Antimicrobial resistance in ophthalmology – an urgent global healthcare priority - PowerPoint Presentation

1. Antimicrobial resistance in ophthalmology – an urgent global healthcare priority11. Antibacterial resistance in ophthalmic infections: a multi-centre analysis across UK care settings//BMC Infectious Diseases.- volume 19, Article number: 768 (2019) Educational MODULENovember 2020NP-FOTE-EMEA-0186 Re-SOLVE antibiotic resistance initiative

2. Antimicrobial resistance in ophthalmologyDevelopment of antibiotic resistancePrinciples and challenges of modern antibiotic therapyClassification and pharmacology of antibioticsContents

3. Antimicrobial resistance in ophthalmology01

4. What are antibiotics?Commonly used antibiotics for the prevention of eye infections include: cefuroxime, cefazolin, vancomycin, gentamicin, tobramycin and moxifloxacin21. Mandell: Principles and Practice of Infectious Diseases, 5th ed., 2000 Churchill Livingstone, Inc;2. Barry P, et al. ESCRS Guidelines for Prevention and Treatment of Endophthalmitis Following Cataract Surgery: Data, Dilemmas and Conclusions; 2013. Available from: https://www.escrs.org/downloads/Endophthalmitis-Guidelines.pdf. Accessed January 2020.Antibiotics (from ‘anti’ and ‘bios’. i.e. ‘life’ in Greek) are chemotherapeutic agents with the ability to destroy or prevent the growth of pathogens Antibiotics can be formed by live microorganisms or obtained by artificial synthesis1

5. What is antimicrobial resistance?WHO definition: the ability of a microorganism to maintain vital functions, including reproduction, despite contact with a drug that was once effective against that microorganism1Resistance is a property of the microbe, not the infected organism1Antibiotic resistance is a subset of antimicrobial resistance, linked to pathogenic bacteria2WHO, World Health Organization1. WHO 2014. Antimicrobial resistance. Available from: https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resistance. Accessed January 2020; 2. MacGowan A, Macnaughton E. Medicine 2017;45(10):622–628.

6. Antimicrobial resistance: The scale of the problemYearly deaths attributable to antimicrobial resistance compared to other major causes of death1AMR, anti-microbial resistance1. O’Neill, J. 2016. Tackling drug-resistant infections globally: Final report and recommendations. Available from: https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf. Accessed January 2020.

7. A public health challenge1. World Health Organization. Antimicrobial resistance. Available from: https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resistance. Accessed January 2020;2. World Health Organization, 2015. Worldwide country situation analysis: response to antimicrobial resistance. Available from: https://www.who.int/drugresistance/documents/situationanalysis/en/. Accessed January 2020; 3. Cassini A, et al. Lancet Infect Dis 2019;19:56–66.Antimicrobial resistance is a major threat to public health worldwide1,2The burden of infections and infection-related deaths has increased from 20073Over 600,000 infections caused by antibiotic-resistant bacteria in Europe in 20153

8. Bacterial pathogens: Gram-positive bacteriaDark blue or violet color by Gram staining1Diseases caused:2PneumoniaMeningitisOtitis mediaEye infectionsAbscessFood poisoningCommon pathogens responsible for eye infections:2Streptococcus pneumoniae (anaerobe)Staphylococcus aureus (facultative anaerobe)1. Brown RC and Hopps HC. AJCP 1973;59:234–340;2. Mandell: Principles and Practice of Infectious Diseases, 5th ed., 2000 Churchill Livingstone, Inc.

9. Bacterial pathogens: Gram-negative bacteriaPink color by Gram staining1Diseases caused:2Otitis mediaRespiratory infectionsEye infectionsEndocarditisMeningitisUrinary tract infectionsBacteraemiaBurn wound infectionsNosocomial opportunistic infectionsCommon pathogens responsible for eye infections:2Moraxella catarrhalis (aerobe)Klebsiella pneumoniae (facultative anaerobe)Pseudomonas aeruginosa (obligate anaerobe)Haemophilus influenzae (facultative anaerobe)1. Brown RC and Hopps HC. AJCP 1973;59:234–340;2. Mandell: Principles and Practice of Infectious Diseases, 5th ed., 2000 Churchill Livingstone, Inc.

