Drug Mech: Antibiotics 4

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Drug Mech: Antibiotics 4
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Drug Mech Antibiotics
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Drug Mech: Spring 2011, Antibiotics
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  1. Which drug classes inhibit Protein Synthesis of the Bacterial cell?
    • Tetracyclines
    • Aminoglycosides
    • Macrolides
    • Lincosamides
    • Chloramphenicol
    • Streptogramins
    • Linezolid
    • Pleuromutilins (Retapamulin)
  2. What is a Bacterial Ribosome?
    The bacterial ribosome is a cytoplasmic nucleoprotein particle whose main function is to serve as the site of mRNA translation and protein synthesis. It consists of two subunits denoted 30S (small subunit) and 50S (large). When joined, the ribosome has a sedimentation coefficient of 70S as opposed to 80S (which is what eukaryotic cells have) due to tertiary structure. The subunits' shape and arrangement are illustrated below.

  3. What is the difference between Bacterial Ribosomes and Eukaryotic Ribosomes and why are these differences significant?
    The differences outlined below allow for drug selectivity. In other words, these antibiotics can come in and bind to the bacteria with high affinity, but not disturb a eukaryotic (human) cell (low affinity). Recall that the more selective a drug is, the better.

    • BACTERIAL RIBOSOMES:
    • 70s ribosomes (proteins + ribosomal RNA)

    30s and 50s subunits

    They are not bound to the endoplasmic reticulum

    • EUKARYOTIC RIBOSOMES:
    • 80s ribosomes (proteins + ribosomal RNA)

    40s and 60s subunits

    They are ~ 50% larger than bacterial ribosomes

    They are fewer in number than bacterial ribosomes

    They are bound to the endoplasmic reticulum
  4. What are two reasons why Inhibitors of Bacterial Protein Synthesis can have selectivity against bacterial cells?
    • There are two main reasons these antibiotics are selective in their toxicity:
    • 1) Bacterial ribosomes differ from human ribosomes. Therefore, these drugs have high affinity for the 70s ribosomes found in bacterial cells and low affinity for the 80s ribosomes found in human cells.

    2) These drugs penetrate the bacterial cell by active transport systems.
  5. If given at a high enough dose, will Inhibitors of Bacterial Protein Synthesis affect human cells?
    Inhibitors of bacterial protein synthesis are selectively active against bacterial cells. However, at high concentrations, these compounds are capable of inhibiting protein synthesis in mammalian cells resulting in toxicity. (In other words, at a high enough dose, these drugs will affect human cells negatively!)
  6. What kind of bacteria do Inhibitors of Bacterial Protein Synthesis work on and how do they enter those bacteria?
    They enter Gram-negative bacterial cells by the following mechanisms:

    1) Passive diffusion through the outer cell membrane channels (Porin proteins).

    2) Energy-dependent active transport system that pumps the antibiotic across the cytoplasmic membrane.

    Although permeation of these antibiotics into Gram-positive bacteria is not well understood, it is also energy-dependent.
  7. What is selectivity at the clinical dose attributed to in Inhibitors of Bacterial Protein Synthesis?
    Selectivity against bacterial cells at the clinical dose is attributed to:

    1) Lack of 70s ribosomes in mammalian cells (with the exception of the mitochondria). Mammalian ribosomes have very low affinity for these antibiotics.

    2) Lack of bacterial active transport systems in mammalian cells.
  8. Which Inhibitors of Bacterial Protein Synthesis are Bacteriostatic at the clinical dose?
    • Tetracyclines
    • Glycylcyclines (Tigecycline)
    • Macrolides
    • Lincosamides
    • Chloramphenicol
    • Oxazolidinones (Linezolid)
    • Pleuromutilins (Retapamulin)

    Pnuemonic: Tell Grandma That My Last Cat Out Lived Patricia Richardson.
  9. Which Inhibitors of Bacterial Protein Synthesis are Bactericidal at the clinical dose?
    • Aminoglycosides
    • Streptogramins (Quinupristin/Dalfopristin)
    • Ketolides (Telithromycin)

    Pneumonic: A Swift Quick Dart Kills Tigers.
  10. Which Inhibitors of Bacterial Protein Synthesis have the 30s subunit as their site of action? Which ones have the 50s subunit as their site of action?
    Inhibitors of Bacterial Protein Synthesis with site of action at the:

    • 30s subunit
    • Aminoglycosides
    • Tetracyclines
    • Glycylcyclines (Tigecycline)

    • Note the rest are on the other subunit:
    • 50s subunit
    • Macrolides
    • Lincosamides
    • Streptogramins (Quinupristin/Dalfopristin)
    • Ketolides (Telithromycin)
    • Chloramphenicol
    • Oxazolidinones (Linezolid)
    • Pleuromutilins (Retapamulin)
  11. General Properties of Aminoglycosides
    They are broad-spectrum antibiotics.

