Choosing Wisely: Antibiotic Use in Ophthalmic Surgery

Rethinking the use of antibiotics before and after surgery.

By Andrea Grosso, MD; Giuseppe Scarpa, MD; Mario Romano, MD; Piero Ceruti, MD; Brian Joondeph, MD; Regis P. Kowalski, MS, M(ASCP); Michael Engelbert, MD; Franco Giardini; Giovanni Di Perri, MD; