OPHTHALMIC ANTIMICROBIALS

Transcription

1 OPHTHALMIC ANTIMICROBIALS Alison Clode, DVM, DACVO Port City Veterinary Referral Hospital Portsmouth, New Hampshire New England Equine Medical and Surgical Center Dover, New Hampshire

2 Overview Interpretation of efficacy Mechanisms of resistance Antibacterial agents Mechanism of action Applications in ophtho Antifungal agents Mechanism of action Applications in ophtho

3 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

4 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

5 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

6 Time- versus Concentration-Dependent

7 Mechanisms of Resistance Intrinsic to the bacteria Acquired by the bacteria

8 Acquired Mechanisms of Resistance 1. Modification of the antibiotic 2. Preventing antibiotic from reaching target 3. Modification of the target

9 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

10 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

11 Acquired Mechanisms of Resistance 3. Modification of target by altering: Binding proteins Ribosomes Chromosomes Cell physiology

12 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

13 Antibacterial Agents

14 Antibacterial Agents Mechanisms of action = disruption of: 1. Cell wall synthesis 2. Cell membrane integrity 3. Protein synthesis 4. Folate metabolism 5. DNA synthesis

15 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

16 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

17 1. Cell Wall Synthesis Inhibitors Penicillins Cephalosporins Bacitracin Glycopeptides

18 Penicillins Structure and function Side chain: Spectrum Susceptibility to destruction Pharmacokinetic properties side chain thiazolidine ring β-lactam: Function Bind transpeptidase à inhibit formation of peptide linkages between polysaccharides à inhibit formation of peptidoglycan β-lactam

19 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

20 Penicillins Resistance 2. Alter transpeptidases Penicillins unable to bind to and inactivate transpeptidase MRSA

21 Penicillins Classes Effective versus G+ Resistant to penicillinase Extended spectrum Anti-pseudomonal

22 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

23 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

24 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

25 Penicillins Anti-pseudomonal activity Carbenicillin Ticarcillin (+/- clavulanate) Piperacillin (+/- tazobactam) Mezlocillin Also effective versus Proteus and Enterobacter

26 Cephalosporins Structure and Function Side chains: Spectrum/classification Susceptibility to destruction Pharmacokinetic properties side chain dihydrothiazine ring β-lactam: Function Bind transpeptidase à inhibit formation of peptide linkages between polysaccharides à inhibition of peptidoglycan formation β-lactam side chain

27 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

28 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

29 Cephalosporins First generation Second generation Third generation Fourth generation Drugs Cephalexin Cefazolin Cefadroxil Cephradine Cefuroxime Cefoxitin Cefaclor Cefprozil Cefotetan Ceftazidime Cefotaxime Ceftriaxone Cefixime Cefdinir Cefepime Other Good G+ activity Modest G- activity Increasing resistance of Streptococcus pneumoniae to cefazolin Good G+ activity Improved G- activity Modest G+ activity Improved enteric G- activity Ceftazidime has excellent activity versus Pseudomonas aeruginosa Good G+ activity Good G- activity

30 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

31 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

32 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

33 Glycopeptides Strong activity vs G+ Drug of choice for MRSA, penicillinresistant Strep pneumoniae Most G- are resistant Vancomycin Teicoplanin vancomycin

34 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)

35 Glycopeptides Resistance 2. Altered antibiotic penetration Inability to penetrate bacterial membrane (G- organisms) Intrinsic resistance

36 Glycopeptides Resistance

37 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

38 Vancomycin Ocular Application Reaches therapeutic AH levels when applied topically (50 mg/ml) Effective versus corneal infections with MRSA and MRSE Associated with cystoid macular edema when used intracamerally during cataract surgery Non-toxic to the retina at 1 mg dose Intravitreal injection in combination with amikacin or ceftazadime for endophthalmitis * Alster Y, et al., BJO 2000 ** Sotozono C, et al., Cornea 2002 *** Penha FM, et al., Ophthalmic Res 2010

39 Teicoplanin Ocular Application Alternative therapy for MRSA infections No vitreal penetration when administered topically Poor vitreal penetration when administered IV

40 2. Cell Membrane Disruptors Polymyxin B Gramicidin Similarities between bacterial and human cell membranes limit use

