OPHTHALMIC ANTIMICROBIALS Alison Clode, DVM, DACVO Port City Veterinary Referral Hospital Portsmouth, New Hampshire New England Equine Medical and Surgical Center Dover, New Hampshire
Overview • Interpretation of efficacy • Mechanisms of resistance • Antibacterial agents • Mechanism of action • Applications in ophtho • Antifungal agents • Mechanism of action • Applications in ophtho
Interpretation of Efficacy – in vitro 1. MIC = minimum inhibitory concentration • Lowest concentration of antibiotic that inhibits growth of a specific organism 2. MBC = minimum bactericidal concentration • Lowest concentration of an antibiotic at which bacteria are killed 3. Breakpoint • Antibiotic concentration dividing susceptible and resistant • MIC < breakpoint à S • MIC ≥ breakpoint à I, R
Interpretation of Efficacy – in vivo 4. PK/PD = pharmacokinetics (what the body does to the drug) pharmacodynamics (what the drug does to the body) 5. Susceptible = bacteria inhibited by usually achievable concentrations of antibiotic when recommended dose used for particular site of infection 6. Intermediate = bacteria inhibited in sites were antibiotic is physiologically concentrated or when higher-than-normal dosage can be used 7. Resistant = bacteria not inhibited by usually achievable concentrations of antibiotic with normal dosing schedules or when microbial resistance mechanisms are likely
Interpretation of Efficacy • Indices utilized: • T > MIC = % time plasma concentration is above MIC • Cmax/MIC = max plasma concentration relative to MIC • AUC/MIC = plasma concentration time curve (duration of drug exposure) relative to MIC • Determined by various animal models www.rxkinetics.com
Time- versus Concentration-Dependent www.slideshare.net
Mechanisms of Resistance • Intrinsic to the bacteria • Acquired by the bacteria
Acquired Mechanisms of Resistance 1. Modification of the antibiotic 2. Preventing antibiotic from reaching target 3. Modification of the target
Acquired Mechanisms of Resistance 1. Modification of the antibiotic • Enzyme-induced damage to antibiotic à inactive antibiotic • Enzyme-induced acetylation, adenylation, phosphorylation of antibiotic à alter affinity of antibiotic for target
Acquired Mechanisms of Resistance 2. Prevent antibiotic from reaching target • Preventing intracellular drug accumulation • Alteration of porin channels à reduced drug entry • Production of active efflux pumps à reduced drug retention
Acquired Mechanisms of Resistance 3. Modification of target by altering: • Binding proteins • Ribosomes • Chromosomes • Cell physiology
Acquired Mechanisms of Resistance • Vertical gene transfer = transfer of R-conferring gene to progeny • Horizontal gene transfer = sharing of R-conferring DNA among bacteria • Same or different strains • Transformation = DNA uptake from environment • Transduction = DNA transfer by viruses • Conjugation = plasmid exchange via cell-to-cell contact
Antibacterial Agents
Antibacterial Agents • Mechanisms of action = disruption of: 1. Cell wall synthesis 2. Cell membrane integrity 3. Protein synthesis 4. Folate metabolism 5. DNA synthesis
Bacterial Cell Wall • Main component = peptidoglycan • PS + peptide crosslinks • Formed by transpeptidases (penicillin binding proteins) • Gram positive : • Thick cell wall with greater peptidoglycan content and teichoic acid • Cytoplasmic membrane
Bacterial Cell Wall • Main component = peptidoglycan • PS + peptide crosslinks • Formed by transpeptidases (penicillin binding proteins) • Gram negative : • Outer membrane of LPS and phospholipids • Thinner cell wall with lesser peptidoglycan content • Cytoplasmic membrane
1. Cell Wall Synthesis Inhibitors • Penicillins • Cephalosporins • Bacitracin • Glycopeptides
Penicillins – Structure and function thiazolidine ring • Side chain: side chain • Spectrum • Susceptibility to destruction • Pharmacokinetic properties • β -lactam: • Function • Bind transpeptidase à inhibit formation of peptide linkages between polysaccharides à inhibit formation of peptidoglycan β -lactam
Penicillins – Resistance 1. β -lactamase production • à hydrolysis of β -lactam ring • Occurs extracellularly in G+ • Occurs between cell membrane and wall in G- • Induced by drug binding to bacterial cell wall or • Constitutively produced by bacteria www.wiley.com
