The Challenge of Antibiotic Resistance in Corneal Infection

  • Paulo J. M. BispoEmail author
  • Lawson Ung
  • James Chodosh
  • Michael S. Gilmore


The discovery and development of antibiotics for treatment of bacterial infections was one of the greatest medical advances of the last century, and it has saved millions of lives. However, as early as 1945, Sir Alexander Fleming expressed concern about the consequences of antibiotic overuse. Seven decades later, antimicrobial resistance (AMR) has reached alarming levels and is now a major public health threat in the twenty-first century. The emergence of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), antibiotic-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus, multidrugresistant Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae among others is raising the specter of a post-antibiotic era. AMR organisms, which initially were largely confined to hospitals, have now found their ways into communities, posing a serious threat to otherwise healthy individuals. MRSA, for instance, caused an estimated 80,461 invasive infections and 11,285 deaths in the US in 2011, and are now common causes of ocular infection. Most derive from specific MRSA lineages that have disseminated throughout the US and other locations, and are associated with particularly serious ocular and orbital infections.


Antimicrobial resistance Fluoroquinolones Topical fortified antibiotics Pharmacokinetics/pharmacodynamics (PK/PD) Infectious keratitis 


  1. 1.
    Spellberg B, Gilbert DN. The future of antibiotics and resistance: a tribute to a career of leadership by John Bartlett. Clin Infect Dis. 2014;59(Suppl 2):S71–5.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    World Health Organization, WHO. Antimicrobial resistance: global report on surveillance. 2014.Google Scholar
  3. 3.
    Centers for Disease Control and Prevention, CDC. Antibiotic resistance threats in the United States. 2013.Google Scholar
  4. 4.
    Alanis AJ. Resistance to antibiotics: are we in the post-antibiotic era? Arch Med Res. 2005;36(6):697–705.PubMedCrossRefGoogle Scholar
  5. 5.
    Livermore DM. The need for new antibiotics. Clin Microbiol Infect. 2004;10(Suppl 4):1–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Livermore DM. Has the era of untreatable infections arrived? J Antimicrob Chemother. 2009;64(Suppl 1):i29–36.PubMedCrossRefGoogle Scholar
  7. 7.
    van Duin D, Paterson DL. Multidrug-resistant bacteria in the community: trends and lessons learned. Infect Dis Clin N Am. 2016;30(2):377–90.CrossRefGoogle Scholar
  8. 8.
    Dantes R, Mu Y, Belflower R, Aragon D, Dumyati G, Harrison LH, et al. National burden of invasive methicillin-resistant Staphylococcus aureus infections, United States, 2011. JAMA Intern Med. 2013;173(21):1970–8.PubMedGoogle Scholar
  9. 9.
    Asbell PA, Colby KA, Deng S, McDonnell P, Meisler DM, Raizman MB, et al. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008;145(6):951–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Asbell PA, Sahm DF, Shaw M, Draghi DC, Brown NP. Increasing prevalence of methicillin resistance in serious ocular infections caused by Staphylococcus aureus in the United States: 2000 to 2005. J Cataract Refract Surg. 2008;34(5):814–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Asbell PA, Sanfilippo CM, Pillar CM, DeCory HH, Sahm DF, Morris TW. Antibiotic resistance among ocular pathogens in the United States: five-year results from the antibiotic resistance monitoring in ocular microorganisms (ARMOR) surveillance study. JAMA Ophthalmol. 2015;133(12):1445–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Cavuoto K, Zutshi D, Karp CL, Miller D, Feuer W. Update on bacterial conjunctivitis in South Florida. Ophthalmology. 2008;115(1):51–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Rutar T, Chambers HF, Crawford JB, Perdreau-Remington F, Zwick OM, Karr M, et al. Ophthalmic manifestations of infections caused by the USA300 clone of community-associated methicillin-resistant Staphylococcus aureus. Ophthalmology. 2006;113(8):1455–62.PubMedCrossRefGoogle Scholar
  14. 14.
    D’Costa VM, King CE, Kalan L, Morar M, Sung WW, Schwarz C, et al. Antibiotic resistance is ancient. Nature. 2011;477(7365):457–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Benveniste R, Davies J. Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc Natl Acad Sci U S A. 1973;70(8):2276–80.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bispo PJ, Alfonso EC, Flynn HW, Miller D. Emerging 8-methoxyfluoroquinolone resistance among methicillin-susceptible Staphylococcus epidermidis isolates recovered from patients with endophthalmitis. J Clin Microbiol. 2013;51(9):2959–63.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Fintelmann RE, Hoskins EN, Lietman TM, Keenan JD, Gaynor BD, Cevallos V, et al. Topical fluoroquinolone use as a risk factor for in vitro fluoroquinolone resistance in ocular cultures. Arch Ophthalmol. 2011;129(4):399–402.PubMedCrossRefGoogle Scholar
  18. 18.
    Kim SJ, Toma HS. Ophthalmic antibiotics and antimicrobial resistance a randomized, controlled study of patients undergoing intravitreal injections. Ophthalmology. 2011;118(7):1358–63.PubMedGoogle Scholar
  19. 19.
    Kim SJ, Toma HS. Antimicrobial resistance and ophthalmic antibiotics: 1-year results of a longitudinal controlled study of patients undergoing intravitreal injections. Arch Ophthalmol. 2011;129(9):1180–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Marangon FB, Miller D, Alfonso EC. Impact of prior therapy on the recovery and frequency of corneal pathogens. Cornea. 2004;23(2):158–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Cariello AJ, Passos RM, Yu MCZ, Hofling-Lima AL. Microbial keratitis at a referral center in Brazil. Int Ophthalmol. 2011;31(3):197–204.PubMedCrossRefGoogle Scholar
  22. 22.
    Ibrahim YW, Boase DL, Cree IA. Epidemiological characteristics, predisposing factors and microbiological profiles of infectious corneal ulcers: the Portsmouth corneal ulcer study. Br J Ophthalmol. 2009;93(10):1319–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Ni N, Nam EM, Hammersmith KM, Nagra PK, Azari AA, Leiby BE, et al. Seasonal, geographic, and antimicrobial resistance patterns in microbial keratitis: 4-year experience in eastern Pennsylvania. Cornea. 2015;34(3):296–302.PubMedCrossRefGoogle Scholar
  24. 24.
    Tan S, Walkden A, Au L, Fullwood C, Hamilton A, Qamruddin A, et al. Twelve-year analysis of microbial keratitis trends at a UK tertiary hospital. Eye. 2017;31(8):1229.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Lalitha P, Manoharan G, Karpagam R, Prajna NV, Srinivasan M, Mascarenhas J, et al. Trends in antibiotic resistance in bacterial keratitis isolates from South India. Br J Ophthalmol. 2016:108–13.PubMedCrossRefGoogle Scholar
  26. 26.
    Srinivasan M, Mascarenhas J, Rajaraman R, Ravindran M, Lalitha P, Glidden DV, et al. Corticosteroids for bacterial keratitis: the steroids for corneal ulcers trial (SCUT). Arch Ophthalmol. 2012;130(2):143–50.PubMedCrossRefGoogle Scholar
  27. 27.
    Fong C-F, Tseng C-H, Hu F-R, Wang I-J, Chen W-L, Hou Y-C. Clinical characteristics of microbial keratitis in a university hospital in Taiwan. Am J Ophthalmol. 2004;137(2):329–36.PubMedCrossRefGoogle Scholar
  28. 28.
    Bourcier T, Thomas F, Borderie V, Chaumeil C, Laroche L. Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases. Br J Ophthalmol. 2003;87(7):834–8.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Truong DT, Bui M-T, Cavanagh HD. Epidemiology and outcome of microbial keratitis: private university versus urban public hospital care. Eye Contact Lens. 2016;44(Suppl 1):S82–6.Google Scholar
  30. 30.
    Keay L, Edwards K, Naduvilath T, Taylor HR, Snibson GR, Forde K, et al. Microbial keratitis: predisposing factors and morbidity. Ophthalmology. 2006;113(1):109–16.PubMedCrossRefGoogle Scholar
  31. 31.
    Stapleton F, Naduvilath T, Keay L, Radford C, Dart J, Edwards K, et al. Risk factors and causative organisms in microbial keratitis in daily disposable contact lens wear. PLoS One. 2017;12(8):e0181343.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea. 2008;27(1):22–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Sun J-P, Chen W-L, Huang J-Y, Hou Y-C, Wang I-J, Hu F-R. Microbial keratitis after penetrating keratoplasty. Am J Ophthalmol. 2017;178:150–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Chen H-C, Lee C-Y, Lin H-Y, Ma DH-K, Chen PY-F, Hsiao C-H, et al. Shifting trends in microbial keratitis following penetrating keratoplasty in Taiwan. Medicine. 2017;96(5):e5864.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Wagoner MD, Al-Swailem SA, Sutphin JE, Zimmerman MB. Bacterial keratitis after penetrating keratoplasty: incidence, microbiological profile, graft survival, and visual outcome. Ophthalmology. 2007;114(6):1073–9. e2.CrossRefGoogle Scholar
  36. 36.
    Robert M-C, Moussally K, Harissi-Dagher M. Review of endophthalmitis following Boston keratoprosthesis type 1. Br J Ophthal. 2012:bjophthalmol-2011-301263.Google Scholar
  37. 37.
    Ortega-Usobiaga J, Llovet-Osuna F, Djodeyre MR, Llovet-Rausell A, Beltran J, Baviera J. Incidence of corneal infections after laser in situ keratomileusis and surface ablation when moxifloxacin and tobramycin are used as postoperative treatment. J Cataract Refract Surg. 2015;41(6):1210–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Llovet F, de Rojas V, Interlandi E, Martín C, Cobo-Soriano R, Ortega-Usobiaga J, et al. Infectious keratitis in 204 586 LASIK procedures. Ophthalmology. 2010;117(2):232–8. e4.CrossRefGoogle Scholar
  39. 39.
    Chang MA, Jain S, Azar DT. Infections following laser in situ keratomileusis: an integration of the published literature. Surv Ophthalmol. 2004;49(3):269–80.PubMedCrossRefGoogle Scholar
  40. 40.
    Wright TM, Afshari NA. Microbial keratitis following corneal transplantation. Am J Ophthalmol. 2006;142(6):1061–2.PubMedCrossRefGoogle Scholar
  41. 41.
    Constantinou M, Jhanji V, Vajpayee RB. Clinical and microbiological profile of post-penetrating keratoplasty infectious keratitis in failed and clear grafts. Am J Ophthalmol. 2013;155(2):233–7. e2.PubMedCrossRefGoogle Scholar
  42. 42.
    Solomon R, Donnenfeld ED, Holland EJ, Yoo SH, Daya S, Güell JL, et al. Microbial keratitis trends following refractive surgery: results of the ASCRS infectious keratitis survey and comparisons with prior ASCRS surveys of infectious keratitis following keratorefractive procedures. J Cataract Refract Surg. 2011;37(7):1343–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Austin A, Lietman T, Rose-Nussbaumer J. Update on the management of infectious keratitis. Ophthalmology. 2017;124(11):1678–89.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Panel. AAoOCED. Preferred practice pattern guidelines. Bacterial keratitis. San Francisco, CA: American Academy of Ophthalmology; 2013.Google Scholar
  45. 45.
    McDonald EM, Ram FS, Patel DV, McGhee CN. Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials. Br J Ophthalmol. 2014;98(11):1470–7.CrossRefGoogle Scholar
  46. 46.
    Hsu HY, Nacke R, Song JC, Yoo SH, Alfonso EC, Israel HA. Community opinions in the management of corneal ulcers and ophthalmic antibiotics: a survey of 4 states. Eye Contact Lens. 2010;36(4):195–200.PubMedCrossRefGoogle Scholar
  47. 47.
