Antimicrobials Amy J
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Antimicrobials Amy J. Rankin Diplomate ACVO Associate Professor Ophthalmology Kansas State University Antimicrobial Agents • Interpretation of efficacy • Prophylactic vs therapeutic treatment • Antibacterial agents • Antifungal agents “Best” Antimicrobial • Legal • Efficacy • Safe – patient, owner, consumer • Available • Readily administered • Financial constraints Terminology • MBC-Minimum Bactericidal Concentration – Lowest concentration of an antibacterial agent required to kill a particular bacterium – Bactericidal -- MBC is no more than 4x the MIC • MIC-Minimum Inhibitory Concentration – Lowest concentration of an antimicrobial drug that will inhibit visible growth of a microorganism Terminology • Breakpoint in vitro – MIC used to indicate susceptible “S”, intermediate “I” or resistant “R” • MIC ˂ breakpoint – S • MIC > breakpoint – I, R – Chosen concentration of an antibiotic which defines whether a species of bacteria is susceptible or resistant to the antibiotic • Breakpoint in vivo – PK/PD = pharmacokinetics (what the body does to the drug) pharmacodynamics (what the drug does to the body) – Empirically based – Individual variation • Susceptible – Infection may be appropriately treated with the dosage regimen of an antimicrobial agent recommended for that type of infection • Intermediate – infection may be appropriately treated in body sites where the drugs are physiologically concentrated, or when a high dosage of a drug can be used • Resistant – Strains are not inhibited by the usually achievable concentration of the agent with normal dosage schedules and/or microbial resistance mechanisms likely T>MIC—optimize the duration of exposure (time-dependent) Cmax/MIC—maximize concentrations (conc.-dependent) Antimicrobial Agents • Concentration dependent – Effects are proportionate to concentration – Aminoglycosides, fluoroquinolones, & amphotericin B – GOAL: maximize concentrations Antibacterial Agents • Time-dependent – Killing capacity directly linked to exposure time – Includes bacteriostatic antibiotics – Beta-lactams & macrolides – GOAL: optimize duration of exposure https//u.osu.edu/beef/2017 Classification of Antibiotics Bacteriostatic Bactericidal • Chloramphenicol • Aminoglycosides • Macrolides • Bacitracin • Sulfonamides • Cephalosporins • Tetracyclines • Fluoroquinolones • Trimethoprim • Gramicidin • Penicillins • Polymyxin B • Vancomycin Antibacterial Agents • MOA – Cell wall synthesis – Cell membrane integrity – Protein synthesis – Folate metabolism – DNA synthesis • Gram positive • Gram negative – Thick cell wall – Outer membrane of LPS & phospholipids – Thinner cell wall www.onlinebiologynotes.com Inhibit Cell Wall Synthesis • Penicillins • Cephalosporins • Bacitracin • Vancomycin Penicillin • Thiazolidine ring & a β-lactam ring connected to a side chain Thiazolidine ring • 1928 Fleming • 1940 drug isolated • Side chain – PK Side chain β-lactam – Spectrum – Susceptibility to destruction • β-lactam ring – Binds transpeptidase and inhibits formation of peptidoglycan Mechanism of Action Penicillins Resistance to Penicillins • Bacteria – Alter their transpeptidases (PBP) – Decreased penetration of outer cell membrane – **Production of β-lactamases • Inactivate the β-lactam portion • Penicillinases subgroup of bacterial β-lactamases www.antimicrobe.org Penicillinase-Resistant Agents • Methicillin, oxacillin, cloxacillin, dicloxacillin, & nafcillin • Resist bacterial β- lactamases “Superbug” • Methicillin-resistant S. aureus (MRSA) • Methicillin-resistant S. pseudointermedius (MRSP) • Oxacillin is used to test for this resistance • Altered PBP/transpeptides • MR Staphyloccus in dogs with keratitis – 4X more likely to be owned by healthcare worker – 23.5% dogs + nasal culture LoPinto et al., Vet Ophthalmol, 2015 www.steemkr.com β-lactamase Inhibitors • Bind to β–lactamase enzyme (irreversible/noncompetitive) • “Suicide inhibitors” • Always combined with another β-lactam antibiotic Riviere & Papich, Veterinary Pharmacology and Therapeutics, 10 Ed. Clavamox® • Amoxicillin-clavulanate – Extends spectrum of amoxicillin to include β- lactamase-producing bacteria – 4:1 ratio of amoxicillin:clavulanate – Augmentin 4:1 or 7:1 ratio Drug Route Spectrum Drawback Penicillin G parenteral Gm + Susceptible to Penicillin V po Gm + organisms that produce β- lactamase S. Aureus S. epidermidis Ampicillin Gm + & Gm - Inactivated by β- Amoxicillin Gm + & Gm - lactamase Carbenicillin Pseudomonas Mezlocillin aeruginosa Piperacillin Some Proteus & Ticarcillin Enterobacter sp. Gm - Cephalosporins • Dihydrothiazine and β-lactam ring connected to a side chain • Interfere with peptidoglycan cross-linking • β-lactam Side chain β-lactam – Antibacterial activity dihydrothiazine – Bind