Skip to main content
Download PDF

Infectious keratitis after corneal crosslinking for keratoconus caused by levofloxacin-resistant microorganisms

BMC Ophthalmology volume 21, Article number: 317 (2021) Cite this article

Abstract

Introduction

We present seven cases of infectious keratitis after corneal crosslinking (CXL) to attenuate keratoconus progression.

Methods

Of 524 consecutive patients who underwent CXL, 7 cases (4 males and 3 females; 21.5 ± 7.1 years) developed postoperative infectious keratitis were retrospectively reviewed. CXL was performed using the Dresden protocol or an accelerated protocol involving epithelial removal.

Results

All cases appeared normal on the day after surgery, but subsequently developed eye pain, blurred vision, corneal infiltration, inflammation of the anterior chamber, and ciliary injection on day 2 or 3. Methicillin-resistant Staphylococcus aureus was cultured from two eyes, methicillin-sensitive Staphylococcus aureus from two eyes, and Streptococcus pneumoniae from one eye. All detected bacteria were resistant to levofloxacin (LVFX). Five of the seven cases, especially four of the five severe cases with hypopyon, had a history of atopic dermatitis. All cases were observed after 2015.

Conclusions

Infectious keratitis after CXL caused by microbes resistant to LVFX is increasing. In addition to careful postoperative observation of the cornea, preoperative evaluation of bacteria within the conjunctival sac evident on nasal swab cultures may be useful to identify potentially problematic microbes and inform the selection of appropriate antibiotics.

Peer Review reports

Introduction

Corneal crosslinking (CXL) attenuates keratoconus progression, as first reported by Wollensak et al. in 2003 [1]. Progression was halted in 90–95 % of cases in clinical trials [2,3,4,5]. However, several rare complications have been described, including delayed epithelial healing [6, 7], stromal melting [7, 8], sterile infiltration [8,9,10], early infectious keratitis [11,12,13,14,15,16,17,18,19,20,21], stromal hazing and demarcation after several weeks [9], deep stromal scarring [22], failure [9],  and progressive flattening [23, 24]. Infectious keratitis is the most concerning complication; scarring and irregular astigmatism may develop even after infection control, thus impairing the vision of young patients. We first used CXL to treat keratoconus 13 years ago, and encountered no case of infectious keratitis up to 2015. Sporadic cases were noted from 2016 onward (Table 1); these cases are summarized in this paper, including the possible causes and preventative measures and treatments that we employ.

Table 1 Demographic of cases with infectious keratitis after CXL at Minamiaoyama Eye Clinic
Full size table

Patients

From February 2007 to May 2020, 524 consecutively enrolled eyes of keratoconus patients, exhibiting pellucid marginal degeneration or keratectasia after laser in-situ keratomileusis, underwent CXL with epithelial debridement under topical anesthesia with application of oxybuprocaine hydrochloride (0.4 % w/v) eyedrops before each procedure. After the eye lid skin was delicately rubbed 2 times using a sterilized cotton swab soaked in the 10 % povidone-iodine solution, a lid speculum was inserted. The eye surface was rinsed with 20 ml of 5 ppm ozone water, followed by removal of the central corneal epithelium (diameter = 7.0–8.0 mm) using a blunt spatula or an excimer laser. Then, 0.1 % (w/v) isotonic riboflavin in dextran 20 % (w/v) solution was instilled every 2 min for 20 min. After confirming stromal riboflavin saturation via slit-lamp examination, the thinnest part of the corneal stroma was measured using an AL-3000 pachymeter (Tomey, Aichi, Japan). If the stromal thickness was < 400 μm, 0.1 % (w/v) hypotonic riboflavin or distilled water was instilled until the minimal thickness reached 400 μm. UV-A radiation was then delivered at 3.0 mW/cm2 for 30 min (KERA-X; Peschke, Huenenberg, Switzerland) or 18.0 mW/cm2 for 5 min (KXL; Avedro, Waltham, MA, USA). At the end of the procedure, a soft bandage contact lens was applied and a drop of levofloxacin (LVFX) instilled. Postoperative medications included LVFX and betamethasone (0.1 % w/v) eyedrops four times daily.

The study protocol was approved by the Internal Review Board of Minamiaoyama Eye Clinic. While this study was the retrospective observational study, the written informed consent was waived by the Internal Review Board of Minamiaoyama Eye Clinic. In all cases, the CXL was performed by experienced ophthalmologists.

