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Infectious Disease I: Antibacterial Agent Overview

Infectious Disease I: Antibacterial Agent Overview. Courses in Therapeutics and Disease State Management. Learning Objectives. Differentiate adverse drug reactions profiles associated with antimicrobial classes List general monitoring parameters of antimicrobial classes

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Infectious Disease I: Antibacterial Agent Overview

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  1. Infectious Disease I:Antibacterial Agent Overview Courses in Therapeutics and Disease State Management

  2. Learning Objectives Differentiate adverse drug reactions profiles associated with antimicrobial classes List general monitoring parameters of antimicrobial classes Identify major drug interactions with antimicrobials

  3. Required and Recommended Reading Required Reading Lee GC, Burgess DS. Chapter 83. Antimicrobial Regimen Selection. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Recommended Readings Lampiris HW, Maddix DS. Clinical Use of Antimicrobial Agents. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015. Deck DH, Winston LG. Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e.New York, NY: McGraw-Hill; 2015. Deck DH, Winston LG. Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015. Deck DH, Winston LG. Aminoglycosides & Spectinomycin. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015. Deck DH, Winston LG. Sulfonamides, Trimethoprim, & Quinolones. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015. Deck, Daniel H., and Lisa G. Winston.. "Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants." Basic & Clinical Pharmacology, 13e. Eds. Bertram G. Katzung, and Anthony J. Trevor. New York, NY: McGraw-Hill, 2015

  4. Antibacterial Agent Overview • Use of any medication has risks and benefits • Adverse reactions • Treatment of disease • Empiric antimicrobial therapy is directed at organisms that are known to cause the infection  • Antibacterial agent factors that affect choice • Tissue penetration • Coverage of most likely bacteria • Drug toxicities

  5. Penicillins (Slide 1 of 3) Mechanism of Action • Inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis • Covalently bind to penicillin-binding protein (PBP) to prevent growth of the cell wall via peptidoglycan synthesis Microbial Resistance Mechanisms • Production of β-lactamase to inactivate penicillin and cephalosporins • Modification of target PBPs • Gram negative bacteria alter out membrane to lessen penetration of drug to target PBPs • Efflux pumps decrease concentrations of antibiotics at PBP sites

  6. Penicillins (Slide 2 of 3) Adverse Effects Monitoring Parameters Monitor for hypersensitivity reactions Bronchospasm Anaphylaxis Angioneurotic edema Immediate urticarial Prolonged and/or high-dose regimens Monitor renal function Hepatic function CBC

  7. Penicillins (Slide 3 of 3)

  8. Cephalosporins (Slide 1 of 3) Mechanism of Action • Inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis • Covalently bind to penicillin-binding protein (PBP) to prevent growth of the cell wall via peptidoglycan synthesis Microbial Resistance Mechanisms • Production of extended spectrum β-lactamase to inactivate cephalosporins • Modification of target PBPs • Gram negative bacteria alter out membrane to lessen penetration of drug to target PBPs • Efflux pumps decrease concentrations of antibiotics at PBP sites

  9. Cephalosporins (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Monitor for hypersensitivity reactions Bronchospasm Anaphylaxis Angioneurotic edema Immediate urticaria Rash Renal function Hepatic function CBC • Hypersensitivity reactions and rash • Drug fever, diarrhea • Interstitial nephritis • Coomb’s positive hemolytic anemia • Leukopenia • Thrombocytopenia • Coagulopathy • Hepatitis • C. Difficile colitis

  10. Cephalosporins (Slide 3 of 3)

  11. Carbopenems (Slide 1 of 3) Mechanism of Action • Inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis • Covalently bind to penicillin-binding protein (PBP) to prevent growth of the cell wall via peptidoglycan synthesis Microbial Resistance Mechanisms • Production of carbapenemases or metallo-β lactamases that inactivate carbopenems • Modification of target PBPs • Gram negative bacteria alter out membrane to lessen penetration of drug to target PBPs • Efflux pumps decrease concentrations of antibiotics at PBP sites

  12. Carbopenems (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Monitor for hypersensitivity reactions Bronchospasm Anaphylaxis Angioneurotic edema Immediate urticaria Rash Renal function Hepatic function CBC • Hypersensitivity reactions and rash • Headache • Nausea • Diarrhea • Seizures • Drug fever • Eosinophilia • Thrombocytopenia • Hepatitis • C. Difficile colitis

  13. Carbopenems (Slide 3 of 3)

  14. Monobactams (Slide 1 of 3) Mechanism of Action • Inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis • Covalently bind to penicillin-binding protein (PBP) to prevent growth of the cell wall via peptidoglycan synthesis Microbial Resistance Mechanisms • Production of AmpC β lactamases and extended-spectrum β lactamases that inactivate aztreonam • Modification of target PBPs • Gram negative bacteria alter out membrane to lessen penetration of drug to target PBPs • Efflux pumps decrease concentrations of antibiotics at PBP sites

  15. Monobactams (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Renal Function Hepatic Function • Rash • Diarrhea • Nausea • Hepatitis • Thrombocytopenia • C. difficile colitis

  16. Monobactams (Slide 3 of 3)

  17. Aminoglycosides (Slide 1 of 3) Mechanism of Action • Generally considered to be irreversible inhibitors of protein synthesis via binding to specific 30S-subunit ribosomal proteins • Interference with the initiation complex of peptide formation • Misreading of mRNA that causes formation of nonfunctional proteins • Fragmentation of polysomes into nonfunctional monosomes Microbial Resistance Mechanisms • Enzymatic inactivation of aminoglycosides by adenylylation, acetylation, or phosphorylation • Decreased permieablity of aminoglycosides into the cell • Alteration or deletion of 30s Ribosomal binding site

  18. Aminoglycosides (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Monitor renal function Serum drug concentrations Serum Calcium Serum Magnesium Serum Sodium Nausea and vomiting Nystagmus Vertigo • Tubular necrosis and renal failure • Vestibular and cochlear toxicity • Neuromuscular blockade • Vertigo • Anemia • Hypersensitivity

  19. Aminoglycosides (Slide 3 of 3)

  20. Glycopeptides (Slide 1 of 3) Mechanism of Action • Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide • Creates an unstable cell wall and the bacteria become susceptible to lysis and damage Microbial Resistance Mechanisms • Modification of the D-Ala-D-Ala binding site • Altered cell wall metabolism that creates a thickened cell wall with increased binding site for vancomycin

  21. Glycopeptides (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Renal Function Serum Drug Levels CBC • Red man syndrome • Phlebitis • Renal dysfunction • Neutropenia • Leukopenia • Eosinophilia • Thrombocytopenia • Drug fever

  22. Glycopeptides (Slide 3 of 3)

  23. Lipopeptides (Slide 1 of 3) Mechanism of Action • Not fully understood • Binds to the cell membrane via calcium-dependent insertion of its lipid tail • Causes depolarization of the cell membrane with potassium efflux leading to rapid cell death Microbial Resistance Mechanisms • Multiple mechanism proposed included genetic polymorphisms and membrane electrostatic charges

  24. Lipopeptides (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Monitor LFTs Development of muscle pain/weakness, or neuropathy Serum CPK levels Baseline Weekly • Hepatotoxicity • CPK elevation with or without myopathy • Diarrhea • Eosinophilic pneumonia • C. Difficile colitis

  25. Lipopeptides (Slide 3 of 3)

  26. Oxazolodinones (Slide 1 of 3) Mechanism of Action Inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis on the on 23S ribosomal RNA of the 50S subunit Microbial Resistance Mechanism Mutation of the binding site on 23S ribosomal RNA

  27. Oxazolodinones (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Signs and symptoms of serotonin syndrome CBC with differential Prolonged therapy Visual function tests Visual acuity Visual field defect • Myelosuppression • Thrombocytopenia • Leukopenia • Anemia • Peripheral neuropathy • Optic neuropathy • Blindness • Lactic acidosis • Diarrhea • Nausea • Serotonin syndrome • Interstitial nephritis

  28. Oxazolodinones (Slide 3 of 3)

  29. Tetracyclines (Slide 1 of 3) Mechanism of Action • Bind reversibly to the 30S subunit of the bacterial ribosome • Blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex • Prevents addition of amino acids onto growing peptides Microbial Resistance Mechanisms • Active transport protein pump alter influx or increased efflux (not tigecycline) • Proteins protect tetracycline bindings via steric hindrance • Inactivation by enzymes

  30. Tetracyclines (Slide 2 of 3) Common Adverse Effects Monitoring Parameters CBC with differential LFTs Renal Function

  31. Tetracyclines (Slide 3 of 3)

  32. Chloramphenical (Slide 1 of 3) Mechanism of Action • Binds reversibly to the 50S subunit of the bacterial ribosome • Inhibits peptide bond formation Microbial Resistance Mechanisms • Decreased permeability into pathogens • Inactivation via chloramphenicol acetyltransferase

