induces CYP2E1 -> potentiates
mycobacterial NAD and NAPD -> formation of one-compartment model coA are identical isoniazid hepatotoxicity
adducts: • The ratio of isoniazid in the • Clearance is classified as: • Children: 10-15 mg/kg/day
• One of the adducts, a nicotinoyl-NAD isomer, epithelial lining fluid to that - One of two phenotypic (max 300mg) • Common: elevated serum aspartate and alanine
inhibits the activities of enoyl acyl carrier protein in plasma is 1-2 and for CSF groups: "slow" and "fast" • Administered with pyridoxine transaminases
reductase (InhA) and -ketoacyl acyl carrier is 0.9. acetylators. (vit B6) to minimize risks of • Hepatic damage:
protein synthase (KasA) Approximately 10% of drug - 3 groups: fast, intermediate, neurological toxicity in patients - rare in patients <20 years old
-> inhibits synthesis of mycolic acid, an is bound to protein. and slow acetylators predisposed to neuropathy - incidence increases with age to 1.2% between
essential component of the mycobacterial cell • Population pharmacokinetic 35 and 49 years and to 2.3% over 50 years of
wall -> leads to bacterial cell death. parameters: estimated and Overdose: age
• Another adduct, a nicotinoyl-NADP isomer, related to NAT2 genotype; the • Intentional overdose occurs - overall risk is increased by co-admin with
potently inhibits (Ki<1nM) mycobacterial number of NAT2*4 alleles most often in young women rifampin to ~3%.
dihydrofolate reductase account for 88% of the with concomitant psychiatric - fatal hepatitis is even rarer (0.02%)
-> interferes with nucleic acid synthesis variability of INH clearance problems prescribed INH for - most cases of hepatitis occur 4-8 weeks after
• AUC to MIC ratio • 75-95% is excreted in the latent TB. As little as 1.5 g can the start of therapy
• Resistance emergence related to both urine within 24h, be toxic.
AUC/MIC and Cmax/MIC predominantly as • Clinical triad of INH overdose: • If pyridoxine is not given concurrently,
• Efficacy is most dependent on drug dose and acetylisoniazin and - seizures refractory to treatment peripheral neuritis (most commonly
CL & thus on the activity of NAT-2 polymorphic isonicotinic acid with phenytoin and barbiturates paresthesias of feet and hands) is encountered
forms - metabolic acidosis with an in ~2% of patients receiving INH 5 mg/kg of the
• Dividing the total dose into more frequent doses anion gap that is resistant to drug daily.
-> detrimental in terms of resistance emergence treatment with sodium • Neuropathy: more frequent in slow acetylators &
bicarbonate in individuals with DM, poor nutrition, anemia
Resistance: - coma • Other neurological toxicities: convulsions in
• Associated with mutation or deletion of katG, • Common early symptoms patients with seizure disorders, optic neuritis &
overexpression of the genes for inhA and ahpC, appear within 0.5-3 hours of atrophy, muscle twitching, dizziness, ataxia,
and mutations in the kasA gene ingestion: ataxia, peripheral paresthesias, stupor, toxic encephalopathy,
• inhA: confers low-level resistance to INH and neuropathy, dizziness, and mental abnormalities
some cross-resistance to ethionamide slurred speech.
• The prevalence of drug-resistant mutants is ~1 • Most dangerous are grand mal • Hypersensitivity may develop
in 106 bacilli seizures and coma,
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy
• Probability of resistance to 2 antimycobacterial
agents is small (~1 in 1012)
• TB cavities may contain as many as 107 to 109
microorganisms -> preexistent resistance can
be expected in pulmonary TB cavities of
untreated patients
• Spontaneous mutants will be amplified by
monotherapy; thus 2+ drugs are used
Pyrazinamide aka pyrazinoic acid amide, pyrazine carboxylamide, pyrazinecarboxamide
• Synthetic pyrazine analog of nicotinamide
• "Activated" by acidic conditions at the edges of • Oral bioavailability is
necrotic TB cavities where inflammatory cells
produce lactic acid
• Parent drug diffuses into M. tb ->
nicotinamidase (pyrazinaminidase) deaminates
PZA -> pyrazinoic acid (POA-) -> exported to
EC milieu by efflux pump
• In an acidic EC milieu, a fraction of POA- is
protonated to POAH, a more lipid-soluble form - an absorption rate constant
> enters the bacillus
• pH of EC medium declines toward pKa of
pyrazinoic acid -> favors formation of POAH ->
equilibration across bacillary membrane ->
accumulation within bacillus
• Although the actual mechanism of microbial kill
is still unclear, three mechanisms have been
proposed:
- inhibition of fatty acid synthase type I ->
interference with mycolic acid synthesis
- binding to ribosomal protein S1 (RpsA) and
inhibition of trans-translation
- reduction of intracellular pH disruption of
membrane transport by HPOA
• Antimicrobial activity only at acidic pH
• At pH of 5.8 – 5.95, 80-90% of clinical isolates
have MIC of ≤ 100mg/L
Resistance:
• PZA-resistant M. tb have pyrazinamidase with
reduced affinity for PZA -> decreases the
conversion of PZA to POA
• Single point mutations in the pncA gene are
found in 70% of resistant clinical isolates
Ethambutol
• Ethambutol hydrochloride (MYAMBUTOL) - water-soluble and heat-stable compound
• Metabolized by microsomal
>90%. deamidase -> POA ->
• Pharmacokinetics are best hydroxylated to 5-hydroxy-
described by a one- POA -> excreted by the
compartment model. kidneys
• GI absorption segregates • Clearance and volume of
patients into two groups: distribution (Vd) increase with
- fast absorbers (56%) with patient mass (0.5 L/hour and
4.3 L for every 10 kg above
of 3.56/hour 50 kg), and Vd is larger in
- slow absorbers (44%) with males (by 4.5 L):
an absorption rate of - T1/2 will vary considerably
1.25/hour based on weight and gender
• The drug is concentrated - AUC will decrease with
20-fold in lung epithelial increase in weight for the
lining fluid same dose (same mg
drug/kg body weight)
• Clearance reduced in renal
failure
- Dosing frequency reduced to
3 times a week at low
glomerular filtration rates
• Hemodialysis removes PZA
-> drug needs to be re-
dosed after each session of
hemodialysis
encountered when patients
ingests 30 mg/kg of the drug.
Mortality in these
circumstances is as high as
20%.
• Treatment of overdose:
- Cessation of INH dosing
- Admin of IV pyridoxine over
5-15 min on a gram-to-gram
basis with the ingested INH
- If dose of ingested INH is
unknown, pyridoxine dose of
70 mg/kg should be used
- In patients with seizures,
benzodiazepines are utilized.
• Co-administration of PZA with
INH or R -> one-third reduction
in the duration of anti-TB
therapy, and a two-thirds
reduction in TB relapse
• Reduction in length of therapy
to 6 months, producing the
current "short course"
chemotherapy.
• Administered at an oral dose
of 15-30 mg/kg/day (-> much
safer dosage)
• Hematological reactions also may occur.
Vasculitis associated with antinuclear antibodies
may appear during treatment, disappears when
the drug is stopped.
• Arthritic symptoms (back pain; bilateral proximal
interphalangeal joint involvement; arthralgia of
the knees, elbows, and wrists; and the
"shoulder-hand" syndrome) have been
attributed to this agent.
• Miscellaneous reactions: dryness of the mouth,
epigastric distress, methemoglobinemia,
tinnitus, and urinary retention.
• Injury to the liver: most serious side effect of
pyrazinamide.
• With an oral dose of 40-50mg/kg, S/S of hepatic
disease appear in ~15%, with jaundice in 2-3%,
and death due to hepatic necrosis rarely
• Elevations of plasma alanine/aspartate
aminotransferases are the earliest
abnormalities produced
• Prior to admin, all patients should undergo
studies of hepatic function & should be
repeated at frequent intervals during the entire
period of treatment.
• If evidence of significant hepatic damage
becomes apparent, therapy must be stopped.
• Should not be given to individuals with hepatic
dysfunction unless unavoidable.
• Inhibits excretion of urate -> hyperuricemia ->
acute episodes of gout.
• Arthralgias, anorexia, nausea and vomiting,
dysuria, malaise, and fever.
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy
• Inhibits arabinosyl transferase III -> disrupts
transfer of arabinose in arabinogalactan
biosynthesis -> disrupts the assembly of
mycobacterial cell wall.
• The arabinosyl transferases are encoded by
embB genes.