10. Infections of the front of the eye: Causative agents11. Callegan MC, et al. Adv Ther 2003;20:246–252.Gram-positiveGram-negativeStaphylococcus epidermidisPseudomonas aeruginosaStaphylococcus aureusKlebsiella pneumoniaeStreptococcus pneumoniaeHaemophilus influenzaeStreptococcus pyogenesEnterobacter aerogenesBacillus cereusNocardia asteroidsEnterococcus faecalisMycobacterium chelonaeGram-positive microorganisms, primarily Staphylococcus, are the most common pathogens responsible for inflammatory eye diseases of an infectious nature1

11. Endophthalmitis in focus1. Asbell PA, et al. Lancet 2005;365:599–609; 2. Gower EW, et al. Cochrane Database Syst Rev 2017;2:CD006364; 3. Endophthalmitis Vitrectomy Study Group. Am J Ophthalmol 1996; 122:830–46; 4. Garg P, et al. Curr Opin Ophthalmol 2017;28:67–72.Severe inflammation of the eye1,2Generally occurs in patients undergoing cataract surgery1,2 Gram-positive bacteria are the main causative agents494%The most serious sight-threatening post-operative complication312

12. Development of antibiotic resistance02

13. Causes of antibiotic resistanceAntibiotic resistance develops naturally, primarily through gene mutations1However, the modern over-use of antibiotics has accelerated the problem2,31. D’Costa VM, et al. Nature 2011;477:457–461; 2. Cassini A, et al. Lancet Infect Dis 2019;19:56–66;3. Barry P, et al. ESCRS Guidelines for Prevention and Treatment of Endophthalmitis Following Cataract Surgery: Data, Dilemmas and Conclusions; 2013. Available from: https://www.escrs.org/downloads/Endophthalmitis-Guidelines.pdf. Accessed January 2020.Source: www.who.int/drugresistance

14. Mechanisms of antibiotic resistance1Antibiotic inactivation (enzyme inactivation)Membrane permeability impairmentTarget modification (alteration)Active effluxMacGowan A, Macnaughton E. Medicine 2017;45(10):622–628. Image adapted from original article.

15. 1. Antibiotic inactivation by enzymes1Examples:- hydrolysis of β-lactam antibiotics by β-lactamases- inactivation of aminoglycosides by aminoglycoside modifying enzymes1. MacGowan A, Macnaughton E. Medicine 2017;45(10):622–628.Image adapted from original article.

16. 2. Modification of the drug target1Examples:- conformational change of large (50S) subunit of the bacterial ribosome - resistance to microlides (azithromycin)1 - atypical penicillin-binding proteins in staphylococci lead to MRSA strains21. B. Vester et al. Antimicrob Agents Chemoter. 2001 Jan; 45(1): 1–12. 2. MacGowan A, Macnaughton E. Medicine 2017;45(10):622–628.Image adapted from original article.

17. 3. Decreased permeability of the cell membrane1Examples:development of resistance to aminoglycosides in Pseudomonas aeruginosa (i.e. tobramycin) - resistance to triazole in Candida fungi1. MacGowan A, Macnaughton E. Medicine 2017;45(10):622–628.Image adapted from original article.

18. 4. Active efflux1Example:- Pseudomonas aeruginosa can actively eliminate carbapenems and fluoroquinolones (ciprofloxacin, ofloxacin etc)1. MacGowan A, Macnaughton E. Medicine 2017;45(10):622–628.Image adapted from original article.

19. Classification and pharmacology of antibiotics03

20. Classification of antibiotics by target1. Hooper DC. Clin Infect Dis 2000;31(Suppl 2):S24–28. Fluoroquinolones interact with bacterial enzymes DNA gyraseand topoisomerase IV, forming complexes that block DNA replication1Source of the image: intranet.tdmu.edu.ua; February, 2020.

21. Types of antibiotic activityBacteriostatic:1 antibiotics inhibit the growth and reproduction of microbial cells, but do not cause cell death Tetracyclines, lincomycin, chloramphenicolBactericidal:2 antibiotics bind irreversibly to the cellular target, killing the microorganismCephalosporins, aminoglycosides, fluoroquinolones1. Gower EW, et al. Cochrane Database Syst Rev 2017;2:CD006364; 2. Van Bambeke F, et al. Clin Microbiol Infect 2005;11:256–280.

22. Antibiotics and spectrum of action1Broad spectrum: fluoroquinolones, levomycetin, tetracyclines and cephalosporins (2nd and 3rd generations)Narrow spectrum: Colistin (Gr-) etcAnti-TB: streptomycin, rifampicin, florimycinAnti-fungal: nystatin, levorin, griseofulvin, amphotericin BTB, tuberculosis1. Coleman, JP and Smith, CJ. Microbial Classification. 2007 Elsevier Inc.

23. Pharmacokinetic profiles of antibiotics1,2Dose-dependentFluoroquinolones (levofloxacin)Macrolides (azithromycin)Aminoglycosides (tobramycin)MetronidazoleMIC, Minimum inhibitory concentration.1. Barry P, et al. ESCRS Guidelines for Prevention and Treatment of Endophthalmitis Following Cataract Surgery: Data, Dilemmas and Conclusions; 2013. Available from: https://www.escrs.org/downloads/Endophthalmitis-Guidelines.pdf. Accessed January 2020; 2. Van Bambeke F, et al. Clin Microbiol Infect 2005;11:256–280.Time-dependentPenicillinsCephalosporinsMonobactamsCarbapenemsTetracyclinesImages adapted from original article.

24. Emergence of resistance during antibiotic treatmentMBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration.1. Barry P, et al. ESCRS Guidelines for Prevention and Treatment of Endophthalmitis Following Cataract Surgery: Data, Dilemmas and Conclusions; 2013. Available from: https://www.escrs.org/downloads/Endophthalmitis-Guidelines.pdf. Accessed January 2020.Danger of antibiotic resistancePlasma antibiotic concentrationMBCMICTimeBacteriostatic effectBactericidal effectBacteriostatic effectSub-inhibitory effectPost-antibiotic effectImage adapted from original article.

25. Principles and challenges of modern antibiotic therapy04

26. Perspectives on modern antibiotic therapy1. World Health Organization. Antimicrobial resistance. Available from: https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resistance. Accessed January 2020;2. World Health Organization, 2015. Worldwide country situation analysis: response to antimicrobial resistance. Available at: Global Guidelines for the Prevention of Surgical Site Infections. WHO 2018. Available from: https://apps.who.int/iris/bitstream/handle/10665/277399/9789241550475-eng.pdf. Accessed January 2020; 3. Barry P, et al. ESCRS Guidelines for Prevention and Treatment of Endophthalmitis Following Cataract Surgery: Data, Dilemmas and Conclusions; 2013. Available from: https://www.escrs.org/downloads/Endophthalmitis-Guidelines.pdf. Accessed January 2020.Increased spread of resistant strainsChanges in the spectrum of pathogensHeterogeneous approach to the prophylaxis and treatment of microbial infectionsIncrease in the number of generic antibiotic drugs with unconfirmed efficacy The latest clinical recommendations acknowledge the growing problem of antibiotic resistanceA rational use of antibiotics is suggested, with reduced treatment duration to prevent the development of resistanceTreatment challenges1,2 Clinical guidelines2,3Contains animations.There is currently a need for antibiotics with proven efficacy against a range of pathogens, which allow for shorter treatment duration to avoid the development of antimicrobial resistance

27. Evolution of fluoroquinolonesThe development of fluoroquinolones has aimed to offer the best combination of pharmacokinetics and clinical activity1Newer fluoroquinolones have greater antimicrobial activity, which is more balanced across the two enzymatic targets21. Hooper DC. Clin Infect Dis 2000;31(Suppl 2):S24–28; 2. Van Bambeke F, et al. Clin Microbiol Infect 2005;11:256–280.Source: https://api.intechopen.com/

28. Classification of quinolones1. King DE, et al. Am Fam Physician 2000;61(9):2741-48; 2. Hooper DC. Clin Infect Dis 2000;31(Suppl 2):S24–28.1st generation: Non-fluorinated2nd generation: Gram-negativeNewer generation:Gram-negative and Gram-positiveNalidixic acidCiprofloxacinSparfloxacineOxolinic acidNorfloxacinLevofloxacinPipemidic acidOfloxacinMoxifloxacinPefloxacinLomefloxacinBased on the spectrum of activity1,2

29. Levofloxacin: A newer generation fluoroquinolone11. Liu HH. Drug Saf 2010;33:353–69; 2. Schwab IR, et al. Ophthalmology 2003;110:457–65; 3. Norrby SR. Expert Opin Pharmacother 1999;1:109–19; 4. Kanda Y, et al. Drugs R D 2012;12:177–85.Greater activity than older-generation fluoroquinolones1–3 Broad spectrum of actionagainst Gram-positive and Gram-negative bacteria1,2,4High water solubilityat a neutral pH, allowing for high concentrations4Levofloxacin is a L-enantiomer of ofloxacin2Levofloxacin can address the requirements of a modern antibiotic

30. Three main mechanisms of quinolone resistance1Levofloxacin is hydrophobic and thus not easily ejected through active efflux2Levofloxacin also inhibits the synthesis of signal molecules required to form the lipid bilayer (main component of the biofilm)2.3Biofilm formation is known to enhance resistance in bacterial strains31. Van Bambeke F, et al. Clin Microbiol Infect 2005;11:256–280; 2. Jumbe NL, et al. Antimicr Agents Chemother 2006;310–317;3. Shafreen, RMB et al. J Bioscience Bioeng 2011;112(4)345-350.3. Changes in the outer-membrane porins and active efflux leading to reduced entry of hydrophilic quinolones such as ciprofloxacin1. Target site alterations, resulting from mutations in the genes encoding for DNA gyrase and topoisomerase IV2. Synthesis of protective proteins that inhibit the binding of quinolonesSource: https://openi.nlm.nih.gov

31. Clinical studies of levofloxacin: Pharmacokinetics of levofloxacin in healthy volunteers1MIC, Minimum Inhibitory Concentration 1. Raizman MB, et al. Clin Ther 2002;24(9):1439-50. Key finding: peak concentration was attained at 15 minutes after instillation and remained above the MIC for most suspected ophthalmic pathogens (2 μg/ml) for at least 6 hours in most subjects and for up to 24 hours in some volunteersAim: to assess the pharmacokinetics and ocular bioavailability of 0.5% levofloxacin in human tears following a single-dose topical administration in healthy volunteers (N=30)100010010200123456Time(h)Mean Levofloxacin Concentration (μg/mL)Time versus mean concentrationMICx0 (μg/mL)Mean concentration of levofloxacin in tears over 6 hrs (n=6 at each time point)Image adapted from original article.

32. Clinical studies of levofloxacin: Activity in paediatric patients11. Lichtenstein SJ, et al. J AAPOS 2003;7(5):317–24. Key finding: in both the actively-controlled and placebo-controlled studies, levofloxacin demonstrated superior eradication of pathogens- These results were statistically significant in the group of children aged 2 to 11 years Aim: to compare the efficacy and safety of 5-day therapy with topical 0.5% levofloxacin ophthalmic solution vs. 0.3% ofloxacin or placebo in children with bacterial conjunctivitis (N=118)Image adapted from original article.

33. Levofloxacin in the ESCRS Endophthalmitis Study GroupFigure adapted from Endophthalmitis Study Group, European Society of Cataract & Refractive Surgeons. Prophylaxis of post-operative endophthalmitis following cataract surgery: Results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007;33:978–88.Number of patients: 4,000Endophthalmitis: 2 (0.050%);1 provenNumber of patients: 3,984Endophthalmitis: 10 (0.251%);7 provenNumber of patients: 3,997Endophthalmitis: 3 (0.075%);2 provenNumber of patients: 3,990Endophthalmitis: 13 (0.326%);9 provenGroup A+ (no IC injection and placebo vehicle eye drops)Post-operativeprophylaxis:Group B+ (only IC cefuroxime; placebo vehicle eye drops)Group D+ (both IC cefuroxime and levofloxacin 0.5% eye in peri-operative period)Group C+ (only levofloxacin 0.5% eye drops in peri-operative period; no IC injection) Post-operative prophylaxis:Topicallevofloxacin0.5% eye drops+Pre-operative prophylaxis:Povidone iodine 5% eye drops

34. Levofloxacin in the ESCRS Endophthalmitis Study Group1ESCRS, European Society of Cataract and Refractive Surgeons 1. ESCRS Endophthalmitis Study Group. J Cataract Refract Surg 2007;33:978-988.Key finding: in this large, multi-centre, controlled study, patients who received levofloxacin eye drops perioperatively had a lower risk of developing endophthalmitis than those who received placebo*Use of intracameral cefuroxime at the end of surgery reduced the occurrence of post-operative endophthalmitisIncidence rates of endophthalmitis were 0.049% (presumed) and 0.025% (proven) in the group receiving intra-cameral cefuroxime and peri-operative topical levofloxacin These rates were the lowest of the 4 treatment groupsAim: to investigate the role of antibiotics in preventing endophthalmitis in patients undergoing phacoemulsification cataract surgery

35. Summary: Key learning points1. World Health Organization. Antimicrobial resistance. Available from: https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resistance. Accessed January 2020;2. World Health Organization, 2015. Worldwide country situation analysis: response to antimicrobial resistance. Available from: https://www.who.int/drugresistance/documents/situationanalysis/en/. Accessed January 2020; 3. Cassini A, et al. Lancet Infect Dis 2019;19: 56–66; 4. Callegan MC, et al. Adv Ther 2003;20:246–252; 5. Prashant G. Curr Opin Ophthalmol 2017, 28:67 72; 6. D’Costa VM, et al. Nature 2011;477:457–461; 7. Hooper DC. Clin Infect Dis 2000;31(Suppl 2):S24–28; 8. Van Bambeke F, et al. Clin Microbiol Infect 2005;11:256–280; 9. Schwab IR, et al. Ophthalmology 2003;110:457–65; 10. Schwab IR, et al. Ophthalmology 2003;110:457–65.Antimicrobial resistance is a major threat to public health worldwide,1,2 and its burden is increasing3Gram-positive bacteria, mainly Staphylococcus, are the most common pathogens responsible for eye infections,4 including endophthalmitis5While resistance to antibiotics develops naturally,6 the modern over-use of antibiotic drugs has contributed to the problem3The development of quinolones has optimised their pharmacokinetics and clinical activity, while reducing toxicity and the risk of resistance7,8Levofloxacin is a newer generation fluoroquinolone that can address the requirements of a modern antibiotic for broad spectrum of action, high efficacy and short treatment duration9,10Contains animations.