    Park J, Lee KM, Zhou H, Rabin M, Jwo K, Burton WB, et al. Community practice patterns for bacterial corneal ulcer evaluation and treatment. Eye Contact Lens. 2015;41(1):12–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Ray KJ, Prajna L, Srinivasan M, Geetha M, Karpagam R, Glidden D, et al. Fluoroquinolone treatment and susceptibility of isolates from bacterial keratitis. JAMA Ophthalmol. 2013;131(3):310–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis. 2000;31(Suppl 4):S131–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Woodford N, Ellington MJ. The emergence of antibiotic resistance by mutation. Clin Microbiol Infect. 2007;13(1):5–18.PubMedCrossRefGoogle Scholar
  51. 51.
    Katayama Y, Ito T, Hiramatsu K. A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 2000;44(6):1549–55.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12(3):348–60.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kaye S. Microbial keratitis and the selection of topical antimicrobials. BMJ Open Ophthalmol. 2017;1(1):e000086.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Proksch JW, Ward KW. Ocular pharmacokinetics/pharmacodynamics of besifloxacin, moxifloxacin, and gatifloxacin following topical administration to pigmented rabbits. J Ocul Pharmacol Ther. 2010;26(5):449–58.PubMedCrossRefGoogle Scholar
  55. 55.
    Strukova EN, Portnoy YA, Zinner SH, Firsov AA. Predictors of bacterial resistance using in vitro dynamic models: area under the concentration-time curve related to either the minimum inhibitory or mutant prevention antibiotic concentration. J Antimicrob Chemother. 2016;71(3):678–84.PubMedCrossRefGoogle Scholar
  56. 56.
    Nagai K, Davies TA, Dewasse BE, Jacobs MR, Appelbaum PC. Single- and multi-step resistance selection study of gemifloxacin compared with trovafloxacin, ciprofloxacin, gatifloxacin and moxifloxacin in Streptococcus pneumoniae. J Antimicrob Chemother. 2001;48(3):365–74.PubMedCrossRefGoogle Scholar
  57. 57.
    Milder E, Vander J, Shah C, Garg S. Changes in antibiotic resistance patterns of conjunctival flora due to repeated use of topical antibiotics after intravitreal injection. Ophthalmology. 2012;119(7):1420–4.PubMedCrossRefGoogle Scholar
  58. 58.
    Yin VT, Weisbrod DJ, Eng KT, Schwartz C, Kohly R, Mandelcorn E, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol. 2013;131(4):456–61.PubMedCrossRefGoogle Scholar
  59. 59.
    Maffett M, O’Day DM. Ciprofloxacin-resistant bacterial keratitis. Am J Ophthalmol. 1993;115(4):545–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Snyder ME, Katz HR. Ciprofloxacin-resistant bacterial keratitis. Am J Ophthalmol. 1992;114(3):336–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in South Florida and emerging resistance to fluoroquinolones. Ophthalmology. 2000;107(8):1497–502.PubMedCrossRefGoogle Scholar
  62. 62.
    Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology. 1999;106(7):1313–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Kunimoto DY, Sharma S, Garg P, Rao GN. In vitro susceptibility of bacterial keratitis pathogens to ciprofloxacin. Emerging resistance. Ophthalmology. 1999;106(1):80–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Afshari NA, Ma JJ, Duncan SM, Pineda R, Starr CE, Decroos FC, et al. Trends in resistance to ciprofloxacin, cefazolin, and gentamicin in the treatment of bacterial keratitis. J Ocul Pharmacol Ther. 2008;24(2):217–23.PubMedCrossRefGoogle Scholar
  65. 65.
    Al-Dhaheri HS, Al-Tamimi MD, Khandekar RB, Khan M, Stone DU. Ocular pathogens and antibiotic sensitivity in bacterial keratitis isolates at King Khaled Eye Specialist Hospital, 2011 to 2014. Cornea. 2016;35(6):789–94.PubMedCrossRefGoogle Scholar
  66. 66.