• Activity against a wide range of mycobacteria
but has no activity against any other genus.
• Susceptible: M. tuberculosis, M. kansasii, M.
avium, M. gordonae, M. marinum, M.
scrofulaceum, M. szulgai
• Resistant: M. xenopi, M. fortuitum, M. chelonae
Resistance:
• Mycobacterial resistance to the drug develops
via mutations in the embB gene.
• In 30-70% of clinical isolates that are resistant
to ethambutol, mutations are encountered at
codon 306 of the embB gene. Mutations in this
codon are also encountered in ethambutol-
susceptible mycobacteria, as though this
mutation is necessary, but not sufficient, to
confer ethambutol resistance.
• Enhanced efflux pump activity may induce
resistance to both isoniazid and ethambutol
Aminoglycosides: Streptomycin, Amikacin, and Kanamycin
• Bind to the 30S ribosomal subunit -> inhibits
protein synthesis
• The MICs for M. tuberculosis in Middlebrook
broth are 0.25-3.0 mg/L for all three
aminoglycosides. For M. avium streptomycin
and amikacin, MICs are 1-8 mg/L; those of
kanamycin are 3-12 mg/L. M. kansasii is
frequently susceptible to these agents, but
other nontuberculous mycobacteria are only
occasionally susceptible.
Clofazimine
• Clofazimine (LAMPRENE) - a fat-soluble riminophenazine dye. It was discontinued in 2005 but remains licensed as an orphan drug
• Inhibition ofmacrophages, T cells, neutrophils,
complement -> antibacterial activity and anti-
inflammatory activity
• The biochemical basis for the antimicrobial
actions of clofazimine remains to be established
• Possible mechanisms of action include:
- membrane disruption
- inhibition of mycobacterial phospholipase A2
- inhibition of microbial K+ transport
- generation of hydrogen peroxide
- interference with the bacterial ETC
• Activity against M. avium, M. tuberculosis, and
many gram-(+) bacteria
• Oral bioavailability of
ethambutol is ~80
• Approximately 10-40% of
the drug is bound to
plasma protein.
• The decline in ethambutol
is biexponential
- t1/2 of 3h in the first 12 h
- t1/2 of 9h between 12 and
24h, due to redistribution
of drug.
• Clearance and Vd are
greater in children than in
adults on a per kilogram
basis
• Slow and incomplete
absorption common in
children
• Oral bioavailability is • Metabolized in the liver in • Administered orally at doses
variable, 45-60%
• Increased 2-fold by high-fat -
meals and decreased 30% - hydrolytic deamination
by antacids - glucuronidation
- hydroxylation.
• After a single 200mg dose,
tmax = 5.3-7.8 hours.
• After prolonged repeated
dosing , the t1/2 = ~70 days
• Result of good penetration
into many tissues ->
reddish black discoloration
of skin and body
• Oxidized by alcohol • Oral administration in tablets
dehydrogenase -> aldehyde containing the D-isomer
-> oxidized by aldehyde • For the treatment of TB,
dehydrogenase -> disseminated MAC, and in M.
dicarboxylic acid. kansasii infection
• 80% of the drug is not • Administered at 15-25 mg/kg
metabolized -> renally per day for both adults and
excreted children.
• ~30% excreted as aldehyde • In renal failure, dosed at 15-25
and dicarboxylic acid mg/kg, 3x a week
derivatives
• Treatment of mycobacterial
diseases
four steps: up to 300 mg a day.
hydrolytic dehalogenation • Component of multiple drug
therapy for leprosy
• Treatment of chronic skin
ulcers produced by M.
ulcerans
• Produces very few serious untoward reactions.
• Fewer than 2% of patients who receive daily
doses of 15 mg/kg of ethambutol have adverse
reactions: ~1% experience diminished visual
acuity, 0.5% a rash, and 0.3% drug fever.
• Pruritus, joint pain, GI upset, abdominal pain,
malaise, headache, dizziness, mental
confusion, disorientation, possible
hallucinations
• Anaphylaxis and leukopenia are rare. Therapy
results in an increased concentration of urate in
the blood in ~50% of patients, owing to
decreased renal excretion of uric acid.