The characteristics of the seven patients are summarized in Table 2: bacterial infections were proven or strongly suspected in all patients. Microbiological evaluations were performed for five patients; methicillin-resistant Staphylococcus aureus (MRSA) was cultured from two eyes, methicillin-sensitive Staphylococcus aureus from two eyes, and Streptococcus pneumoniae from one eye. All detected bacteria were resistant to LVFX. Four experienced surgeons performed the CXL for the seven cases, and there was no remarkable prevalence among individuals.

Table 2 Characteristics of cases with infectious keratitis after corneal crosslinking
Full size table

Five patients (1, 3, 4, 5 and 7) exhibited severe infectious keratitis with hypopyons. One patient (Case 1) underwent implantation of a pair of Ferrara rings contemporaneously with CXL. All five patients with severe keratitis appeared normal on the day after surgery, but complained of eye pain on day 2 or 3. All patients exhibited corneal epithelial defects accompanied by infiltration, ciliary injection, and a hypopyon on day 3. The infections were controlled by antibiotics, and the corneas healed but with stromal scarring. In the two patients without hypopyons, two (Cases 2 and 6) complained of pain on day 2 or 3 and were diagnosed with infectious keratitis on day 3. These two patients recovered quickly after application of topical antibiotics, without stromal scarring.

Discussion

We encountered 7 cases (among 524 cases; rate of 1.34 %) of infectious keratitis after CXL to treat keratoconus, all within the past 5 years. MRSA and MRSA resistant to LVFX were the most frequent causative microbes, followed by S. pneumoniae (also resistant to LVFX). The frequency of infectious keratitis after CXL has been reported by several clinicians; the microbes involved were gram-positive bacteria (Staphylococcus epidermidis[21], S. aureus[11,12,13,14,15,16] and Streptococcus salivarius and/or S. oralis[17, 18]); gram-negative bacteria (Escherichia coli[19] and Pseudomonas aeruginosa[20]), herpes virus[25], and a fungus and Acanthamoeba[26]. Many microbes were resistant to the new quinolone antibiotics, similar to our findings.

As stated above, post-CXL infections were not observed until 2016 in our institute. In the 9 years from 2007 to 2015, we performed CXL on 141 eyes and experienced no case of infection. After the first case in 2016, the incidence increased to 3 of 134 eyes (2.2 %) in 2019 (Table 1).

We used ofloxacin eyedrops until 2000, and later LVFX eyedrops from 2001 still now, as preventative therapies after CXL, PRK, and PTK. The new quinolone antibiotics, such as LVFX, gatifloxacin, and moxifloxacin, have widely been used to prevent infection after various ophthalmological surgeries. The trends in antibiotic resistance among ocular microorganisms have been investigated. Asbell et al. showed that antibiotic resistance was prevalent among staphylococcal isolates, but only a few small changes were observed from 2009 to 2018 in the USA. [27, 28] Deguchi et al. found that the prevalence of MRSA and methicillin-resistant-coagulase-negative staphylococci (MR-CNS) decreased significantly from 2005 to 2014 in Japan, but over 50 % of Corynebacteriumisolates remained resistant to LVFX[29]. Kamo et al. showed that the prevalence of LVFX-resistant MSSA increased significantly from 2008 to 2018, although the prevalence of MRSA did not increase. MR-CNS was not detected in 2008.[30, 31] Thus, microorganisms resistant to new quinolone antibiotics may have increased in recent years, raising the rate of postoperative infectious keratitis.

A history of atopic dermatitis may increase the risk of post-CXL infection. Skin MRSA levels are elevated in patients with atopic dermatitis[13, 32, 33]. Five of the seven patients (71 %) in this study had been diagnosed with atopic dermatitis, including four of the five (80 %) with severe infectious keratitis accompanied by a hypopyon. Patients on long-term steroids or immunosuppressants to treat allergic disorders, such as vernal keratoconjunctivitis, bronchial asthma, and eczema, require special attention in terms of the evaluation of drug-resistant bacteria, especially those with atopic dermatitis. Although there were no healthcare workers among our patients, that group also requires special attention because they frequently come into contact with drug-resistant bacteria[33]..

In this study, all symptoms of infection became apparent on postoperative day 2 to 3; no symptoms were noted on day 1. Postoperative examinations should be performed on day 2 or 3; if suspicious symptoms are seen, immediate microbiological testing (including for drug sensitivity) is required. We recently began to preoperatively screen for microbes via nasal culture; the conjunctival sac is seldom culture-positive when patients do not develop conjunctivitis. Furthermore, we prescribe additional effective antibiotics, such as chloramphenicol, postoperatively, if some bacteria resistant to LVFX and/or other drugs were detected.

