Anti-Fungals, Anti-Influenza, Anti-TB Flashcards
MOA of Amphotericin B
• Forms a complex with ergosterol and disrupts the fungal plasma membrane
- Ergosterol is a cell membrane sterol that is found in the cell membrane of fungi
- The predominant cell membrane sterol in human cells and bacteria is cholesterol
- Binds to ergosterol and alters the permeability of the cell
- This happens because multiple amphotericin B molecules form pores in the fungal membrane
- Amphotericin B binds with lipids (i.e., ergosterol) along the double bond rich side of its structure and associates with water molecules along the hydroxyl-rich side of its structure
- Forms pore
- Leakage of intracellular ions and macromolecules leads to cell death
Resistance of Amphotericin B
• Ergosterol binding is impaired
- Decreased membrane concentration of ergosterol
- Modified ergosterol that had less of an affinity for amphotericin B
Adverse Effects of Amphotericin B
• Immediate reactions related to IV infusion
- FEVER, CHILLS, MUSCLE SPASMS, VOMITING, HEADACHE, AND HYPOTENSION
- Can be prevented by slowing the infusion rate or decreasing the dose
- Premedication with corticosteroids, antipyretics, antihistamines, or meperidine can be
helpful in preventing these adverse effects
• Long term effects that occur over time:
- RENAL DAMAGE
- Occurs in nearly all patients given a clinically relevant dose
- Decreased renal perfusion
~ Reversible
- Renal tubular injury and subsequent dysfunction
~ Irreversible - Toxicity manifests as tubular acidosis and severe potassium and magnesium wasting
- ANEMIA
- Reduced erythropoietin production by damaged renal tubular cells
- SEIZURES
- May develop during intrathecal therapy
Flucytosine: MOA
• Taken up into the fungal cell by the enzyme cytosine permease
• Converted intracellularly to 5-FU and then to 5-fluorodeoxyuidine monophosphate (FdUMP)
and fluorouridine triphosphate (FUTP)
- FdUMP inhibits DNA synthesis
- FUTP inhibits RNA synthesis
- Selective toxicity achieved because human cells are unable to convert flucytosine to its active metabolites
- Synergy with amphotericin B
- Enhanced penetration of flucytosine through amphotericin-damaged fungal cell membranes
Flucytosine: Resistance
• Altered metabolism of flucytosine
- Develops rapidly in flucytosine monotherapy
Flucytosine: Adverse Effects
- Structurally related the the chemotherapeutic agent 5-fluorouracil (5-FU)
- Adverse effects result from the metabolism of flucytosine to 5-FU outside the fungal cell
- Possibly conducted by intestinal flora
• Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia
- Most common
• Derangement of liver enzymes
- Occurs less frequently
Azoles: MOA
• Reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes
• Selective toxicity
- Greater affinity for fungal than for human cytochrome P450 enzymes
- Ketoconazole has less selectivity versus the triazoles
Azoles: Resistance
Upregulation of fungal cytochrome P450 enzymes causes standard azole dosages to be less
efficacious
Azoles: Adverse Effects
- Ketoconazole has less selectivity versus the triazoles, therefore ketoconazole has a greater propensity for adverse effects
- Azoles in general are relatively nontoxic
- Minor upset GI symptoms are possible
• All azoles can cause abnormalities in liver enzymes
- Rarely elicit clinical hepatitis
• Drug-drug interactions possible due to potential off target effects of azoles on mammalian
cytochrome P450 system
Ketoconazole
• Greater propensity to inhibit mammalian cytochrome P450 enzymes
- Less selective for fungal P450 enzymes versus the triazoles
• Systemic ketoconazole rarely used for systemic fungal infections in the US
- Ketoconazole and other imidazoles are more common for dermatological functions
Itraconazole
- Oral and IV formulations
- Reduced bioavailability when taken with rifamycins
- Poor penetration into cerebral spinal fluid
Fluconazole
• High oral bioavailability
- Can also be given by IV
- Good cerebral spinal fluid penetration
- Drug interactions less common
- Least effect of all azoles on hepatic enzymes
• Widest therapeutic index of all azoles
- Allows for more aggressive dosing
• Spectrum
- Azole of choice for treatment and secondary prophylaxis of cryptococcal meningitis
- Most commonly used for the treatment of mucocutaneous candidiasis
- No activity against Aspergillus spp. or other filamentous fungi
Voriconazole
- Oral and IV formulations
- Well absorbed orally with a high bioavailability
- Inhibits mammalian CYP3A4 ***
- Dose reduction in medications normally metabolized by CYP3A4 required when
voriconazole initiated~ Examples: cyclosporine, tacrolimus, statins
• Specific toxicities
- Rash
- Elevated hepatic enzymes
- Visual disturbances
~Common (30% of patients)
~ Blurring, changes in color vision or brightness
~ Occur immediately and resolve within about 30 minutes
- Photosensitivity dermatitis
~ Common with chronic oral therapy
• Treatment of choice for invasive aspergillosis and some environmental molds
Posaconazole
- Rapidly distributes to tissues with a low dosage level in the circulation
- Inhibits mammalian CYP3A4
- Dose reduction in medications normally metabolized by CYP3A4 required when
posaconazole initiated - Only azole with significant activity against mucormycosis
- Activity against most species of Candida and Aspergillus
Echinocandins: MOA
- Inhibit synthesis of beta(1-3)-glucan at the fungal cell wall by inhibiting glucan synthase
- This disrupts the fungal cell wall and leads to fungal cell death
Caspofungin
• Disseminated and mucocutaneous candidal infections
• Empiric anti-fungal therapy during febrile neutropenia
- Replaced amphotericin B in this indication
• Invasive aspergillosis
- Only as salvage therapy in amphotericin B non-responders
- Not primary therapy
Micafungin
- Mucocutaneous candidiasis
- Candidemia
- Prophylaxis of candidal infections in bone marrow transplant patients
Anidulafungin
Esophageal candidiasis and invasive candidiasis, including candidemia
Echinocandins: Resistance
Point mutations in glucan synthase
Echinocandins: Adverse Effects
- Well tolerated
* Minor GI side effects and flushing reported infrequently
Neuraminidase inhibitors: MOA
• Competitive inhibitors of viral neuraminidase
- Bind to enzyme’s active site
• Inhibition of viral neuraminidase results in bunching of newly released influenza virions to each other and clumping of virions to the membrane of the infected host cell
• This halts the spread of the infection within the respiratory tract due to a reduction in the
released influenza A and B virus progeny from infected host cells
Neuraminidase inhibitors: Resistance
Can develop but is rare
Neuraminidase inhibitors: Adverse Effects
Increased risk of hallucinations, delirium, and abnormal behavior
Oseltamivir
- Oral administration
- Prodrug activated by hepatic esterases
- Adverse effects
- Nausea, vomiting, and headache
- Fatigue and diarrhea more common with prophylactic use
Zanamivir
- Administered directly to respiratory tract by inhalation
- Adverse effects
- Cough, bronchospasm (occasionally severe), reversible decrease in pulmonary
function, and transient nasal and throat discomfort - Administration not recommended for patients with underlying airway disease
Peramivir
- Administered as a single IV dose for treatment of acute uncomplicated influenza in adults
- Adverse effects
- Diarrhea (most common)
- Skin or hypersensitivity reactions (less common)
Adamantanes
• Block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing replication
- Interfering with the function of the M2 proton ion channel:
- Inhibits acid-mediated dissociation of the ribonucleoprotein complex early in
replication - Potentiates acidic pH-induced conformational changes in hemagglutinin during its
intracellular transport later in replication~ Hemagglutinin is a antigenic surface glycoprotein partially responsible for helping
influenza virions bind to and infect new host cells
- Inhibits acid-mediated dissociation of the ribonucleoprotein complex early in
Neuraminidase inhibitors: Resistance
- High rates in H1N1 and H3N2
* Not commonly used in the treatment or prevention of influenza
Neuraminidase inhibitors: Adverse Effects
- Nausea, anorexia, nervousness, difficulty in concentrating, insomnia, and light-headedness
- Birth defects have been reported after exposure during pregnancy
Isoniazid: MOA
The most active drug for the treatment of tuberculosis caused by susceptible strains.
• Inhibits mycolic acid synthesis
- Mycolic acids are essential components of mycobacterial cell walls
• Prodrug that is activated by KatG
- KatG is the mycobacterial catalase-peroxidase
• The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis
Isoniazid: Resistance
- Overexpression of inhA
- Mutation or deletion of the katG gene
- Promoter mutations resulting in overexpression of ahpC
- Mutations in kasA
- Resistance develops quickly if used as monotherapy
Isoniazid: Adverse Effects
- Related to dosage and duration of administration
- Isoniazid-induced hepatitis is the most major toxic effect
- Peripheral neuropathy (10-20% of patients on a high dose)
Rifampin: MOA
• Inhibits RNA synthesis by binding to the beta subunit of bacterial DNA-dependent RNA
polymerase
• Bactericidal
• Very good penetration and can kill intracellular organisms and those sequestered in
abscesses and lung cavities
• Strong inducer of cytochrome P450 isoforms, which increases the metabolism of many other
drugs
Rifampin: Resistance
• Point mutations in rpoB, the gene for the beta subunit of RNA polymerase
- These mutations prevent rifampin from binding to RNA polymerase and prevents
inhibition of RNA synthesis - Resistance develops quickly if used as monotherapy
- Cross resistance to other rifamycin derivatives (i.e., rifabutin and rifapentine)
Rifampin: Adverse Effect
• Harmless orange color to urine, sweat, and tears
- May permanently stain soft contact lenses
• Occasional adverse effects include rashes, thrombocytopenia, and nephritis
Ethambutol: MOA
• Inhibition of mycobacterial arabinosyl transferases
- These are encoded by the embCAB operon
- Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall
Ethambutol: Resistance
• Mutations resulting in overexpression of emb gene products or within the embB structural
gene
- Overexpression overwhelms the action of ethambutol and mutations within the structure
prevent ethambutol binding
• Ethambutol resistance emerges rapidly if used as a monotherapy
Ethambutol: Adverse Effects
• Most common adverse effect is retrobulbar neuritis
- Results in loss of visual acuity and red-green color blindness
- Recommended to establish a baseline visual acuity and color discrimination and to re-
test monthly after beginning ethambutol - Ethambutol is contraindicated in children too young to permit assessment of visual acuity
and red-green color discrimination
Pyrazinamide: MOA
• Converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase
- Pyrazinamidase is encoded by pncA
• Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions
Pyrazinamide: Resistance
• Impaired uptake of pyrazinamide
- Results in not a high enough concentration in the cell to be efficacious
• Mutations in pncA that impair conversion of pyrazinamide to its active form
- Results in not enough of the active form of pyrazinamide within the cell which leads to lower efficacy
Pyrazinamide: Adverse Effects
Hepatotoxicity (1-5%), nausea, vomiting, drug fever, photosensitivity, and hyperuricemia
Streptomycin: MOA
- Streptomycin is an aminoglycoside antibiotic
* Aminoglycosides are protein synthesis inhibitors
Streptomycin: Resistance
Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle
bacilli
Streptomycin: Adverse Effects
- Ototoxic and nephrotoxic
- Vertigo and hearing loss are the most common adverse effects
- Hearing loss can be permanent
• Toxicity reduced by limiting therapy to no more than 6 months
Ethionamide: MOA
- Chemically related to isoniazid
* Blocks the synthesis of mycolic acids in a similar fashion to isoniazid
Ethionamide: Resistance
- Same as isoniazid
- Resistance develops rapidly if used as a single agent
- Low cross-resistance between isoniazid and ethionamide
Ethionamide: Adverse Effects
• Dose limiting toxicities include gastric irritation and neurologic symptoms
- Neurologic symptoms can be relieved by pyridoxine (vitamin B6)
Capreomycin: MOA
Peptide protein synthesis inhibitor
Capreomycin: Resistance
- Stains of M. tuberculosis that are resistant to streptomycin are usually susceptible to capreomycin
- Cross resistance to strains resistant to amikacin and kanamycin
Capreomycin: Adverse Effects
- Nephrotoxic and ototoxic
* Tinnitus, deafness, and vestibular disturbances can occur
Cycloserine: MOA
• Structural analog of D-alanine
• Inhibits cell wall synthesis by inhibiting the incorporation of D-alanine into the peptidoglycan
pentapeptide by inhibiting alanine racemase and D-alanyl-D-alanine ligase
- Alanine racemase converts L-alanine to D-alanine
Cycloserine: Adverse Effect
• Peripheral neuropathy and central nervous system dysfunction, including depression and psychosis
- Also headaches, tremors, and convulsions
- Pyridoxine (vitamin B6) should be given with cycloserine to ameliorate the neurologic toxicity
- Adverse effects are most common in the first two weeks of therapy
• Adverse effects occur in 25% of patients
psychoses
Aminosalicylic acid: MOA
• Folate synthesis inhibitor active exclusively against M. tuberculosis
• Has a similar structure to p-amino-benzoic acid (PABA) and has a similar mechanism of
action as the sulfonamides (i.e., sulfamethoxazole)
Aminosalicylic acid: Adverse Effects
- GI adverse effects, peptic ulceration, and hemorrhage
- Hypersensitivity reactions can occur 3-8 weeks after aminosalicylic acid treatment
- Symptoms include fever, joint pains, skin rashes, hapatosplenomegaly, hepatitis, adenopathy, and granulocytopenia
Kanamycin / amikacin : MOA
- Kanamycin and amikacin are aminoglycoside antibiotics
* Aminoglycosides are protein synthesis inhibitors
Kanamycin / amikacin : Resistance
- Amikacin has no cross resistance with streptomycin
* Amikacin has cross resistance with kanamycin
Kanamycin / amikacin : Adverse Effect
- Ototoxic and nephrotoxic
- Vertigo and hearing loss are the most common adverse effects
- Hearing loss can be permanent
• Toxicity reduced by limiting therapy to no more than 6 months
Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin: MOA
- Ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin are fluoroquinolone antibiotics
- Fluoroquinolones inhibit topoisomerase II (DNA gyrase) and topoisomerase IV
Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin: Resistance
• Point mutations in DNA gyrase
- Develops rapidly if a fluoroquinolone is used as a single agent
Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin: Adverse Effects
• GI side effects
- Abdominal discomfort, nausea, vomiting, C. difficile colitis
• CNS effects
- Mild headache, dizziness
• Achiles tendon rupture
• QT prolongation and torsades de pointes
- Mainly moxifloxacin
Linezolid: MOA
- Linezolid is an oxazolidinone antibiotic
* Oxazolidinones are protein synthesis inhibitors
Linezolid: Resistance
• Typical of oxazolidinone drug class
- Point mutations at the oxazolidinone binding site
- Methyltransferases altering oxazolidinone binding to the ribosome
Linezolid: Adverse Effects
• Typical of oxazolidinone drug class
- Myelosuppression
- Mitochondrial toxicity
- Drug-drug interactions
• Specific to linezolid’s use in TB treatment (prolonged use)
- Bone marrow suppression and irreversible peripheral and optic neuropathy have been
reported - Limiting the dose prevents the emergence of these side effect
Rifabutin: MOA
• Bacterial RNA polymerase inhibitor
• Same as rifampin
- Inhibits RNA synthesis by binding to the beta subunit of bacterial DNA-dependent RNA
polymerase
- Bactericidal
- Very good penetration and can kill intracellular organisms and those sequestered in
abscesses and lung cavities - Strong inducer of cytochrome P450 isoforms, which increases the metabolism of many
other drugs
Rifabutin: Resistance
• Rifabutin is cross resistant with rifampin and rifapentine
- They all have similar mechanisms of resistance
- Point mutations in rpoB, the gene for the beta subunit of RNA polymerase~ These mutations prevent rifampin from binding to RNA polymerase and prevents
inhibition of RNA synthesis
Rifabutin: Adverse Effects
- Similar to rifampin (hepatotoxicity and rash)
* Can also cause leukopenia, thrombocytopenia, and optic neuritis
Rifapentine: MOA
- Bacterial RNA polymerase inhibitor
- Same as rifampin
- Inhibits RNA synthesis by binding to the beta subunit of bacterial DNA-dependent RNA polymerase
- Bactericidal
- Very good penetration and can kill intracellular organisms and those sequestered in
abscesses and lung cavities - Strong inducer of cytochrome P450 isoforms, which increases the metabolism of many
other drugs
Rifapentine: Resistance
• Rifapentine is cross resistant with rifampin and rifabutin
- Point mutations in rpoB, the gene for the beta subunit of RNA polymerase~ These mutations prevent rifampin from binding to RNA polymerase and prevents
inhibition of RNA synthesis
Rifapentine: Adverse Effect
Similar to rifampin (hepatotoxicity and rash)
Bedaquiline: MOA
- Inhibits ATP synthase in mycobacteria
- Highly protein bound (> 99%) with a terminal half-life of 5.5 months
- Includes bedaquiline and its active metabolite
Bedaquiline: Resistance
Upregulation of a multi-substrate efflux pump
Bedaquiline: Adverse Effects
• Nausea, arthralgia, and headache
- > 25% of patients
- Associated with both hepatotoxicity and cardiac toxicity
- Black box warning related to the risk of QT prolongation and associated mortality
- Used with caution in patients with other risk factors for cardiac conduction abnormalities