    They are bactericidal at the clinical dose.

    They are water soluble and strongly basic; most of them are available as the sulfate salts.

    They are not orally active to treat systemic infections because they are not absorbed from the GI Tract. Therefore they must be parenterally administered.

    They cause nephrotoxicity (kidney damage), ototoxicity (hearing loss), and neuromuscular blockade (paralysis). An increased dose increases the chance of toxicity.

    They are excreted in urine by glomerular filtration.

    Their concentrations in the renal cortex are much higher than their serum levels.

    • They are well distributed in extracellular fluids.
    • They cross the placenta; however, they do not achieve significant levels in the CSF.

  12. Aminoglycoside Mechanism of Action
    • 1) Bind to the 30s Ribosomal Subunit, thus blocking the initiation of protein synthesis.
    • 2) Blocks further translation & elicits premature termination of bacterial protein synthesis.
    • 3) Incorporates incorrect amino acid residues, which makes non-functional or inactive proteins, and thus the bacterial cell dies.

  13. Mechanisms of Microbial Resistance to Aminoglycosides
    • 1) Target Modification
    • Ribosomal alteration

    • 2) The production of inactivating enzymes
    • -Encoded by R-Factors (plasmids).
    • -They cause acetylation (acetyltransferases), phosphorylation (phosphotransferases), and/or adenylation (nucleotidyltransferases) of the aminoglycoside molecule.

    • 3) Inhibition of the active transport mechanism
    • The active transport system is required for the transport of aminoglycosides across the bacterial cell
    • membrane. Divalent cations, such as Ca and Mg, can also antagonize the transport of aminoglycosides by binding to membrane phospholipids.
  14. Which drug, out of all the Aminoglycosides, is least susceptible to enzymatic inactivation?
    Of all the aminoglycosides, Amikacin is the least susceptibleto enzymatic inactivation.

    It is susceptible only to a few of the inactivating enzymes. As a result, Amikacin is generally reserved for treatment of serious infections caused by Gram-negative bacteria known or suspected to be resistant to the other aminoglycosides.
  15. General Properties & Toxicities of Tetracyclines
    They are broad-spectrum antibiotics.

    Tetracyclines are bacteriostatic at the clinical dose.

    They are well distributed throughout the body, including the CSF.

    At high concentrations, tetracyclines inhibit mammalian protein synthesis leading to an antianabolic effect (inhibiting protein synthesis in human cells) and an increase in BUN levels (Azotemia, which is a medical condition characterized by abnormally high levels of nitrogen-containing compounds, such as urea, creatinine, various body waste compounds, and other nitrogen-rich compounds in the blood). The point is, at high levels, tetracyclines can be toxic to human cells.

    Tetracyclines, especially those with a C-7 chlorine substituent (causing a highly conjugated structure...which means single-double-single-double bonds and so on...chlorine is one of the worst for this), absorb light in the visible region leading to free radical generation; consequently, they can cause severe phototoxicity in sensitive patients when exposed to intense sunlight or UV-light. Demeclocycline is the most phototoxic.

    Tetracyclines form insoluble salts through chelation (meaning forming salts or complexes) with metal ions, such as Ca (II), Mg (II), Al (III), and Fe (II). These salts of polyvalent metal ions are insoluble at neutral pHs (i.e., not absorbed from the GI Tract). Therefore, it is contraindicated to co-administer tetracyclines with antacids, iron supplements, calcium supplements, dairy products, and any other products or supplements that contain polyvalent metal ions.

    They have a very high affinity for calcified tissues (bones and teeth) because they chelate calcium. As a result, tetracyclines are contraindicated in pregnant women and children under the age of 13 (because bones of the fetus are forming in a pregnant woman and most children have all their adult teeth by age 13).

    The extent of teeth discoloration by tetracyclines is directly proportional to the dose and the duration of therapy.

  16. Tetracycline Mechanism of Action
    Tetracycline binds to the A-site on the 30s bacterial ribosome and blocks protein synthesis.

  17. Mechanisms of Microbial Resistance to Tetracyclines
    • 1) Target Modification
    • Ribosomal alteration

    • 2) Ribosomal protection
    • Production of a ribosomal protein that displaces the tetracycline molecule from its binding site *Note: this is a new, unique mechanism of resistance!

    3) Energy-dependent active efflux

    4) Decreased antibiotic influx

    5) Enzymatic inactivation
  18. General Properties of the Glycylcyclines: Tigecycline (Tygacil®)
    It is a broad-spectrum antibiotic.

    It is bacteriostatic at the clinical dose.

    It is administered parenterally via IV infusion.

    Tigecycline, a glycylcycline antibiotic, is structurally related to the tetracyclines.
  19. The Glycylcyclines: Tigecycline (Tygacil®) Mechanism of Action
    • 1) It inhibits protein translation in bacterial cells by binding to the 30s ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome.
    • 2) This prevents incorporation of amino acid residues into elongating peptide chains and inhibits bacterial protein synthesis.
  20. Mechanisms of Microbial Resistance to the Glycylcyclines: Tigecycline (Tygacil®)
    Tigecycline is not affected by the major mechanisms of microbial resistance to the tetracyclines because of its unique chemical structure (which is different from the structures of the tetracyclines) and unique binding site on the 30s ribosomal subunit.

    The substitution pattern in the chemical structure of tigecycline is not present in any naturally occurring or semisynthetic tetracycline antibiotic. As a result, tigecycline may be useful in treating bacterial infections caused by strains that are resistant to the tetracyclines.
  21. Is there cross resistance between Tigecycline and any other antibiotics?
    There has been no cross resistance observed between tigecycline and other antibiotics.
  22. Is there any drug interactions between Tigecycline and other drugs?
    Tigecycline has been shown to decrease warfarin clearance (ie, increase the biological half-life of warfarin).

    In other words, Tigecycline inhibits the excretion of warfarin, and therefore warfarin will stick around longer, so if dosed simultaneously, you will need to decrease the dose of warfarin.

    Also, Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.
  23. Toxicity of the Glycylcyclines: Tigecycline (Tygacil®)
    The glycylcycline antibiotics are structurally similar to the tetracyclines. As a result, tigecycline and the tetracyclines share a number of toxicities including phototoxicity.

    • Tigecycline may cause fetal harm when administered to a pregnant woman (e.g., reduction
    • in fetal weight, delay in bone ossification, increased incidence of fetal loss).
    • It may cause permanent discoloration of the teeth (and bones) if administered to infants and children. As a result, it should not be administered to children under the age of 13 years unless other drugs are not likely to be effective or are contraindicated (it is not recommended for patients under 18 years of age).

    It should be administered with caution in patients with known hypersensitivity to the tetracyclines because Tigecycline chelates just like tetracylines, and therefore the same contraindications as tetracyclines are produced.
  24. Which five drugs are Macrolides?
    • 1) Azithromycin
    • 2) Clarithromycin

    3) Dirithromycin

    4) Erythromycin

    5) Troleandomycin
  25. General Properties of Macrolides
    Macrolide antibiotics are intermediate-spectrum antibiotics.

    They are bacteriostatic at the clinical dose.

    They are well distributed throughout the body; however, they do not cross the blood-brain barrier into the CNS.

    • All macrolides (except Dirithromycin and Azithromycin) are potent inhibitors of cyt. P450
    • enzymes (drug-metabolizing enzymes) in the liver.

    Clarithromycin is contraindicated during pregnancy (teratogenic in animals).

    Erythromycin as the free base is acid unstable and orally inactive. Consequently, the free base of erythromycin is administered orally in the form of enteric coated tablets (or pellets). Water insoluble esters/salts (ethyl succinate ester; estolate ester; stearate salt) of erythromycin are also available for oral administration.

  26. Macrolides Mechanism of Action
    • 1) Binds to the 50s Ribosomal Subunit.
    • 2) Blocks further translation by blocking movement of the A site to the P site.
    • 3) Initiates a transpeptidation reaction at the site (basically forms peptide bonds).

  27. Which drugs inhibit P450 enzymes in the liver? Which drugs promote P450 enzymes in the liver?
  28. Which two drugs are Lincosamides?
    1) Lincomycin

    2) Clindamycin
  29. General Properties of Lincosamides
    They are narrow-spectrum antibiotics.

    They are bacteriostatic at the clinical dose.

    They have the same binding site on the 50s ribosomal subunit (and the same mechanism of action) as the macrolides (cross-resistance).

    Toxicities of the lincosamides include hepatotoxicity and GI irritation (colitis).

    Clindamycin is more lipophilic than lincomycin. As a result, clindamycin has better oral absorption and distribution properties than lincomycin (ie, it causes less GI upset).
  30. If macrolides and lincosamides share a binding site and have the same mechanism of action, then why are they in a separate class?
  31. General Properties of the Streptogramins: Quinupristin + Dalfopristin (Synercid®)
    The combination is generally bactericidal.

    • The synergistic combination consists of the antibiotics Quinupristin (30%) and Dalfopristin
    • (70%).

    Indicated for the treatment of Vancomycin-resistant Enterococcus faecium (VREF) bacteremia and resistant Staph. aureus and Strep. pyogenes infections.

    The combination is an inhibitor of CYP3A4 isozyme (a drug-metabolizing enzyme). As a result, it increases the effect and toxicity of many other drugs that are primarily metabolized by this isozyme (drug-drug interactions).
  32. Streptogramins: Quinupristin + Dalfopristin (Synercid®) Mechanism of Action
    • 1) Quinupristin (Streptogramin B) and dalfopristin (Streptogramin A) inhibit protein synthesis by binding to the 50s ribosomal subunit.
    • 2) Quinupristin binds at the same site as the macrolides and lincosamides and has a similar effect, with inhibition of polypeptide elongation and early termination of protein synthesis (cross-resistance).
    • 3) Dalfopristin binds at a site nearby, resulting in a conformational change in the 50s ribosome, synergistically enhancing the binding of quinupristin at its target site. In addition, Dalfopristin directly interferes with polypeptide-chain formation.
    • 4) The net effect, in many bacterial species, is bactericidal.
  33. Mechanisms of Microbial Resistance to the Streptogramins: Quinupristin + Dalfopristin (Synercid®)
    • Resistance to quinupristin is mediated by either:
    • 1) Target Modification
    • Ribosomal Alteration (similar to the main resistance mechanism against erythromycin).
    • 2) The production of lactonases
    • Lactonases are enzymes capable of inactivating quinupristin.

    • Resistance to dalfopristin is mediated by either:
    • 1) The production of acetyltransferases
    • Acetyltransferases are enzymes capable of inactivating dalfopristin.
    • 2) The production of ATP-binding efflux proteins Active pumps that eject dalfopristin out of the cell.
  34. General Properties of the Ketolides: Telithromycin (Ketek®)
    It is an intermediate-spectrum antibiotic

    It is bactericidal at the clinical dose.

    Indicated for the treatment of community acquired pneumonia of mild to moderate severity (acquiredoutside of hospitals or long-term care facilities), including pneumonia caused by multi-drug resistant (MDR) isolates of Strep. pneumoniae

    For patients 18 years old and above.

    Ketolides are semisynthetic 14-membered-ring lactones.

    They are structurally related to the macrolides.

    • Telithromycin, a ketolide antibiotic, is structurally
    • related to erythromycin.
  35. The Ketolides: Telithromycin (Ketek®) Mechanism of Action
    Telithromycin blocks bacterial protein synthesis by binding to two different binding sites or domains of rRNA on the 50s ribosomal subunit.

    One of these two binding sites is the same binding site for Erythromycin.
  36. Why might Telithromycin work against an infection when a Macrolide will not work?
    Many macrolide-resistant strains are actually susceptible to telithromycin because of three main reasons:

    1) Although related, Ketolides and macrolides are structurally different. As a result, the ketolides are poor substrates for bacterial protein pumps that mediate active efflux of the macrolides. (In other words, the bacteria do not have a way to pump out ketolides via active efflux).

    2) Telithromycin (a Ketolide) binds to two different sites on the 50s ribosomal subunit. As a result, it retains activity against Gram-positive cocci (e.g., Strep. pneumoniae) in the presence of resistance mediated by methylases (which alter only the binding site that telithromycin shares with erythromycin and the macrolides).

    Telithromycin does not induce resistance through methylase gene expression in erythromycin inducibly resistant bacteria (because telithromycin and erythromycin have different chemical structures).

    In other words, because Telithromycin binds to two different places, it doesn't matter that the bacteria prevent binding at one place because Telithromycin has a back up binding spot.

    • 3) Ketolides bind to ribosomes of some bacterial
    • species with higher affinity than macrolides.
  37. The Ketolides: Telithromycin (Ketek®) Cross Resistance
    Cross-resistance exists between telithromycin and the macrolides, lincosamides, and streptogramins, ONLY at the binding site that telithromycin shares with these three classes of antibiotics.
  38. Drug Interactions with the Ketolides: Telithromycin (Ketek®)
    Telithromycin is metabolized in the liver by CYP3A4. As a result, its plasma levels (and its therapeutic/adverse effects) can be altered by concomitant use of CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital) and inhibitors (e.g., ketoconazole, itraconazole).

    • Telithromycin is also an inhibitor of CYP3A4. Concomitant use of telithromycin with drugs that are primarily metabolized by CYP3A4 (such as the statins, benzodiazepines, …etc) may result in increased plasma levels of these drugs, leading to an increase in their therapeutic and adverse effects.
    • Therefore, appropriate dosage adjustments may be necessary.

    Concomitant use of telithromycin and oral anticoagulants may potentiate (increase) the effects of oral anticoagulants. Therefore, prothrombin time and International Normalized Ratio (INR) [which are measures of the external pathway of coagulation] should be monitored.

    Telithromycin increases plasma peak and trough levels of digoxin. As a result, digoxin serum levels and adverse effects should be monitored when administered concomitantly with telithromycin.
  39. Toxicity of the Ketolides: Telithromycin (Ketek®)
    Acute liver failure and severe liver injury, in some cases fatal, have been reported in patients treated with telithromycin.

    Less severe hepatic dysfunction associated with increased liver enzymes, hepatitis, and in some cases jaundice was reported with the use of telithromycin. These less severe events were reversible.

    Patients with signs or symptoms of hepatitis or jaundice must discontinue telithromycin and immediately seek medical evaluation, which should include liver function tests.

    • Telithromycin has the potential to prolong the QT interval of the ECG in some patients. This may
    • lead to fainting and an increased risk for ventricular arrhythmias. As a result, telithromycin should be avoided in patients with prolonged QT interval and patients with proarrhythmic conditions.

    Telithromycin may cause visual disturbances, including blurred vision and difficulty focusing. It may also cause transient loss of consciousness. As a result, patients should minimize activities such as driving a motor vehicle or operating heavy machinery during treatment with telithromycin. Patients should avoid these activities if they experience visual disorders or loss of consciousness while taking telithromycin.
  40. General Properties of Chloramphenicol
    It is a broad-spectrum antibiotic.

    It is a bacteriostatic at the clinical dose.
  41. Chloramphenicol Mechanism of Action
    It binds to the 50s ribosomal subunit (near to the same piece of "real estate" that macrolides and lincosamides bind to) and inhibits protein synthesis of the bacterium.

  42. Is there any cross resistance with Chloramphenicol and other antibiotics?
    • Chloramphenicol binds to the 50s ribosomal subunit near the site of action of the macrolides/lincosamides, therefore it mainly inhibits the transpeptidation step.
    • However, the macrolide and lincosamide agents interfere with the binding of chloramphenicol and, as a result, may interfere with its activity if administered concurrently.
  43. Is quinapristin and chloramphenicol a good drug combination?
    No. These two would be an antagonistic combination because quinapristin is related to the macrolides and lincosamides. Chloramphenicol binds to essentially the same spot as these other drugs. Therefore, these other drugs will act as allosteric inhibitors.
  44. Toxicity of Chloramphenicol
    Toxicities of chloramphenicol include dose-related bone marrow depression, immunosuppression, aplastic anemia (irreversible and usually fatal; 1:100,000), inhibition of vitamin K production, and alcohol intolerance.

    Chloramphenicol is contraindicated in the infant and newbornbecause the livers in infants and newborns have not yet started producing the enzyme that metabolizes this drug, and therefore, their bodies cannot handle the toxicity of this drug. A lot of babies [on accident] were killed by being administered Chloramphenicol (Gray Baby Syndrome).

    Patients with hepatic dysfunction and neonates are most susceptible to chloramphenicol toxicity because a specific enzyme made in the liver metabolizes chloramphenicol. If the liver does not work, you will lack this enzyme. Also, the human body doesn't start making this enzyme until one is about two or three years old.
  45. General Properties of the Oxazolidinones: Linezolid (Zyvox®)
    It is active against Gram-positive bacteria. It has poor activity against most Gram-negative aerobic or anaerobic bacteria.

    It is generally a bacteriostatic antibiotic.

    Indicated for the treatment of Vancomycin-resistant Enterococcus faecium (VREF) bacteremia, nosocomial pneumonia and community-acquired pneumonia infections caused by Staph. aureus (methicillin susceptible and -resistant strains) or Strep. pneumoniae.
  46. Oxazolidinones: Linezolid (Zyvox®) Mechanism of Action
    It inhibits bacterial protein synthesis by binding to the P site of the 50s ribosomal subunit.

    It inhibits the initiation of protein synthesis by inhibiting the ribosome-assembly step and the formation of the larger ribosomal-fMet-tRNA complex.
  47. Mechanisms of Microbial Resistance for Linezolid (Zyvox®)
    • Target Modification
    • Resistance to linezolid is due to mutation of the ribosomal binding site.
  48. Contraindications of the Oxazolidinones: Linezolid (Zyvox®)
    • Linezolid is a weak reversible, nonselective inhibitor of monoamine oxidase (MAO). As a
    • result, its use is contraindicated in patients who are taking:
    • 1) MAO inhibitors (e.g., phenelzine),
    • 2) adrenergic agents, or
    • 3) serotonergic agents (e.g., serotonin reuptake inhibitors, tricyclic
    • antidepressants, …etc).
  49. Toxicity of the Oxazolidinones: Linezolid (Zyvox®)
    Toxicities include PMC (pseudomembraneous colitis) and thrombocytopenia (myelosuppression).
  50. General Characteristics of Pleuromutilins: Retapamulin (Altabax®)
    It is a topical antibiotic approved for the treatment of impetigo (skin infection) due to Strep. pyogenes and methicillin-susceptible Staph. aureus.

    • It is bacteriostatic at very low concentrations (i.e., the MICs) against Staph. aureus, including MRSA,
    • and Strep. pyogenes.

    It is bactericidal against these organisms at higher concentrations.
  51. Pleuromutilins: Retapamulin (Altabax®) Mechanism of Action
    It binds to the 50s ribosomal subunit and inhibits bacterial protein synthesis by inhibiting peptidyl transfer, blocking P-site interactions, and preventing the normal formation of active 50s ribosomal subunits.
  52. Mechanisms of Microbial Resistance for Pleuromutilins: Retapamulin (Altabax®)
    Mechanisms of microbial resistance to retapamulin include target modification, also called ribosomal alteration (mutations) and active efflux.
  53. Is there any cross resistance with Retapamulin (Altabax®) and other antibiotics?
    There is no cross-resistance with other classes of antibiotics.
  54. Which drug classe(s) inhibit nucleic acid synthesis in the bacterial cell?
    • Rifamycins
    • Quinolones
  55. Which antibiotics are included in the Rifamycin drug class?
    • 1) Rifampin
    • 2) Rifabutin
    • 3) Rifapentine
  56. General Characteristics of Rifamycins
    Rifamycins are intermediate-spectrum antibiotics.

    They are bactericidal at the clinical dose.

    They are indicated for the prevention and/or treatment of mycobacterial infections (TB; atypical mycobacterial infections).

    They are highly conjugated and colored (orange-red).
  57. Rifamycin Mechanism of Action
    They inhibit RNA synthesis in bacterial cells by inhibiting bacterial DNA-dependent RNA polymerase (they do not inhibit the mammalian enzyme).

  58. Is there any cross resistance with Rifamycins and other antibiotics?
    There is no cross-resistance between the rifamycins and other classes of antibiotics; however, cross-resistance exists among the rifamycins.
  59. Contraindications of Rifamycins
    They are inducers of cytochrome P450 enzymes in the liver (rifampin and rifapentine are potent inducers; rifabutin is a less potent inducer than the other two rifamycins). As a result, they decrease blood levels of other drugs that are metabolized by these enzymes.
  60. Toxicity of Rifamycins
    • Major toxicities/side effects include hepatotoxicity in patients with preexisting liver dysfunction or when administered with other hepatotoxic
    • drugs, and discoloration of urine,
    • feces, sweat, tears, saliva, and contact lenses.

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