In conclusion, postoperative infectious keratitis after CXL is caused mainly by LVFX-resistant bacteria. As microbial resistance to the new quinolone antibiotics has increased recently, drug-resistant bacteria on the ocular surface, especially in patients with atopic dermatitis, should be screened for in patients undergoing CXL for keratoconus.

Availability of data and materials

All data generated or analyzed during this study are summarized in this published article as Table 2.

References

  1. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003; 135: 620–627.

    Article  CAS  Google Scholar 

  2. Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008; 34: 796–801.

    Article  Google Scholar 

  3. Wittig-Silva C, Whiting M, Lamoureux E, et al. Randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008; 24: S720-725.

    Google Scholar 

  4. Hersh PS, Stulting RD, Muller D, et al. United States Crosslinking Study Group. United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment. Ophthalmology. 2017; 124: 1259–1270.

    Article  Google Scholar 

  5. Kobashi H, Rong SS. Corneal Collagen Cross-Linking for Keratoconus: Systematic Review. Biomed Res Int. 2017;2017:8145651.

    Article  Google Scholar 

  6. Mohamed-Noriega K, Butrón-Valdez K, Vazquez-Galvan J, et al. Corneal melting after collagen cross-linking for keratoconus in a thin cornea of a diabetic patient treated with topical nepafenac: A case report with a literature review. Case Rep Ophthalmol. 2016; 7: 119–124.

    Article  Google Scholar 

  7. Seiler TG, Schmidinger G, Fischinger I, et al. Complications of corneal cross-linking. Complications of corneal cross-linking. Ophthalmologe. 2013; 110: 639–644.

    Article  CAS  Google Scholar 

  8. Sasaki T, Ide T, Toda I, et al. Amniotic Membrane Transplantation as a Treatment for sterile infiltration and corneal melting after corneal crosslinking for keratoconus. Case Rep Ophthalmol. 2018; 9: 185–189.

    Article  Google Scholar 

  9. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 2009; 35: 1358–1362.

    Article  Google Scholar 

  10. Mereaux D, Knoeri J, Jouve L, et al. Sterile keratitis following standard corneal collagen crosslinking: A case series and literature review. J Fr Ophtalmol. 2019; 42: 603–611.

    Article  CAS  Google Scholar 

  11. Shetty R, Kaweri L, Nuijts RM, et al. Profile of microbial keratitis after corneal collagen cross-linking. Biomed Res Int. 2014;2014:340509.

  12. Kodavoor SK, Sarwate NJ, Ramamurhy D. Microbial keratitis following accelerated corneal collagen cross-linking. Oman J Ophthalmol. 2015; 8: 111–3.

    Article  Google Scholar 

  13. Fasciani R, Agresta A, Caristia A, et al. Methicillin-Resistant Staphylococcus aureus Ocular Infection after Corneal Cross-Linking for Keratoconus: Potential Association with Atopic Dermatitis. Case Rep Ophthalmol Med. 2015;2015:613273.

  14. Oakey Z, Thai K, Garg S. Bilateral corneal perforation due to MRSA keratitis in a crosslinking patient. GMS Ophthalmol Cases. 2017;7: Doc21.

    PubMed  PubMed Central  Google Scholar 

  15. Kodavoor SK, Tiwari NN, Ramamurthy D. Profile of infectious and sterile keratitis after accelerated corneal collagen cross-linking for keratoconus. Oman J Ophthalmol. 2020; 13: 18–23.

    Article  Google Scholar 

  16. Schear M, Ragam A, Seedor J, et al. Rapid keratitis and perforation after corneal collagen cross-linking. Am J Ophthalmol Case Rep. 2020; 18: 100658.

    Article  Google Scholar 

  17. Al-Amry M, Mudhaiyan T, Al-Huthail R, et al. Infectious crystalline keratopathy after corneal cross-linking. Middle East Afr J Ophthalmol. 2017; 24: 100–102.

    Article  Google Scholar 

  18. Zamora KV, Males JJ. Polymicrobial keratitis after a collagen cross-linking procedure with postoperative use of a contact lens: a case report. Cornea. 2009; 28: 474–476.

    Article  Google Scholar 

  19. Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg. 2009; 35: 588–589.

    Article  Google Scholar 

  20. Sharma N, Maharana P, Singh G, et al. Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature. J Cataract Refract Surg. 2010; 36: 517–520.

    Article  Google Scholar 

  21. Pérez-Santonja JJ, Artola A, Javaloy J, et al. Microbial keratitis after corneal collagen crosslinking. J Cataract Refract Surg. 2009; 35: 1138–1140.