    Chang VS, Dhaliwal DK, Raju L, Kowalski RP. Antibiotic resistance in the treatment of staphylococcus aureus keratitis: a 20-year review. Cornea. 2015;34(6):698–703.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Lalitha P, Manoharan G, Karpagam R, Prajna NV, Srinivasan M, Mascarenhas J, et al. Trends in antibiotic resistance in bacterial keratitis isolates from South India. Br J Ophthalmol. 2016:bjophthalmol-2016-308487.Google Scholar
  68. 68.
    Oldenburg CE, Lalitha P, Srinivasan M, Rajaraman R, Ravindran M, Mascarenhas J, et al. Emerging moxifloxacin resistance in Pseudomonas aeruginosa keratitis isolates in South India. Ophthalmic Epidemiol. 2013;20(3):155–8.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Sand D, She R, Shulman IA, Chen DS, Schur M, Hsu HY. Microbial keratitis in los angeles: the doheny eye institute and the los angeles county hospital experience. Ophthalmology. 2015;122(5):918–24.PubMedCrossRefGoogle Scholar
  70. 70.
    Chang DF, Braga-Mele R, Mamalis N, Masket S, Miller KM, Nichamin LD, et al. Prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2007 ASCRS member survey. J Cataract Refract Surg. 2007;33(10):1801–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Scoper SV. Review of third-and fourth-generation fluoroquinolones in ophthalmology: in-vitro and in-vivo efficacy. Adv Ther. 2008;25(10):979–94.PubMedCrossRefGoogle Scholar
  72. 72.
    Moshirfar M, Mirzaian G, Feiz V, Kang PC. Fourth-generation fluoroquinolone-resistant bacterial keratitis after refractive surgery. J Cataract Refract Surg. 2006;32(3):515–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Peng MY, Cevallos V, McLeod SD, Lietman TM, Rose-Nussbaumer J. Bacterial keratitis: isolated organisms and antibiotic resistance patterns in San Francisco. Cornea. 2018;37(1):84–7.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Asbell PA, Pandit RT, Sanfilippo CM. Antibiotic resistance rates by geographic region among ocular pathogens collected during the ARMOR surveillance study. Ophthalmol Therapy. 2018:1–13.Google Scholar
  75. 75.
    DeLeo FR, Chambers HF. Reemergence of antibiotic-resistant Staphylococcus aureus in the genomics era. J Clin Invest. 2009;119(9):2464–74.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Elsahn AF, Yildiz EH, Jungkind DL, Abdalla YF, Erdurmus M, Cremona FA, et al. In vitro susceptibility patterns of methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus corneal isolates to antibiotics. Cornea. 2010;29(10):1131–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Hayashi S, Suzuki T, Yamaguchi S, Inoue T, Ohashi Y. Genotypic characterization of Staphylococcus aureus isolates from cases of keratitis and healthy conjunctival sacs. Cornea. 2014;33(1):72–6.PubMedCrossRefGoogle Scholar
  78. 78.
    McDougal L, Steward C, Killgore G, Chaitram J, McAllister S, Tenover F. Pulse- field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol. 2003;41(11):5113–20.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Hudson L, Reynolds C, Spratt B, Enright M, Quan V, Kim D, et al. Diversity of methicillin-resistant staphylococcus aureus strains isolated from residents of 26 nursing homes in orange county, California. J Clin Microbiol. 2013;51(11):3788–95.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Tenover F, McAllister S, Fosheim G, McDougal L, Carey R, Limbago B, et al. Characterization of Staphylococcus aureus isolates from nasal cultures collected from individuals in the United States in 2001 to 2004. J Clin Microbiol. 2008;46(9):2837–41.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Magiorakos AP, Srinivasan A, Carey R, Carmeli Y, Falagas M, Giske C, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268–81.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Vazirani J, Wurity S, Ali MH. Multidrug-resistant Pseudomonas aeruginosa keratitis: risk factors, clinical characteristics, and outcomes. Ophthalmology. 2015;122(10):2110–4.CrossRefGoogle Scholar
  83. 83.