• The most important side effect is optic neuritis,
resulting in decreased visual acuity and loss of
ability to differentiate red from green. The
incidence of this reaction is proportional to the
dose of ethambutol and is observed in 15% of
patients receiving 50 mg/kg/day, in 5% of
patients receiving 25 mg/kg/day, and in <1% of
patients receiving daily doses of 15 mg/kg.
• GI problems in 40-50% of patients: abdominal
pain, diarrhea, nausea, and vomiting.
• In patients who died following abdominal pain,
crystal deposition in intestinal mucosa, liver,
spleen, and abdominal lymph nodes were
demonstrated.
• Body secretion discoloration, eye discoloration,
and skin discoloration in most patients
• Depression in some patients
• Anti-inflammatory effects may be inhibited by
dapsone.
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy

secretions, take a long

time to resolve.
Fluoroquinolones
• DNA gyrase inhibitors
• Drugs such as ofloxacin and ciprofloxacin: second-line anti-TB agents for many years, but limited by the rapid development of resistance. Adding C8 halogen and C8 methoxy groups markedly reduces
the propensity for drug resistance. Of the C8 methoxy quinolones, moxifloxacin is furthest along in clinical testing as an anti-TB agent. Moxifloxacin is being studied to replace either isoniazid or
ethambutol
• Highly active against M. TB • In TB patients, moxifloxacin • The most important cause of pharmacokinetic
• Important drug for MDR TB (400 mg/day) -> bactericidal variability for moxifloxacin is concomitantly
• Gatrifloxacin and moxifloxacin -> most active effects similar to that of administered drugs for tuberculosis.
and least likely to select for quinolone standard doses of isoniazid
resistance • When replacing ethambutol,
• Mycobacterial resistance to one fluroquinolone 400 mg/day of moxifloxacin
-> cross-resistance for the entire class -> faster sputum conversion at
4 weeks
• Currently being studied in a
phase 3 trial that may lead to
4-month duration of anti-TB
therapy
TMC-207 (R207910)
• Is an experimental diarylquinone discovered by Andries et al. in 2005
• Targets subunit c of the ATP • After oral ingestion of 400 mg, the • Anti-TB activity is correlated with • Mild adverse effects
synthase of M. tb -> inhibition of the tmax = 4 hours, Cmax = 5.5 mg/L, and time above MIC. In murine TB, TMC- • Nausea in 26% of patients and
proton pump activity of the ATP the AUC = 65 mg·h/L 207 had superior bactericidal activity diarrhea in 13% of patients
synthase • CL is ~6.2 L/h, although systemic compared to INH and R, and • Arthralgia, pain in extremities, and
• Targets bacillary energy metabolism clearance reportedly is accelerated sterilization when hyperuricemia in a small proportion
"triexponential." combined with R, INH, and PZA. of patients.
• MIC for M. tuberculosis is 0.03-0.12 • In patients with drug-susceptible TB, • Only a limited number of patients
mg/L the rate of sputum bacillary decline have been exposed to this drug, so
• Good activity against MAC, M. was similar to R and INH. that the full side-effect profile is
leprae, M. bovis, M. marinum, M. • TMC207 400 mg daily for 2 weeks unclear
kansasii, M. ulcerans, M. fortuitum, followed by 200 mg 3x day was
M. szulgai, and M. abscessus added to a background second-line
• Resistance is associated with two regimen of either kanamycin or
point mutations: D32V and A63P amikacin, ofloxacin with or without
- encodes the membrane-spanning ethambutol in patients with TB
domain of the ATP synthase c resistant to both INH and R (MDR-
subunit TB), and led to an 8-week sputum
conversion of ~50% with TMC207
compared to 9% without.
PA-824
• Is a nitroimidazopyran discovered by Stover et al. in 2000.
