Infectious Disease I Antibacterial Agent Overview Courses in

Infectious Disease I: Antibacterial Agent Overview Courses in Therapeutics and Disease State Management Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Learning Objectives • Differentiate adverse drug reactions profiles associated with antimicrobial classes • List general monitoring parameters of antimicrobial classes • Identify major drug interactions with antimicrobials Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Required and Recommended Reading Required Reading Lee GC, Burgess DS. Chapter 83. Antimicrobial Regimen Selection. In: Di. Piro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9 e. New York, NY: Mc. Graw-Hill; 2014. Recommended Readings • Lampiris HW, Maddix DS. Clinical Use of Antimicrobial Agents. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck DH, Winston LG. Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck DH, Winston LG. Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck DH, Winston LG. Aminoglycosides & Spectinomycin. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck DH, Winston LG. Sulfonamides, Trimethoprim, & Quinolones. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck, Daniel H. , and Lisa G. Winston. . "Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants. " Basic & Clinical Pharmacology, 13 e. Eds. Bertram G. Katzung, and Anthony J. Trevor. New York, NY: Mc. Graw-Hill, 2015 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Penicillins (Slide 2 of 3) Monitoring Parameters Adverse Effects • Hypersensitivity • reactions and rash • • Drug fever • Diarrhea • • Emesis • • Abdominal pain • • Hepatitis • Interstitial nephritis • Leukopenia Thrombocytopenia Coomb’s positivehemolytic anemia C. Difficile colitis Electrolyte abnormalities Seizures Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved • Monitor for hypersensitivity reactions • • Bronchospasm Anaphylaxis Angioneurotic edema Immediate urticarial • Prolonged and/or high-dose regimens • Monitor renal function • Hepatic function • CBC

Drug Penicillin (Penicillin G, Penicillin VK) Aminopenicillins (Ampicillin, Amoxicillin) Penicillinase Resistant Penicillins (Nafcillin, Oxacillin, Dicloxicillin) Carboxypenicillins (Ticarcillin) Ureidopenicillins (Piperacillin) Penicillins (Slide 3 of 3) Combination Beta-lactam/ Beta-lactam inhibitors Ampcillin/ Sulbactam, Amoxicillin/ Clavulanate Ticarcillin/clavulanate, piperacillin/tazobactam Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Cephalosporins (Slide 2 of 3) Monitoring Parameters Common Adverse Effects • • • Hypersensitivity reactions and rash Drug fever, diarrhea Interstitial nephritis Coomb’s positive hemolytic anemia Leukopenia Thrombocytopenia Coagulopathy Hepatitis C. Difficile colitis Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved • Monitor for hypersensitivity reactions • • Bronchospasm Anaphylaxis Angioneurotic edema Immediate urticaria Rash Renal function Hepatic function CBC

Cephalosporins (Slide 3 of 3) Drug 1 st Generation (cephalexin, cefazolin, cefadroxil) Oral 2 nd Generation (Cefuroxime, Cefaclor, Cefprozil) IV 2 nd Generation (Cefoxitin, Cefuroxime, Cefotetan) 3 rd Generation ( cefotaxime, ceftriaxone, ceftazidime, cefpodoxime) 4 th Genration (cefepime) 5 th Generation (ceftaroline) Combination Beta-lactam/ Beta-lactam inhibitors avibactam/ceftazidime, ceftolozane/tazobactam Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Carbopenems (Slide 2 of 3) Monitoring Parameters Common Adverse Effects • • • Hypersensitivity reactions and rash Headache Nausea Diarrhea Seizures Drug fever Eosinophilia Thrombocytopenia Hepatitis C. Difficile colitis Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved • Monitor for hypersensitivity reactions • • Bronchospasm Anaphylaxis Angioneurotic edema Immediate urticaria Rash Renal function Hepatic function CBC

Carbopenems (Slide 3 of 3) Drug Imipenem/ Cilastatin Meropenem Doripenem Ertapenem Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Amp. C 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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Monobactams (Slide 2 of 3) Common Adverse Effects • Rash • Diarrhea • Nausea • Hepatitis • Thrombocytopenia • C. difficile colitis Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Renal Function • Hepatic Function

Monobactams (Slide 3 of 3) Drug Aztreonam Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Aminoglycosides (Slide 1 of 3) Mechanism of Action • Generally considered to be irreversible inhibitors of protein synthesis via binding to specific 30 S-subunit ribosomal proteins • Interference with the initiation complex of peptide formation • Misreading of m. RNA 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 30 s Ribosomal binding site Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Aminoglycosides (Slide 2 of 3) Monitoring Parameters Common Adverse Effects • Tubular necrosis and renal failure • Vestibular and cochlear toxicity • Neuromuscular blockade • Vertigo • Anemia • Hypersensitivity Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved • • Monitor renal function Serum drug concentrations Serum Calcium Serum Magnesium Serum Sodium Nausea and vomiting Nystagmus Vertigo

Aminoglycosides (Slide 3 of 3) Drug Gentamicin Tobramycin Amikacin Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Glycopeptides (Slide 2 of 3) Common Adverse Effects • • Red man syndrome Phlebitis Renal dysfunction Neutropenia Leukopenia Eosinophilia Thrombocytopenia Drug fever Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Renal Function • Serum Drug Levels • CBC

Glycopeptides (Slide 3 of 3) Drug Vancomycin Teicoplanin Telavancin Dalbavancin Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Lipopeptides (Slide 2 of 3) Common Adverse Effects • Hepatotoxicity • CPK elevation with or without myopathy • Diarrhea • Eosinophilic pneumonia • C. Difficile colitis Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Monitor LFTs • Development of muscle pain/weakness, or neuropathy • Serum CPK levels • Baseline • Weekly

Lipopeptides (Slide 3 of 3) Drug Daptomycin Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 23 S ribosomal RNA of the 50 S subunit Microbial Resistance Mechanism • Mutation of the binding site on 23 S ribosomal RNA Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Oxazolodinones (Slide 2 of 3) Common Adverse Effects • Myelosuppression • • • Thrombocytopenia • Leukopenia • Anemia Peripheral neuropathy Optic neuropathy Blindness Lactic acidosis Diarrhea Nausea Serotonin syndrome Interstitial nephritis Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Signs and symptoms of serotonin syndrome • CBC with differential • Prolonged therapy • Visual function tests • Visual acuity • Visual field defect

Oxazolodinones (Slide 3 of 3) Drug Linezolid Tedizolid Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Tetracyclines (Slide 1 of 3) Mechanism of Action • Bind reversibly to the 30 S subunit of the bacterial ribosome • Blocking the binding of aminoacyl-t. RNA to the acceptor site on the m. RNA-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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Tetracyclines (Slide 2 of 3) Common Adverse Effects • Vertigo • Nausea and • Hyperpigmentati vomiting on • Diarrhea • Hepatotoxicity • Deposition on teeth • Esophageal • Hemolytic ulcerations anemia • Photosensitivity • Pseudotumor • Azotemia cerebri • Visual • Pancreatitis disturbances • C. Difficile colitis • GI upset Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • CBC with differential • LFTs • Renal Function

Tetracyclines (Slide 3 of 3) Drug Tetracycline Minocycline Doxycycline Tigecycline Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Chloramphenical (Slide 1 of 3) Mechanism of Action • Binds reversibly to the 50 S subunit of the bacterial ribosome • Inhibits peptide bond formation Microbial Resistance Mechanisms • Decreased permeability into pathogens • Inactivation via chloramphenicol acetyltransferase Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Chloramphenical (Slide 2 of 3) Common Adverse Effects • • • Myelosuppression Aplastic anemia “Gray baby syndrome” Optic neuritis Peripheral neuropathy Digital paresthesias GI upset C. Difficile colitis Hypersensitivity Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Baseline CBC with differential and every 2 days during therapy • Monitor serum drug levels • Liver function • Renal function