  33. Chloramphenical (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Baseline CBC with differential and every 2 days during therapy Monitor serum drug levels Liver function Renal function • Myelosuppression • Aplastic anemia • “Gray baby syndrome” • Optic neuritis • Peripheral neuropathy • Digital paresthesias • GI upset • C. Difficile colitis • Hypersensitivity

  34. Chloramphenical (Slide 3 of 3)

  35. Rifamycines (Slide 1 of 3) Mechanism of Action • Rifampin binds to the β subunit of bacterial DNA-dependent RNA polymerase • Inhibits RNA synthesis Microbial Resistance Mechanisms • Mutations in rpoB, the gene for the β subunit of RNA polymerase

  36. Rifamycines (Slide 2 of 3) Common Adverse Effects Monitoring Parameters LFTs Bilirubin Renal function CBC at baseline and every 2–4 weeks in patients with hepatic impairment or receiving concomitant hepatotoxic drugs • Discoloration of urine, tears, contact lens, sweat • Hepatotoxicity • GI upset • Flu-like syndrome • Hypersensitivity • Thrombocytopenia • Leukopenia • Drug fever • Interstitial nephritis • Thrombocytopenia

  37. Rifamycines (Slide 3 of 3)

  38. Macrolides/azalides (Slide 1 of 3) Mechanism of Action • Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA • Inhibits the formation of the 50S ribosomal subunit  Microbial Resistance Mechanisms • Reduced permeability of the cell membrane or active efflux • Production of esterases that hydrolyze macrolides • Genetic modification of the ribosomal binding site by chromosomal mutation or by a macrolide-inducible or constitutive methylase

  39. Macrolides/azalides (Slide 2 of 3) Common Adverse Effects Monitoring Parameters LFTs ECG in high-risk patients • GI intolerance • Diarrhea • Prolonged QTc / torsade de pointes • Cholestatic hepatitis • Reversible ototoxicity • Rash • Hypothermia • Exacerbation of myasthenia gravis

  40. Macrolides/azalides (Slide 3 of 3)

  41. Clindamycin (Slide 1 of 3) Mechanism of Action • Binds to the 50S subunit of the bacterial ribosome • Inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions Microbial Resistance Mechanisms • Mutation of the ribosomal receptor site • Genetic modification of the ribosomal binding site by chromosomal mutation or by a macrolide-inducible or constitutive methylase • Enzymatic inactivation of clindamycin

  42. Clindamycin (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Liver function Renal function • Diarrhea • C. difficile colitis • Nausea and vomiting • Generalized rash • Hypersensitivity

  43. Clindamycin (Slide 3 of 3)

  44. Fluoroquinolones (Slide 1 of 3) Mechanism of Action • Block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV • Inhibiting DNA Gyrase interferes with normal transcription and replication of DNA • Inhibiting topoisomerase IV interferes with separation of replicated chromosomal DNA  Microbial Resistance Mechanisms • Mutations and genetic modifications at the binding site • Production of Qnr proteins that protect bacterial DNA and acetyltransferase that degrade fluoroquinolones provide a low level of resistance

  45. Fluoroquinolones (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Renal function Encephalopathic changes Confusion Hallucinations Tremor

  46. Fluoroquinolones (Slide 3 of 3)

  47. Polymixins (Slide 1 of 3) Mechanism of Action • Cationic detergents that attach to and disrupt bacterial cell membranes • Bind and inactivate endotoxin Microbial Resistance Mechanisms • Efflux pumps • Modifications to cell membranes

  48. Polymixins (Slide 2 of 3) Common Adverse Effects Monitoring Parameters Obtain baseline renal function tests and regularly during therapy. Monitor for signs of neuromuscular blockade Respiratory depression Apnea Muscle weakness • Nephrotoxicity • Neurotoxicity • Paresthesia • Vertigo • Ataxia • Blurred vision • Slurred speech • Neuromuscular blockade • Bronchospasm (administered via inhalation)

  49. Polymixins (Slide 3 of 3)

  50. Sulfonamides and Trimethoprim(Slide 1 of 3) Mechanism of Action • Sulfonamides and trimethoprim reduce the production of purines required for DNA synthesis • Sulfonamides inhibit dihydropteroate synthase and folate production • Trimethoprim inhibits bacterial dihydrofolic acid reductase Microbial Resistance Mechanisms • Exogenous sources of folic acid • Genetic mutations that produce • Overproduction of para aminobenzoic acid (PABA) • Folic acid-synthesizing enzyme that has low affinity for sulfonamides and trimethoprim • An impaired permeability to the sulfonamides and trimethoprim

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