• Inhibits M. tuberculosis mycolic acid and protein synthesis at the step between hydroxymycolate and ketomycolate. Similar to the structurally related metronidazole, PA-824 is a pro-drug that requires
activation by the bacteria via a nitro-reduction step that requires, among other factors, a specific glucose-6-phosphate dehydrogenase, FGD1, and the reduced deazaflavin co-factor F420. Another
mechanism involves generation of reactive nitrogen species such as NO by PA-824's des-nitro metabolite, which then augment the kill of intracellular nonreplicating persistent bacilli by the innate
immune system
• Resistance:
• The proportion of mutants resistant to 5 mg/L of PA-824 is 10-6. Resistance arises due to changes in structure of FGD, which is due to a variety of point mutations in fgd gene. However, resistant isolates
have also been identified that lack fgd mutations, so that resistance may also be due to other mechanisms

Ethionamide (TRECATOR)
• a congener of thioisonicotinamide
• Mycobacterial EthaA, an NADPH-specific, FAD-
containing monooxygenase, converts
ethionamide to a sulfoxide, and then to 2-ethyl-
• The oral bioavailability of • Ethionamide is cleared by • is administered only orally. The • 50% of patients unable to tolerate a single dose
ethionamide approaches hepatic metabolism; six initial dosage for adults is 250 larger than 500 mg because of GI upset:
100%. The metabolites have been mg twice daily; it is increased
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy
4-aminopyridine. Although these products are
not toxic to mycobacteria, it is believed that a
closely related and transient intermediate is the
active antibiotic.
• Inhibits mycobacterial growth by inhibiting the
activity of the inhA gene product, the enoyl-ACP
reductase of fatty acid synthase II > same
enzyme that activated isoniazid inhibits.
• Although the exact mechanisms of inhibition
may differ, the results are the same: inhibition
of mycolic acid biosynthesis and consequent
impairment of cell-wall synthesis.
• Resistance:
• Via changes in the enzyme that activates
ethionamide, and mutations are encountered in
a transcriptional repressor gene that controls its
expression, etaR. Mutations in inhA gene lead
to resistance to both ethionamide and isoniazid.
Para-aminosalicylic acid (PAS)
• discovered by Lehman in 1943, was the first effective treatment for TB.
• a structural analog of para-aminobenzoic acid,
the substrate of dihydropteroate synthase
(folP1/P2). As a result, thought to be a
competitive inhibitor folP1. However, in vitro the
inhibitory activity against folP1 is very poor.
• Only 37% of the PAS-resistant clinical isolates
or spontaneous mutants encode a mutation in
thyA gene, or in any genes encoding enzymes
in the folate pathway or biosynthesis of thymine
nucleotides. Unidentified actions of PAS likely
play more important roles in its anti-TB effects
• PAS is bacteriostatic. In vitro, most strains of M.
tuberculosis are sensitive to a concentration of
1 mg/L. It has no activity against other bacteria
• Resistance:
• Mutations in thyA gene lead to drug resistance
in a minority of drug-resistant isolates.
Cycloserine (SEROMYCIN)
• is D-4-amino-3-isoxazolidone. It is a broad-spectrum antibiotic produced by Streptococcus orchidaceous
• Cycloserine and d-alanine are structural
analogs
• Cycloserine inhibits alanine racemase which
converts L-alanine to d-alanine and d-alanine:
d-alanine ligase, stopping reactions in which d-
alanine is incorporated into bacterial cell-wall
synthesis
• Cycloserine is a broad-spectrum antibiotic. It
inhibits M. tuberculosis at concentrations of 5-
20 mg/L. It has good activity against MAC,
enterococci, E. coli, S. aureus, Nocardia
species, and Chlamydia.
• Resistance:
pharmacokinetics are
adequately explained by a
one-compartment model
with first-order absorption
and elimination.
• After oral administration of
500 mg of ethionamide, a
Cmax of 1.4 mg/L is
achieved in 2 hours. The
t1/2 is ~2 hours. The
concentrations in the blood
and various organs are
approximately equal.
• PAS oral bioavailability is
>90%
• The Cmax increases 1.5-
fold and AUC 1.7-fold with
food compared to fasting >
mean that PAS should be
administered with food,
which also greatly reduces
gastric irritation
• Protein binding is 50-60%.
PAS is N-acetylated in the
liver to N-acetyl PAS, a
potential hepatotoxin
• Oral cycloserine is almost
completely absorbed.
• T1/2 = 9 hours. Cmax in
plasma is reached in 45
minutes in fasting subjects,
but is delayed for up to 3.5
hours with a high-fat meal
• Well distributed throughout
body
• No appreciable barrier to
CNS entry for cycloserine,
and CSF conc are
identified. Metabolites are
eliminated in the urine, with
<1% of ethionamide excreted
in an active form.
• Over 80% of the drug is
excreted in the urine
• >50% is in the form of the
acetylated compound.
• Excretion of PAS acid is
reduced by renal dysfunction
• Dose must be reduced in
renal dysfunction.