Chloramphenical (Slide 3 of 3) Drug Chloramphenical Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 rpo. B, the gene for the β subunit of RNA polymerase Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Rifamycines (Slide 2 of 3) Common Adverse Effects • • • Discoloration of urine, tears, contact lens, sweat Hepatotoxicity GI upset Flu-like syndrome Hypersensitivity Thrombocytopenia Leukopenia Drug fever Interstitial nephritis Thrombocytopenia Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • LFTs • Bilirubin • Renal function • CBC at baseline and every 2– 4 weeks in patients with hepatic impairment or receiving concomitant hepatotoxic drugs

Rifamycines (Slide 3 of 3) Drug Rifampin Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Macrolides/azalides (Slide 1 of 3) Mechanism of Action • Inhibition of protein synthesis occurs via binding to the 50 S ribosomal RNA • Inhibits the formation of the 50 S 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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Macrolides/azalides (Slide 2 of 3) Common Adverse Effects • • GI intolerance Diarrhea Prolonged QTc / torsade de pointes Cholestatic hepatitis Reversible ototoxicity Rash Hypothermia Exacerbation of myasthenia gravis Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • LFTs • ECG in high-risk patients

Macrolides/azalides (Slide 3 of 3) Drug Erythromycin Azithromycin Clarithromycin Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Clindamycin (Slide 1 of 3) Mechanism of Action • Binds to the 50 S 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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Clindamycin (Slide 2 of 3) Common Adverse Effects • Diarrhea • C. difficile colitis • Nausea and vomiting • Generalized rash • Hypersensitivity Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Liver function • Renal function

Clindamycin (Slide 3 of 3) Drug Clindamycin Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Fluoroquinolones (Slide 2 of 3) Common Adverse Effects • • • GI intolerance • Headache • Malaise • Insomnia • Dizziness Photosensitivity • Qtc prolongation Tendon rupture • Peripheral neuropathy Monitoring Parameters • Renal function Crystalluria Seizure • Encephalopathic changes Interstitial • Confusion nephritis • Hallucinations Stevens-johnson syndrome • Tremor Allergic pneumonitis C. Difficile colitis Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Fluoroquinolones (Slide 3 of 3) Drug Ciprofloxacin Levofloxacin Moxifloxacin Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Polymixins (Slide 2 of 3) Common Adverse Effects • Nephrotoxicity • Neurotoxicity • • • Paresthesia Vertigo Ataxia Blurred vision Slurred speech • Neuromuscular blockade • Bronchospasm (administered via inhalation) Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Obtain baseline renal function tests and regularly during therapy. • Monitor for signs of neuromuscular blockade • Respiratory depression • Apnea • Muscle weakness

Polymixins (Slide 3 of 3) Drug Colistimethate Sodium Polymixin B sulfate Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

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 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Sulfonamides and Trimethoprim (Slide 2 of 3) Common Adverse Effects • GI intolerance • Urolithiasis • Rash • Methemoglobinemia • Hyperkalemia • Stevens-johnson syndrome • Bone marrow suppression • Toxic epidermal necrolysis • Anemia with folate deficiency • Aseptic meningitis • Thrombocytopenia • Pancreatitis • Leukopenia • Interstitial nephritis • Serum sickness • Sweet’s syndrome • Hepatitis • Neurologic toxicity • Photosensitivity • Crystalluria with azotemia Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Monitor for hypersensitivity reactions and rash • CBC • Renal function • Hepatic function • Serum potassium • Serum glucose

Sulfonamides and Trimethoprim (Slide 3 of 3) Drug Sulfamethoxazole/ trimethiprim Trimethoprim Sulfadiazine Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Metronidazole (Slide 1 of 3) Mechanism of Action • Once inside susceptible anaerobic pathogens it is reduced by ferredoxin which results in by-products that are toxic to the cell • Metabolites of metronidazole form unstable molecules in bacterial DNA Microbial Resistance Mechanisms • Resistance rate of anaerobic bacteria a low Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Metronidazole (Slide 2 of 3) Common Adverse Effects • • • GI intolerance Headache Metallic taste Dark urine Peripheral neuropathy Disulfiram reactions with alcohol Insomnia Stomatitis Aseptic meningitis Dysarthria Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved Monitoring Parameters • Hepatic function • Mental/neurologic status