transpeptidase – Inhibit peptidoglycan formation • Side chain Side chain – Determines spectrum Cephalosporins • Resistance – Destruction by β-lactamases – Less susceptible than penicillins • S. aureus produces penicillinases • Gm – bacteria produce β-lactamases – Generation classification – Based on spectrum of activity Cephalosporin Generations First Second Third Fourth Cephalexin Cefamandole Cefoperazone Cefquinome Cephalothin Cefmetazole Cefotaxime Cefepime Cefadroxil Cefonicid Ceftazidime Cephapirin Cefprozil Ceftizoxime Cefazolin Cefotetan Ceftriazone Cephradine Cefoxitin Moxalactam Cefaparin Cefuroxime Cefixime Cefaclor Ceftiofur Cefpodoxime Cefovecin Cephalosporin Generations First Second Third Good Gm + activity Good Gm + activity Modest Gm + activity (except Enterococcus) Modest Gm - activity Improved Gm - activity Improved Gm – activity (enteric bacteria) Cefazolin has greatest Increased resistance to Ceftazidime- Gm - activity β-lactamases Pseudomonas aeruginosa Penicillins and Cephalosporins • Not commercially available topically • Compound cefazolin 5% solution • Systemic administration – Adnexal disease – Orbital disease • Wang et al, Vet Ophtho, 2009 • 100% canine isolates-ceftiofur, ticarcillin • 78.3% canine isolates-Clavamox • 100% feline isolates-Clavamox, ampicillin, cefazolin cefpodoxime Bacitracin • Good Gm+ activity • Does not penetrate cornea • Not administered systemically due to nephrotoxicity • Inhibits movement of a peptidoglycan precursor from cytoplasm to cell wall www.faculty.ccbmd.edu Vancomycin • Glycopeptide (vancomycin, teicoplanin (Europe)) • Good Gm+ activity – Staphylococcus spp. (including MRSA),Streptococcus spp., Clostridium difficile, Enterococcus faecium & E. faecalis, Neisseria • Good Gm + anaerobic cocci – Not Gm – anaerobes • Increasing resistance to vancomycin among MRSA isolates Vancomycin • Ophthalmic use – Topical-infectious keratitis • First 2 hr after administration 0.52 µl/ml detected in AH • Therapeutic for most Gm + bacteria • Levels undetectable by 4 hours • Recommend 1 drop q 2 hr – Huerva et al., J Ocul Pharmacol, 1993 – Cystoid macular edema after cataract surgery • Vancomycin 10 µg.ml in the BSS irrigating solution • 55% of patients vs 19% in control group – Axer-Siegel, et al, Ophthalmolol, 1999 – Intravitreal injection-endophthalmitis Disrupt Cell Membrane • Polymyxin B • Gramicidin • Similarities btwn. bacterial and mammalian cell membranes limit systemic use Polymyxin B • Spectrum limited to Gm – – All Gm + resistant – Aerobacter, Escherichia, Histophilus, Klebsiella, Pasteurella, Pseudomonas, Salmonella, & Shigella – Proteus spp. and most Serratia spp. not effective • Not absorbed from GIT- administered IV • Poor penetration intact epithelium • Local hypersensitivity • Anaphylactic reaction-cats • Neurotoxic, nephrotoxic Gramicidin • Gr + spectrum • Forms membrane channel • Stable in solution • Causes hemolytic anemia if administered systemically www.nature.com David & Rajasekaran, J Kidney Cancer, 2015 Affect Bacterial Protein Synthesis • Aminoglycosides • Macrolides – Gentamicin – Erythromycin – Neomycin – Azithromycin – Tobramycin – Clarithromycin – Amikacin • Chloramphenicol – Kanamycin • Oxazolidinones • Tetracyclines – Linezolid Aminoglycosides • Irreversibly bind to receptor protein on 30S subunit • Disrupt initiation complex btwn mRNA and 30S subunit • Incorporation of incorrect aa in protein www.faculty.ccbcmd.edu Aminoglycosides • Poor oral absorption • Administered topically or parenterally • Strong Gm – activity – P. aeruginosa, Proteus, E. coli, Enterobacter... • Gm + efficacy restricted to S. aureus Aminoglycoside Toxicity • Nephrotoxicity – Concentrate in proximal tubule – Initial subclinical phase • Decreased urinary concentrating – Followed by azotemic phase – Risk factors • Dehydration, fever, old age, preexisting renal disease – If identified early aminoglycoside-induced renal injury can be reversed Aminoglycoside Toxicity • Ototoxicity/Vesibulartoxicity – Systemic aminoglycoside therapy (rarely topical) – Localization in hair cells, cochlea, spiral ganglion neurons, organ of Corti Aminoglycoside Toxicity • Neuromuscular blockade – Decrease the release of Ach – Decrease sensitivity of the end-plate to ACh – Increase clinical duration and time to recovery with neuromuscular blockers (atracurium vercuronium) with aminoglycosides Dupuis et al., Canadian J of Anaesthesia, 1989 Forsyth et al., Am J Vet Res, 1990 Aminoglycosides in Ophthalmology Topical Intravitreal • Neomycin • Gentamicin • Gentamicin – Chemical ablation • Tobramycin • Amikacin • Effects on cornea – Endophthalmitis treatment (may be – Delayed re- combined with epithelialization, punctate epithelial vancomycin to erosions, chemosis increase Gm + coverage) Plasma Concentration of Gentamicin • Post chemical ablation