• About 50% of cycloserine is
excreted unchanged in the
urine in the first 12 hours; a
total of 70% is recoverable in
the active form over a period
of 24 hours. The drug may
accumulate to toxic
concentrations in patients
with renal failure. About 60%
of it is removed by
hemodialysis, and the drug
must be re-dosed after each
hemodialysis session
by 125 mg/day every 5 days
until a dose of 15-20
mg/kg/day is achieved. The
maximal dose is 1 g daily. The
drug is best taken with meals
in divided doses to minimize
gastric irritation. Children
should receive 10-20
mg/kg/day in two divided
doses, not to exceed 1 g/day
• Pyridoxine (vitamin B6)
relieves the neurologic
symptoms, and its concomitant
administration is
recommended.
• PAS is administered orally in a
daily dose of 12 g.
• The drug is best administered
after meals, with the daily dose
divided into three equal
portions.
• Children should receive 150-
300 mg/kg/day in 3-4 divided
doses.
• Cycloserine is available for
oral administration. The usual
dose for adults is 250-500 mg
twice daily.
anorexia, nausea and vomiting, gastric irritation,
and a variety of neurologic symptoms.
• Severe postural hypotension, mental
depression, drowsiness, and asthenia are
common.
• Convulsions and peripheral neuropathy are
rare.
• Olfactory disturbances, blurred vision, diplopia,
dizziness, paresthesias, headache,
restlessness, and tremors.
• Severe allergic skin rashes, purpura, stomatitis,
gynecomastia, impotence, menorrhagia, acne,
and alopecia have also been observed. A
metallic taste also may be noted. Hepatitis has
been associated with the use of the
ethionamide in ~5% of cases.
• Hepatic function should be assessed at regular
intervals in patients receiving the drug.
• The incidence of untoward effects is ~10-30%.
• GI problems predominate and often limit patient
adherence.
• Hypersensitivity reactions to PAS are seen in 5-
10% of patients and manifest as skin eruptions,
fever, eosinophilia, and other hematological
abnormalities
• Neuropsychiatric symptoms are common and
occur in 50% of patients on 1 g/day ->
nickname of drug: “psych-serine”
• Headache and somnolence to severe
psychosis, seizures, and suicidal ideas.
• Large doses of cycloserine or the concomitant
ingestion of alcohol increases the risk of
seizures.
• Contraindicated in individuals with a history of
epilepsy and should be used with caution in
individuals with a history of depression
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy

• Mutations involved in cycloserine resistance to approximately the same as

pathogenic Mycobacteria are currently those in plasma.
unknown.
• Resistance in clinical isolates of M. tuberculosis
has been detected in 10-82% of isolates
Capreomycin (CAPASTAT)
• An antimycobacterial cyclic peptide. It consists of four active components: capreomycins IA, IB, IIA, and IIB. The agent used clinically contains primarily IA and IB. Antimycobacterial activity is similar to
that of aminoglycosides as are adverse effects, and capreomycin should not be administered with other drugs that damage cranial nerve VIII.
• Bacterial resistance to capreomycin develops when it is given alone; such microorganisms show cross-resistance with kanamycin and neomycin. The adverse reactions associated with the use of
capreomycin are hearing loss, tinnitus, transient proteinuria, cylindruria, and nitrogen retention. Severe renal failure is rare. Eosinophilia is common. Leukocytosis, leukopenia, rashes, and fever have
also been observed. Injections of the drug may be painful. Capreomycin is a second-line antituberculosis agent. The recommended daily dose is 1g (no more than 20 mg/kg) per day for 60-120 days,
followed by 1 g two to three times a week.
• Macrolide.