41 Polymyxin B Detergent/surfactant Disrupts cell membrane phospholipids à increased permeability à cell death Positively charged drug binds negatively charged LPS layer Binds to and inactivates endotoxin G- activity good Effective versus Pseudomonas Not effective versus Proteus G+ activity poor Thick cell membrane Absence of LPS Neurotoxic, nephrotoxic

42 Gramicidin Functions as membrane channel Alters permeability Selective movement of monovalent cations and water Stable in solution Predominantly G+ activity Hemolysis when administered systemically, therefore topical administration only

43 3. Protein Synthesis Disruptors Aminoglycosides Tetracyclines Macrolides Chloramphenicol Oxazolidinones

44 Protein Synthesis Short Version Translation = mrna à protein Ribosomes 50S subunit + 30S subunit = 70S prokaryotic ribosome 40S subunit + 60S subunit = 80S eukaryotic ribosome Peptidyl transferase Enzymatic function of ribosome to create peptide bonds between adjacent amino acids

45 Protein Synthesis Disruptors Target = 30S Aminoglycosides Tetracyclines

46 Protein Synthesis Disruptors Target = 30S Aminoglycosides Tetracyclines G- aerobes (Pseudomonas, Proteus, Klebsiella, E. coli, Enterobacter) Some Staphylococcus spp. Neomycin generally not effective versus Pseudomonas

47 Aminoglycosides MOA Positively charged Bind negatively-charged LPS of G- outer membrane Bind negatively-charged rrna Hydrophilic Poor lipid membrane penetration Different AG have variable specificity for different regions, leading to different spectrum of activity

48 Aminoglycosides MOA 1. Bind outer membrane (electrostatic) 2. Diffuse into periplasmic space 3. Transport into cytoplasm (oxygen-dependent) 4. Bind 16s rrna of 30S subunit (energy-dependent) 5. mrna misreading à missense, premature stop codons Also bind to and disrupt cell membrane

49 Aminoglycosides Resistance 1. Alteration of AG à decreased affinity for ribosome AME (aminoglycoside modifying enzymes) Mutational pressure induced by exposure of bacteria to AG à resistance genes within normal bacterial enzymes à modification of AG Transferred by plasmids or transposons Methylation of binding site on AG à decreased binding to ribosome à decreased function of AG Most common resistance method Results in high-level resistance Resistance not predictable among different AG due enzyme variability * Shakil S, et al., J Biomed Sci 2008

50 Aminoglycosides Resistance 2. Reduced intracellular drug concentration Bacterial efflux pumps Energy-dependent Constitutively expressed à low-level, intrinsic resistance Substrate-induced or mutation-induced overexpression à increased resistance Altered outer membrane permeability Decreased inner membrane transport Drug trapping * Shakil S, et al., J Biomed Sci 2008

51 Aminoglycosides Resistance 3. Enzyme-induced alteration of ribosome Normal bacterial enzymes Alter shape of ribosome à alter contact of AG with ribosome à decreased function of AG * Shakil S, et al., J Biomed Sci 2008

52 AGs Toxicity Positive charge increases toxicity Nephrotoxicity Concentration in proximal tubule epithelial cells à disrupt tubule fxn à cation-wasting in urine Ototoxicity Localization in hair cells à cell death Localize in the cochlea, spiral ganglion neurons, organ of Corti Neuromuscular blockade Affinity for rrna of prokaryotes is only ~10X greater than for eukaryotes

53 Aminoglycosides in Ophthalmology Topical: Neomycin not considered effective versus Pseudomonas Gentamicin Tobramycin Combination with β-lactam for improved G+ spectrum must be applied separately! As a class, noted to have deleterious effects on corneal wound healing Delayed reepithelialization, punctate epithelial erosions, corneal ulceration, chemosis Intravitreal: Amikacin less toxic than gentamicin, may be used in combination with vancomycin (G+ spectrum) for endophthalmitis

54 Protein Synthesis Disruptors Target = 30S Aminoglycosides Tetracyclines Rickettsia spp Borrelia spp Chlamydophila spp Mycoplasma spp Moraxella spp Brucella spp Some Staphylococcus and Streptococcus spp. Generally not effective versus Pseudomonas

55 Tetracyclines Mechanism 1. Enter bacterial cell Outer membrane porins (G-) à passive diffusion through inner cell membrane Active transport across cytoplasmic membrane (G+) 2. Inhibit binding of trna to mrna-ribosome complex 16S subunit of 30S ribosome Reversible Weak binding to eukaryotic ribosomes minimizes toxicity

56 Tetracyclines Resistance Acquisition of tet genes by bacteria Speer et al., Clin Microbiol Rev, 1992

57 Tetracyclines Resistance 1. Efflux pumps 2. Ribosomal protection proteins Block binding of TCN to ribosome Bind to and distort ribosome to still allow t-rna binding Bind to ribosome and dislodge TCN 3. Enzymatic inactivation (rare) Addition of acetyl group to drug Thaker M, et al., Cell Mol Life Sci 2010 D Costa VM, et al., Science, 2006

58 Tetracyclines Short acting (t½ 6-8 hours) Tetracycline (1 st gen) Intermediate acting (t½ 12 hours) Demeclocycline Long acting (t½ 16 hours) Doxycycline (2 nd gen) Oxytetracycline (1 st gen) Minocycline (2 nd gen)

59 Bonus Properties of TCNs Anticollagenase activity Inhibit MMPs Bind zinc and calcium ions within enzyme catalytic domain Likely irreversible May (or may not) modulate MMP expression Inhibit IL-1 synthesis Inhibit activated B cell function Inhibit NO synthesis via LPS activation Golub LM, et al., J Dent Res 1987 Smith VA, et al., Br J Ophthalmol 2004 Solomon A, et al., Invest Ophthalmol Vis Sci 2000 Kuzin II, et al., Int Immunol 2001 D Agostino P, et al., Eur J Pharmacol 1998

60 Tetracyclines in Ophthalmology Federici, Pharmacological Research, 2011

61 Protein Synthesis Disruptors Target = 50S Macrolides CHPC Oxazolidinones

62 Protein Synthesis Disruptors Target = 50S Macrolides CHPC Oxazolidinones G+ cocci Chlamydophila spp, Mycoplasma spp, Borrelia spp Increased G- spectrum (azithromycin) Enterococci resistant Streptococcus spp developing resistance Erythromycin Clindamycin Azithromycin Etc..

63 Macrolides Mechanisms 1. Prevent formation of peptide bond between adjacent amino acids 2. Premature dissociation of peptidyl-trna complex from ribosome 3. Inhibit ribosomal translocation 4. May also affect ribosome assembly Macrolide binding to 50S ribosome is reversible Accumulate within leukocytes faculty.ccbcmd.edu

64 Macrolides Resistance Resistance: Acquired ribosomal alterations Drug-inactivating enzymes (rare) Efflux pumps (rare)

65 Protein Synthesis Disruptors Target = 50S Macrolides CHPC Oxazolidinones G+ G- Rickettsia spp, Chlamydophila spp, Mycoplasma spp Spirochetes Pseudomonas spp are resistant

66 Chloramphenicol Mechanism 1. High lipid solubility à diffusion across cell membrane 2. Inhibition of peptidyl transferase à inhibition of protein elongation

67 Chloramphenicol Resistance 1. Reduced membrane permeability Low-level resistance Most common 2. Enzymatic inactivation High-level resistance Prevents binding to ribosome 3. Mutation of 50S ribosomal subunit Rare

68 Chloramphenicol Side Effects Dose-related bone marrow suppression Due to inhibition of mitochondrial synthesis Reversible with discontinuation Does not predict development of aplastic anemia Idiosyncratic aplastic anemia Not dose-related Weeks to months after discontinuation of therapy Irreversible

69 Dose-Related Bone Marrow Suppression Inhibition of mitochondrial protein synthesis à mild BM hypocellularity, anemia, neutropenia, thrombocytopenia 0.5% ophthalmic solution Four times daily x 7 days à total dose < 19 mg Four times daily x 14 days à total dose < 33 mg No measurable serum levels in either group (< 1 mg) Estimated total dosage for toxicity = 30 mg Estimated total exposure duration for toxicity = 18 days Walker et al., Eye, 1998

70 Aplastic Anemia CHPC intestinal bacteria dehydro-chpc systemic absorption DNA damage in bone marrow cells nitroso-derivatives of CHPC 20X increased cytotoxicity