Metronidazole (Slide 3 of 3) Drug Clindamycin Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Major Drug Interactions with Antimicrobials Antimicrobial Other Agent(s) Mechanism of Action/Effect Clinical Management Aminoglycosides Neuromuscular blocking agents Additive adverse effects Avoid Nephrotoxins (N) or ototoxins (O) (e. g. , amphotericin B [N], cisplatin [N/O], cyclosporine [N], furosemide [O], NSAIDs [N], radiocontrast [N], vancomycin [N]) Additive adverse effects Monitor aminoglycoside SDC and renal function Amphotericin B Nephrotoxins (e. g. , aminoglycosides, cidofovir, cyclosporine, foscarnet, pentamidine) Additive adverse effects Monitor renal function Azoles See Chap. 98 Chloramphenicol Phenytoin, tolbutamide, ethanol Decreased metabolism of other agents Monitor phenytoin SDC, blood glucose Foscarnet Pentamidine IV Increased risk of severe nephrotoxicity/hypocalcemia Monitor renal function/serum calcium Isoniazid Carbamazepine, phenytoin Decreased metabolism of other agents (nausea, vomiting, nystagmus, ataxia) Monitor drug SDC Macrolides/azalides Digoxin Decreased digoxin bioavailability and metabolism Monitor digoxin SDC; avoid if possible Theophylline Decreased metabolism of theophylline Monitor theophylline SDC Metronidazole Ethanol (drugs containing ethanol) Disulfiram-like reaction Avoid Penicillins and cephalosporins Probenecid, aspirin Blocked excretion of β-lactams Use if prolonged high concentration of β-lactam desirable Ciprofloxacin/norfloxacin Theophylline Decreased metabolism of theophylline Monitor theophylline Quinolones Classes Ia and III antiarrhythmics Increased Q-T interval Avoid Multivalent cations (antacids, iron, sucralfate, zinc, vitamins, dairy, citric acid), didanosine Decreased absorption of quinolone Separate by 2 hours Rifampin Azoles, cyclosporine, methadone propranolol, PIs, oral contraceptives, tacrolimus, warfarin Increased metabolism of other agent Avoid if possible Sulfonamides Sulfonylureas, phenytoin, warfarin Decreased metabolism of other agent Monitor blood glucose, SDC, PT Tetracyclines Antacids, iron, calcium, sucralfate Decreased absorption of tetracycline Separate by 2 hours Digoxin Decreased digoxin bioavailability Monitor digoxin SDC; avoid if possible PI, protease inhibitor; PT, prothrombin time; SDC, serum drug concentrations. Azalides: azithromycin; azoles: fluconazole, itraconazole, ketoconazole, and voriconazole; macrolides: erythromycin and clarithromycin; protease inhibitors: amprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, and saquinavir; quinolones: ciprofloxacin, gemifloxacin, levofloxacin, and moxifloxacin. Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

Drugs of Choice, First Choice, Alternative(s) Link: List of Drugs of Choice, First Choice, Alternative(s) Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved

References • Lee GC, Burgess DS. Chapter 83. Antimicrobial Regimen Selection. In: Di. Piro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9 e. New York, NY: Mc. Graw-Hill; 2014. • Lampiris HW, Maddix DS. Clinical Use of Antimicrobial Agents. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck DH, Winston LG. Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck DH, Winston LG. Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck DH, Winston LG. Aminoglycosides & Spectinomycin. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck DH, Winston LG. Sulfonamides, Trimethoprim, & Quinolones. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13 e. New York, NY: Mc. Graw-Hill; 2015. • Deck, Daniel H. , and Lisa G. Winston. . "Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants. " Basic & Clinical Pharmacology, 13 e. Eds. Bertram G. Katzung, and Anthony J. Trevor. New York, NY: Mc. Graw-Hill, 2015 Author: Michael W. Perry Pharm. D, BCPS, BCCCP; Assistant Clinical Professor of Pharmacy Practice; Mylan School of Pharmacy http: //accesspharmacy. mhmedical. com/Learning. Module. Group. aspx? id=8 Copyright © 2017 Mc. Graw-Hill Education. All rights reserved