Dapsone (DDS, diamino-diphenylsulfone)
• Or 4'-diaminodiphenylsulfone, was synthesized by Fromm and Wittman in 1908, and its similarity to sulphonamides led to the establishment of anti-streptococcal effects
• structural analog of para-aminobenzoic acid • After oral administration, • Approximately 70-80% of a • Administered as an oral agent. • G6PD protects red cells against oxidative
(PABA) and a competitive inhibitor of absorption is complete; the dose of dapsone is excreted • Dapsone is combined with damage. However, G6PD deficiency is
dihydropteroate synthase (folP1/P2) in the elimination t1/2 = 20-30h in the urine as an acid-labile chlorproguanil for the encountered in nearly half a billion people
folate pathway. • CL increases 0.03 L/hour mono-N-glucuronide and treatment of malaria. Dapsone worldwide, the most common of 100 variants
• Broad-spectrum agent with antibacterial, anti- and Vd 0.7 L increases for mono-N-sulfamate is also used for P. jiroveci being G6PD-A-. Dapsone, an oxidant, causes
protozoal, and antifungal effects. each 1-kg increase in body • Intestinal reabsorption of infection and prophylaxis, and severe hemolysis in patients with G6PD
• bacteriostatic against M. leprae at weight above 62.3 kg sulfones excreted in the bile for the prophylaxis for T. deficiency. Thus, G6PD deficiency testing
concentrations of 1-10 mg/L. More than 90% of contributes to long-term gondii. The anti-inflammatory should be performed prior to use of dapsone
clinical isolates of MAC and M. kansasii have • Undergoes N-acetylation retention in the bloodstream; effects are the basis for wherever possible
an MIC of 8 mg/L, but the MICs for M. by NAT2. N-oxidation to periodic interruption of therapy for pemphigoid,
tuberculosis isolates are high. It has little dapsone hydroxylamine is treatment is advisable for this dermatitis herpetiformis, linear • Hemolysis develops in almost every individual
activity against other bacteria. via CYP2E1, and to a reason. IgA bullous disease, relapsing treated with 200-300 mg of dapsone per day.
• Highly effective against P. falciparum with IC50 lesser extent by CYP2C. chondritis, and ulcers caused • Doses of 100 mg in healthy persons and 50 mg
of 0.006-0.013 mg/mL (0.6-1.3 mg/L) even in Dapsone hydroxylamine by the brown recluse spider in healthy individuals with a G6PD deficiency do
sulfadoxine-pyrimethamine–resistant strains. enters red blood cells -> not cause hemolysis.
Dapsone has an IC50 of 0.55 mg/L against methemoglobin formation. • Methemoglobinemia also is common. A genetic
Toxoplasma gondii tachyzoites. Sulfones tend to be deficiency in the NADH-dependent
• Effective at concentrations of 0.1/mg/L against retained for up to 3 weeks methemoglobin reductase can result in severe
the fungus Pneumocystic jiroveci. in skin and muscle and methemoglobinemia after administration of
especially in liver and dapsone.
Resistance: kidney. Epithelial lining • Isolated instances of headache, nervousness,
• In P. falciparum, P. jiroveci, and M. leprae, fluid to plasma ratio is insomnia, blurred vision, paresthesias,
results primarily from mutations in genes between 0.76 and 2.91; reversible peripheral neuropathy (thought to be
encoding dihydropteroate synthase. In P. CSF-to-plasma ratio is due to axonal degeneration), drug fever,
falciparum mutations occur at several positions 0.21-2.01 hematuria, pruritus, psychosis, and a variety of
such as 436, 437, 540, 58, and 613. In P. skin rashes have been reported. An infectious
jiroveci isolates, mutations are amino acid mononucleosis-like syndrome, which may be
substitutions at positions 55 and 57. In M. fatal, occurs occasionally.
leprae, mutations are at codons 53 and 55.

Table 56–5 Drugs Used in the Treatment of Mycobacteria Other Than for Tuberculosis, Leprosy, or MAC
MYCOBACTERIAL SPECIES FIRST-LINE THERAPY ALTERNATIVE AGENTS
M. kansasii Isoniazid + rifampina + ethambutol Trimethoprim-sulfamethoxazole; ethionamide; cycloserine; clarithromycin; amikacin; streptomycin; moxifloxacin or
gatifloxacin
M. fortuitum complex Amikacin + doxycycline Cefoxitin; rifampin; a sulfonamide; moxifloxacin or gatifloxacin; clarithromycin; trimethoprim-sulfamethoxazole; imipenem
M. marinum Rifampin + ethambutol Trimethoprim-sulfamethoxazole; clarithromycin; minocycline; doxycycline
Mycobacterium ulcerans Rifampin + streptomycinc Clarithromycinb; rifapentineb
M. malmoense Rifampin + ethambutol ± clarithromycin Fluoroquinolone
M. haemophilum Clarithromycin + rifampin + quinolone -
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy