Antimycobacterial agents Flashcards
State the two major principles for antituberculosis therapy.
1) Combinations of two or more drugs: Overcome obstacles involved in treatment • Drugs are often synergistic Decreases likelihood of resistance • Obtain rate of resistance to combination of drugs by adding exponents (the rate of a resistance mutation in a population of bacilli)
2) Prolonged therapy
o Slow mycobacterial reaction to chemotherapy
Discuss the rationale for the two stages of therapy (active treatment phase and the suppressive treatment phase) and what determines the movement from one stage to the other.
Initial phase
o Reduce mycobacterial mass
o Typically 2 months
Prolonged therapy:
o Helps patient’s immune system take over = prevent relapse
o Typically 4 months
o Begin when bacilli disappear from sputum (culture conversion)
List the first line anti-TB agents
Isoniazid
Rifampin
Ethambutol
Pyrazinamide
Describe the MOA and mechanism of resistance for isoniazid
MOA:
Activated by KatG → Forms inhibitory complex (with AcpM and KasA) with NAD → blocks mycolic acid synthesis
Resistance:
o Overexpressing inhA (encodes NADH-dependent acyl carrier protein reductase)
o Mutation/deletion of katG gene
o Promoter mutations resulting in overexpression of ahpC (putative virulence gene involved in protection of cell from oxidative stress)
o Mutations in kasA
Describe the MOA and mechanism of resistance for rifampin
MOA:
Bids to bacterial subunit of RNA polymerase → inhibits RNA synthesis
Resistance:
o Point mutations in rpoB (gene for beta subunit of RNA polymerase) → reduced binding of rifampin to RNA polymerase
Describe the MOA and mechanism of resistance for ethambutol
MOA:
Blocks arabinosyl transferase II (involved in cell wall synthesis); inhibits RNA synthesis → decreased protein synthesis; may interfere with mycolic acid synthesis
Resistance:
o Mutations leading to overexpression of emb gene (encodes arabinosyl transferase II) → overexpression of products
o Mutations within embN structural gene
Describe the MOA and mechanism of resistance for pyrazinamide
MOA: Unknown but may: 1) Inhibit FA synthetase I 2) Decrease pH 3) Disrupt membrane transport
Resistance:
o Impaired uptake
o Mutations in pncA (encodes mycobacterial pyrazinamidase, which converts it to active form pyrazinoic acid)
Describe the effect of a genetic polymorphism on the pharmacokinetics of isoniazid.
- Genetically determined by N-acetyltransferase activity
- Lower plasma concentration (about 1/3 to ½) in rapid compared to fast acetylators
- Usually not a therapeutic consequence when administered daily
List major toxicities associated with Isoniazid
o Immunologic reactions
• Fever, skin rashes
• Drug induced SLE
o Hepatitis
• Loss of appetite, nausea, vomiting, jaundice, upper right quadrant pain
• Hepatocellular damage and necrosis
• Greater risk with increased age, alcoholics, possibly during pregnancy and postpartum period
o Peripheral neuropathy with higher doses
• More likely in slow acetylators, malnutrition, alcoholism, diabetes, AIDS, uremia
• Due to relative pyridoxine deficiency (reversed by giving pyridoxine)
o CNS toxicity
• Rare
• Memory loss, psychosis, seizures
o Other reactions
• Hematologic abnormalities
• Provocation of pyridoxine deficiency anemia
• Tinnitus
• GI discomfort
• Can reduce phenytoin metabolism → increased blood level and toxicity
List major toxicities associated with Rifampin
o Orange color to urine, sweat, tears, and contact lenses
o Rashes, thrombocytopenia, nephritis
o Cholestatic jaundice
o Hepatitis (occasionally)
o Light-chain proteinuria
o Flu-like symptoms if given <2x weekly (Fever, chills, myalgias, anemia, thrombocytopenia, sometimes acute tubular necrosis)
o Induces cytochrome P450 → increased elimination of numerous drugs
List major toxicities associated with Ethambutol
Rare hypersensitivity
Retrobulbar (optic) neuritis
• Loss of visual acuity; red-green colorblindness
• Dose-related
• Usually reversible
• Contraindicated in children (too young to test vision)
Gout flares (because interferes with uric acid excretion)
List major toxicities associated with Pyrazinamide
o Hepatoxicity o Nausea o Vomiting o Drug fever o Hyperuricemia (may provoke acute gouty arthritis)
List the potential drug interactions that can occur with the use of isoniazid
o Reduces phenytoin metabolism (anticonvulsant) → increased blood level and toxicity
List the potential drug interactions that can occur with the use of Rifampin
o Induces cytochrome P450 → increased elimination of numerous drugs
Describe the current recommended treatment regimens for tuberculosis.