    Article  Google Scholar 

  22. Kato N, Konomi K, Saiki M, et al. Deep stromal opacity after corneal cross-linking. Cornea. 2013; 32: 895–898.

    Article  Google Scholar 

  23. Kato N, Negishi K, Sakai C, et al. Five-year Outcomes of Corneal Cross-Linking for Keratoconus: Comparison Between Conventional and Accelerated Procedures. Cornea. 2020; 39: e1.

    Article  Google Scholar 

  24. Noor IH, Seiler TG, Noor K, et al. Continued Long-term Flattening After Corneal Cross-linking for Keratoconus. J Refract Surg. 2018; 34: 567–570.

    Article  Google Scholar 

  25. Sitaula S, Singh SK, Gurung A. Bilateral viral keratitis following corneal collagen crosslinking for progressive keratoconus. J Ophthalmic Inflamm Infect. 2019; 9: 16.

    Article  Google Scholar 

  26. Maharana PK, Sahay P, Sujeeth M, et al. Microbial Keratitis After Accelerated Corneal Collagen Cross-Linking in Keratoconus. Cornea. 2018; 37: 162–167.

    Article  Google Scholar 

  27. Asbell PA, DeCory HH. Antibiotic resistance among bacterial conjunctival pathogens collected in the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance study. PLoS One. 2018; 13: e0205814.

    Article  Google Scholar 

  28. Asbell PA, Sanfilippo CM, Sahm DF, et al. Trends in Antibiotic Resistance Among Ocular Microorganisms in the United States From 2009 to 2018. JAMA Ophthalmol. 2020; 138: 1–12.

    Article  Google Scholar 

  29. Deguchi H, Kitazawa K, Kayukawa K, et al. The trend of resistance to antibiotics for ocular infection of Staphylococcus aureus, coagulase-negative staphylococci, and Corynebacterium compared with 10-years previous: A retrospective observational study. PLoS One. 2018; 13: e0203705.

    Article  Google Scholar 

  30. Kamo J, Soshiu M, Muramatsu S, et al. Change in conjunctivitis bacteria susceptibilities to antibiotics between 2008 and 2011. J Eye 2014; 31: 1037–1042.

    Google Scholar 

  31. Kamo J, Muramatsu S, Akazawa H, et al. Recommendation of antibiotics for the eyes by age group in 2018 based on microorganism sensitivity. J Eye 2020; 37: 484–489.

    Google Scholar 

  32. Fukuda M, Ohashi H, Matsumoto C, et al. Methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulase-negative Staphylococcus ocular surface infection efficacy of chloramphenicol eye drops. Cornea. 2002; 21: S86-89.

    Article  Google Scholar 

  33. Kitazawa K, Sotozono C, Sakamoto M, et al. Nasal and conjunctival screening prior to refractive surgery: an observational and cross-sectional study. BMJ Open. 2016; 6: e010733

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge Daisuke Todokoro, M.D., Ph.D., Department of Ophthalmology, Gunma University Graduate School of Medicine and Junko Kamo, M.D., Ph.D., Department of Ophthalmology, Kofu Kyoritsu Hospital for their valuable discussion and support for conceptualization of the manuscript.

Funding

No funding was obtained for this work.

Author information

Authors and Affiliations

  1. Minamiaoyama Eye Clinic, Kitaaoyama 3-3-11, Minato-ku, 107-0061, Tokyo, Japan

    Naoko Kato & Ikuko Toda

  2. Department of Ophthalmology, School of Medicine, Keio University, Tokyo, Japan

    Naoko Kato & Hidenaga Kobashi

  3. Tokyo Vision Eye Clinic Asagaya, Tokyo, Japan

    Takeshi Ide

Authors
  1. Naoko Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Ide
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hidenaga Kobashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ikuko Toda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NK analyzed and interpreted the patient data, and drafted the manuscript, TI, HK and IT made contributions to conception and revising critically the manuscript for important intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Naoko Kato.

Ethics declarations

Ethics approval and consent to participate

This retrospective observational study was approved by the Internal Review Board of Minamiaoyama Eye Clinic, and the study protocol was conducted in accordance with the tenets of the Declaration of Helsinki. While this study was the retrospective observational study, the written informed consent was waived by the Internal Review Board of Minamiaoyama Eye Clinic.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kato, N., Ide, T., Kobashi, H. et al. Infectious keratitis after corneal crosslinking for keratoconus caused by levofloxacin-resistant microorganisms. BMC Ophthalmol 21, 317 (2021). https://doi.org/10.1186/s12886-021-02081-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12886-021-02081-4

Keywords

BMC Ophthalmology

ISSN: 1471-2415

Contact us