    Shen EP, Hsieh Y-T, Chu H-S, Chang S-C, Hu F-R. Correlation of Pseudomonas aeruginosa genotype with antibiotic susceptibility and clinical features of induced central keratitis. Invest Ophthalmol Vis Sci. 2015;56(1):365–71.CrossRefGoogle Scholar
  84. 84.
    Clinical and Laboratory Standards Institute, CLSI document M100-S13. Performance standards for antimicrobial susceptibility testing: twenty third informational supplement. Wayne, PA: Clinical Laboratory Standards Institute; 2013.Google Scholar
  85. 85.
    Turnidge J, Paterson DL. Setting and revising antibacterial susceptibility breakpoints. Clin Microbiol Rev. 2007;20(3):391–408, table of contentsPubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Segreti J, Jones RN, Bertino JS Jr. Challenges in assessing microbial susceptibility and predicting clinical response to newer-generation fluoroquinolones. J Ocul Pharmacol Ther. 2012;28(1):3–11.PubMedCrossRefGoogle Scholar
  87. 87.
    Chen A, Prajna L, Srinivasan M, Mahalakshmi R, Whitcher JP, McLeod S, et al. Does in vitro susceptibility predict clinical outcome in bacterial keratitis? Am J Ophthalmol. 2008;145(3):409–12.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Kaye S, Tuft S, Neal T, Tole D, Leeming J, Figueiredo F, et al. Bacterial susceptibility to topical antimicrobials and clinical outcome in bacterial keratitis. Invest Ophthalmol Vis Sci. 2010;51(1):362–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Lalitha P, Srinivasan M, Manikandan P, Bharathi MJ, Rajaraman R, Ravindran M, et al. Relationship of in vitro susceptibility to moxifloxacin and in vivo clinical outcome in bacterial keratitis. Clin Infect Dis. 2012;54(10):1381–7.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Oldenburg CE, Lalitha P, Srinivasan M, Manikandan P, Bharathi MJ, Rajaraman R, et al. Moxifloxacin susceptibility mediates the relationship between causative organism and clinical outcome in bacterial keratitis. Invest Ophthalmol Vis Sci. 2013;54(2):1522–6.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Wilhelmus KR, Abshire RL, Schlech BA. Influence of fluoroquinolone susceptibility on the therapeutic response of fluoroquinolone-treated bacterial keratitis. Arch Ophthalmol. 2003;121(9):1229–33.PubMedCrossRefGoogle Scholar
  92. 92.
    Rex JH, Pfaller MA. Has antifungal susceptibility testing come of age? Clin Infect Dis. 2002;35(8):982–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Lichtinger A, Yeung SN, Kim P, Amiran MD, Iovieno A, Elbaz U, et al. Shifting trends in bacterial keratitis in Toronto: an 11-year review. Ophthalmology. 2012;119(9):1785–90.PubMedCrossRefGoogle Scholar
  94. 94.
    Abu Eleinen KG, Mohalhal AA, Elmekawy HE, Abdulbaki AM, Sherif AM, El-Sherif RH, et al. Polymerase chain reaction-guided diagnosis of infective keratitis–a hospital based study. Curr Eye Res. 2012;37(11):1005–11.CrossRefGoogle Scholar
  95. 95.
    Fang PC, Chien CC, Yu HJ, Ho RW, Tseng SL, Lai YH, et al. A dot hybridization assay for the diagnosis of bacterial keratitis. Mol Vis. 2017;23:306–17.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Tananuvat N, Salakthuantee K, Vanittanakom N, Pongpom M, Ausayakhun S. Prospective comparison between conventional microbial work-up vs PCR in the diagnosis of fungal keratitis. Eye. 2012;26(10):1337–43.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Zhao G, Zhai H, Yuan Q, Sun S, Liu T, Xie L. Rapid and sensitive diagnosis of fungal keratitis with direct PCR without template DNA extraction. Clin Microbiol Infect. 2014;20(10):776–82.CrossRefGoogle Scholar
  98. 98.
    Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet. 2016;17(6):333–51.PubMedCrossRefGoogle Scholar
  99. 99.
    Li Z, Breitwieser FP, Lu J, Jun AS, Asnaghi L, Salzberg SL, et al. Identifying corneal infections in formalin-fixed specimens using next generation sequencing. Invest Ophthalmol Vis Sci. 2018;59(1):280–8.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Duxfield L, Sultana R, Wang R, Englebretsen V, Deo S, Rupenthal ID, et al. Ocular delivery systems for topical application of anti-infective agents. Drug Dev Ind Pharm. 2016;42(1):1–11.PubMedCrossRefGoogle Scholar
  101. 101.
    Wagner RS, Abelson MB, Shapiro A, Torkildsen G. Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin, ofloxacin, and levofloxacin concentrations in human conjunctival tissue. Arch Ophthalmol. 2005;123(9):1282–3.PubMedCrossRefGoogle Scholar
  102. 102.
    Kaye SB, Neal T, Nicholson S, Szkurlat J, Bamber S, Baddon AC, et al. Concentration and bioavailability of ciprofloxacin and teicoplanin in the cornea. Investig Ophthalmol Vis Sci. 2009;50(7):3176–84.CrossRefGoogle Scholar
  103. 103.
    Van Der Bijl P, van Eyk AD, Meyer D. Effects of three penetration enhancers on transcorneal permeation of cyclosporine. Cornea. 2001;20(5):505–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Jansook P, Ogawa N, Loftsson T. Cyclodextrins: structure, physicochemical properties and pharmaceutical applications. Int J Pharm. 2018;535(1–2):272–84.PubMedCrossRefGoogle Scholar
  105. 105.
    Bowman LM, Si E, Pang J, Archibald R, Friedlaender M. Development of a topical polymeric mucoadhesive ocular delivery system for azithromycin. J Ocul Pharmacol Ther. 2009;25(2):133–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Gupta H, Aqil M, Khar R, Ali A, Bhatnagar A, Mittal G. Nanoparticles laden in situ gel of levofloxacin for enhanced ocular retention. Drug Deliv. 2013;20(7):306–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Liu Z, Li J, Nie S, Liu H, Ding P, Pan W. Study of an alginate/HPMC-based in situ gelling ophthalmic delivery system for gatifloxacin. Int J Pharm. 2006;315(1–2):12–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Nanjwade BK, Deshmukh RV, Gaikwad KR, Parikh KA, Manvi FV. Formulation and evaluation of micro hydrogel of Moxifloxacin hydrochloride. Eur J Drug Metab Pharmacokinet. 2012;37(2):117–23.PubMedCrossRefGoogle Scholar
  109. 109.
    Alvarez-Lorenzo C, Yanez F, Barreiro-Iglesias R, Concheiro A. Imprinted soft contact lenses as norfloxacin delivery systems. J Control Release. 2006;113(3):236–44.PubMedCrossRefGoogle Scholar
  110. 110.
    Garhwal R, Shady SF, Ellis EJ, Ellis JY, Leahy CD, McCarthy SP, et al. Sustained ocular delivery of ciprofloxacin using nanospheres and conventional contact lens materials. Investig Ophthalmol Vis Sci. 2012;53(3):1341–52.CrossRefGoogle Scholar
  111. 111.
    Maulvi FA, Soni TG, Shah DO. A review on therapeutic contact lenses for ocular drug delivery. Drug Deliv. 2016;23(8):3017–26.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Paulo J. M. Bispo
    • 1
    Email author
  • Lawson Ung
    • 1
  • James Chodosh
    • 1
  • Michael S. Gilmore
    • 1
  1. 1.Massachusetts Eye and Ear – Harvard Medical School, Department of OphthalmologyBostonUSA

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