71 Aplastic Anemia CHPC intestinal bacteria dehydro-chpc systemic absorption DNA damage in bone marrow cells nitroso-derivatives of CHPC 20X increased cytotoxicity Genetic susceptibility? 1. Increased ability to form nitroso-derivatives 2. Increased sensitivity of bone marrow cell DNA 3. Decreased ability to bone marrow cell DNA to repair itself

72 Aplastic Anemia Lam et al, Hong Kong Med J, 2002

73 Aplastic Anemia Possible association between ocular CHPC and aplastic anemia the absolute risk is very low (Br J Clin Pharmacol 1998) 145 patients with aplastic anemia 1226 age- and sex-matched controls 3 affected and 5 controls used ocular CHPC preparation

74 Aplastic Anemia Possible association between ocular CHPC and aplastic anemia the absolute risk is very low (Br J Clin Pharmacol 1998) 145 patients with aplastic anemia 1226 age- and sex-matched controls 3 affected and 5 controls used ocular CHPC preparation BMJ, patients with aplastic anemia 3118 age- and sex-matched controls 0 affected and 7 controls used CHPC eye drops

75 Aplastic Anemia Possible association between ocular CHPC and aplastic anemia the absolute risk is very low (Br J Clin Pharmacol 1998) 145 patients with aplastic anemia 1226 age- and sex-matched controls 3 affected and 5 controls used ocular CHPC preparation Relative risk = < 1: 1,000,000 BMJ, patients with aplastic anemia 3118 age- and sex-matched controls 0 affected and 7 controls used CHPC eye drops

76 Protein Synthesis Disruptors Target = 50S Macrolides CHPC Oxazolidinones Predominantly G+ aerobes and anaerobes Including methicillin- and vancomycin-resistant strains Some G- activity (anaerobes) Poor activity versus G- aerobes

77 Oxazolidinones MOA Bind 23S subunit of 50S ribosome à non-functional initiation complex portion of 70S ribosome Inhibits translocation May also decrease bacterial virulence factors and increase phagocytosis at sub-mic concentrations

78 Oxazolidinones Resistance Alteration of target ribosomal binding site Development low due to: Synthetic nature of compounds Unique method of inhibiting bacterial protein synthesis Multiple genes encode binding site to 23S ribosomal subunit Difficult to select for linezolid-resistant strains in vitro Risk factors for development of resistance: Lengthy or repeated course of therapy Use in presence of foreign bodies Reversal of resistance has been reported following discontinuation of antibiotic

79 Oxazolidinones Toxicity GI suppression Reversible thrombocytopenia and anemia Neuropathy

80 Oxazolidinones in Ophthalmology Topical administration 0.2% penetrates into rabbit anterior segment 0.2% successfully treated humans with vancomycin-resistant or vancomycin-intolerant bacterial keratitis Intravitreal administration Effective in experimental model of S. aureus endophthalmitis in rabbits (30 mg once) No retinal toxicity Oral administration Achieves levels >MIC for common organisms in human AH and VH following single oral dose Saleh et al., JCRS 2010 Tu et al., AJO 2013 Saleh et al., IOVS 2012 George et al., JOPT 2010

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82 4. Folate Metabolism Disruptors Sulfonamides Trimethoprim Pyrimethamine

83 Folate Metabolism Disruptors Folate Necessary for DNA and RNA synthesis and maintenance Mammals acquire folate (or folic acid) in food Bacteria must synthesize folate MOA = enzyme inhibition Dihydropteroate synthetase Sulfonamides Dihydrofolate reductase Trimethoprim Pyrimethamine (primarily antiprotozoal)

84 Folate Metabolism Disruptors Resistance: 1. Overproduction of PABA by bacteria 2. Decreased enzyme affinity for drug 3. Decreased bacterial permeability of drug 4. Increased inactivation of drug by bacteria If resistant to one sulfonamide, resistant to all

85 Sulfonamide Toxicity KCS Direct toxic effect on lacrimal acinar cells N-containing pyridine and pyrimidine rings Dose-dependent or idiosyncratic 15-25% incidence in dogs treated with sulfas May develop months to years after discontinuation May be reversible upon discontinuation Other systemic toxicity signs variable (i.e., hepatotoxicity) Barnett K, et al., Human Toxicol 1987 Trepanier L. J Vet Pharm Therapeutics 2004 Trepanier L, et al. J Vet Intern Med 2003

86 5. DNA Synthesis Disruptors Fluoroquinolones

87 DNA Synthesis Very Short Version Topoisomerase II (DNA gyrase) gyra + gyrb Relaxes positive supercoils that accumulate ahead of DNA polymerase during DNA replication Topoisomerase IV ParC + ParE Unlinks newly formed DNA strands Relaxes positive supercoils that accumulate ahead of DNA polymerase during DNA replication Bacterial enzyme only Not present in all bacteria

88 Fluoroquinolones MOA 1. Enter bacterial cell Porin- and LPS-mediated (G-) Lipophilicity (G+) 2. Bind to enzyme à interrupt DNA stabilization à inhibit DNA synthesis DNA gyrase target for G- Topoisomerase IV target for G+ Spectrum depends upon substituents added to core structure

89 Fluoroquinolones Resistance Low-level resistance = in vitro determination that may not correlate with clinical failure due to ability to achieve greater local concentrations Single-step mutants High-level resistance = in vitro determination that is more likely to correlate with clinical failure due to inability to achieve appropriate local concentrations Multi-step mutants Due to repeated exposure to sub-lethal concentrations of FQN

90 Fluoroquinolones Resistance Chromosome-mediated (mutational) 1. Mutations in genes encoding protein targets of FQNs Mutation in gyra à low-level resistance Mutation in parc à moderate-level resistance Second mutation in gyra à high-level resistance Second mutation in parc à highest-level resistance 2. Mutations causing reduced drug accumulation Decreased uptake Decreased expression of porins (G-) Increased efflux Upregulation of efflux pumps

91 Fluoroquinolones Resistance Plasmid-mediated 1. Qnr Encodes protein that protects topoisomerases from antibiotic Results in low-level resistance 2. Enzymatic inactivation Alters antibiotic structure à inactivation of antibiotic In combination with Qnr à higher-level resistance 3. QepA Gene encoding for efflux pump

92 Fluoroquinolones Avoiding Resistance Low-level resistance: Maintain drug concentrations above mutant prevention concentration Generally several-fold higher than minimum inhibitory concentration High-level resistance: Avoid repeated exposure to low levels of FQN Avoid intermittent FQN exposure Avoid tapering FQN Newer FQN: Structural features confer less resistance potential Structural features increase ocular tissue concentrations MICs generally lower

93 Fluoroquinolones in Ophthalmology Generation First (quinolone) Drugs Nalidixic acid Norfloxacin Ciprofloxacin Ofloxacin Second Third Fourth Levofloxacin Gemifloxacin Sparfloxacin Moxifloxacin Gatifloxacin Besifloxacin Spectrum G- G- Some G+ G- Some G+ G- G+ Other Weak versus Pseudomonas Improved versus Pseudomonas Increasing resistance of Strep pneumoniae Efficacy versus MRSA, resistant Pseudomonas strains

94 4 th Generation Fluoroquinolones Moxifloxacin Gatifloxacin Besifloxacin (formulated for ophthalmic use) Balanced inhibition of DNA gyrase and topoisomerase IV Strong Gram+ activity, strong anaerobic activity, retain Gramactivity Labeled for bacterial conjunctivitis Clinical efficacy in bacterial keratitis, post-operative endophthalmitis, etc. No difference in tolerability, adverse events O Brien, Adv Thera, 2012 Majmudar, Cornea, 2014 Garg Asia Pac J Ophth 2015 Etc

95 Fluoroquinolones in Vet Ophthalmology [Ofloxacin] > [ciprofloxacin] in canine AH [Moxifloxacin] > [ciprofloxacin] in equine AH [Moxifloxacin] > [ciprofloxacin] in equine tears, cornea, and AH Increased resistance of β-hemolytic Streptococcus to ciprofloxacin in dogs

96 Fluoroquinolones Side Effects Corneal cytotoxicity in vitro Delayed wound healing in vivo 1.5% levo > 0.5% moxi > 0.3% gati > 0.5% levo Corneal precipitates Endothelial damage with intraocular injection Concentration-dependent

97 Summary Important to understand the mechanisms of bacterial resistance Significantly increasing understanding of these mechanisms via genomics Appropriate selection of antibiotic in ophthalmology depends upon spectrum of action and toxicities