Penicillins – Resistance 2. Alter transpeptidases • Penicillins unable to bind to and inactivate transpeptidase • ‘MRSA’ www.wiley.com
Penicillins – Classes • Effective versus G+ • Resistant to penicillinase • Extended spectrum • Anti-pseudomonal
Penicillins Effective versus G+ Penicillin G (parenteral) Penicillin V 1. Highly susceptible to β -lactamases à poor activity versus Staph aureus and Staph epidermidis 2. Ineffective versus altered transpeptidases à poor activity versus Streptococcus pneumoniae , viridans streptococci
Penicillins Resistant to penicillinases Methicillin Oxacillin Cloxacillin Dicloxacillin Nafcillin 1. Structural modifications à increased efficacy versus β - lactamase-producing Staph aureus, Staph epidermidis 2. Resistance now due to altered transpeptidases
Penicillins Extended spectrum Ampicillin (+/- sulbactam) Amoxicillin (+/- clavulanate) 1. Penicillins inactivated by β -lactamases when not in combo 2. Irreversible inactivation of β -lactamases by sulbactam and clavulanate 3. Ineffective versus altered transpeptidases
Penicillins Anti-pseudomonal activity Carbenicillin Ticarcillin (+/- clavulanate) Piperacillin (+/- tazobactam) Mezlocillin Also effective versus Proteus and Enterobacter
Cephalosporins – Structure and Function dihydrothiazine ring • Side chains: side chain • Spectrum/classification • Susceptibility to destruction • Pharmacokinetic properties • β -lactam: • Function • Bind transpeptidase à inhibit formation of peptide linkages between polysaccharides à inhibition of peptidoglycan formation β -lactam side chain
Cephalosporins – Resistance 1. Destruction by β -lactamases • Cephalosporins less susceptible than penicillins • S. aureus produces penicillinases • G- bacteria produce β -lactamases • Extended spectrum β -lactamases ( E. coli, Pseudomonas , etc.) * Zapun A, et al., FEMS Microbiol Rev 2008
Cephalosporins – Resistance 2. Alteration of transpeptidases • Cephalosporins unable to bind to and inactivate enzyme • Less common for cephalosporins than for penicillins • ‘MRSA’ * Zapun A, et al., FEMS Microbiol Rev 2008
Cephalosporins First generation Second Third generation Fourth generation generation Drugs Cephalexin Cefuroxime Ceftazidime Cefepime Cefazolin Cefoxitin Cefotaxime Cefadroxil Cefaclor Ceftriaxone Cephradine Cefprozil Cefixime Cefotetan Cefdinir Other Good G+ activity Good G+ activity Modest G+ Good G+ activity activity Modest G- activity Improved G- Good G- activity activity Improved enteric Increasing G- activity resistance of Streptococcus Ceftazidime has pneumoniae to excellent activity cefazolin versus Pseudomonas aeruginosa
Penicillins and Cephalosporins in Ophtho • No commercially available topical ophthalmic preparations • Systemic administration: • Orbital disease • Adnexal disease • Limited use in ocular surface disease • Staph and Strep resistance (penicillins) • Strep resistance (cephalosporins) • Limited use in endophthalmitis
Bacitracin • Interrupts transporter molecule à inhibits movement of peptidoglycan precursor from cytoplasm to cell wall • G+ • Staphylococcus • Streptococcus pyogenes • Administered topically (ointment) • Nephrotoxicity • May be administered IM in very few approved situations • Poor transcorneal penetration • “Allergen of the Year” 2003 www.ccbcmd.edu
Glycopeptides • Bind D-Ala-D-Ala terminal portion of peptidoglycan precursor à peptidoglycan precursor unavailable for cell wall formation à decreased cell wall growth + decreased cell wall rigidity vancomycin
Glycopeptides • Strong activity vs G+ • Drug of choice for MRSA, penicillin- resistant Strep pneumoniae • Most G- are resistant • Vancomycin • Teicoplanin vancomycin
Glycopeptides – Resistance 1. Alterations of the antibiotic target • VanA resistance: • Reduced affinity via alteration of terminal amino acid residues of peptidoglycan precursor (D-Ala-D-Ala à D-Ala-D-Lac) • VanC resistance: • Steric hindrance caused by substitution (D-Ala-D-Ala à D-Ala-D- Ser)
Glycopeptides – Resistance 2. Altered antibiotic penetration • Inability to penetrate bacterial membrane (G- organisms) • Intrinsic resistance
Glycopeptides – Resistance
Glycopeptides – Resistance Enterococcal spp that are resistant to vancomycin but require vancomycin presence to grow have been isolated … Vancomycin presence induces resistance mechanisms … . This is VERY BAD …
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