• Latent infections
o Isoniazid for 9 months
Standard regimen for active disease
Isoniazid + rifampin + pyrazinamide for 6 months
• If organisms susceptible and HIV-negative patient = can discontinue pyrazinamide after 2 months
• If isoniazid resistance is > 4% = add ethambutol or streptomycin
Rifampin + pyrazinamide + ethambutol for 6 months
• If organisms are isoniazid resistant
• Alternative regimens o Isoniazid + rifampin for 9 months o Rifampin + ethambutol for 12 months o Isoniazid + ethambutol for 18 months o Intermittent (2-3 times/week) high-dose 4 drug regimens
List the major drugs used for the prophylaxis of tuberculosis.
- Isoniazid
* Rifampin (if unable to take isoniazid)
List the second-line agents that are commonly used when there is resistance to the first- line drugs or when patient-related issues warrant their use.
- Ethionamide
- para-Aminosalycilic acid
- Cycloserine
- Capreomycin
- Aminoglycoside antibiotics
- Fluoroquinolone antibiotics
- Kanamycin and Amikacin
- Linezolid
- Rifabutin (ansamycin)
- Rifapentine
Ethionamide
o Chemically related to isoniazid
o Blocks mycolic acid biosynthesis
o Hepatotoxic
o Low-level cross-resistance with isoniazid
para-aminosalycilic acid
o Mimics PABA
o Inhibits dihydropteroate synthase → decreased purine biosynthesis
o Adverse reactions:
• GI symptoms
• Peptic ulcers and hemorrhage
• Hypersensitivity reactions after 3-8 weeks
Cycloserine
o d-alanine analog
o a folate synthesis antagonist active against TB
o Inhibits alanine racemase and d-ala:d-ala ligase → decreased cell wall synthesis
o Peripheral neuropathy and CNS dysfunction (depression, psychotic reactions)
Capreomycin
Cyclic peptide protein synthesis inhibitor
• Binds to 70S ribosomal subunit?
Injectable agent
• Local pain or sterile abscesses at injection site
Nephrotoxic and ototoxic
• Tinnitus, deafness, vestibular disturbances
Aminoglycoside antibiotics
o Bind to 30S ribosomal subunit → inhibit protein synthesis
Fluoroquinolone antibiotics
o Inhibit topoisomerases
o Active against atypical mycobacteria
Kanamycin and Amikacin
o Amikacin = treat streptomycin- or multidrug- resistant strains
o Kanamycin = treat streptomycin-resistant strains
Linezolid
o In combination with other 2nd and 3rd line drugs to treat multidrug resistant strains
o Side effects: bone marrow suppression, irreversible peripheral and optic neuropathy
o Drug of last resort
Rifabutin
(ansamycin
o Similar activity as rifampin
o Induces P450 enzymes but to less effect than rifampin
• Used in HIV infected patients receiving concurrent antiretroviral therapy (cytochrome P450 substrates)
o Effective to prevent and treat disseminated atypical mycobacterial infection in AIDS patients with low CD4 counts
o Preventative therapy for TB
Rifapentine
o Analog of rifampin
o Bacterial RNA polymerase inhibitor
o Induces P450 enzymes
o Used during continuation phase only for TB treatment (after first 2 months)
o Not used to treat HIV patients (high relapse rate)
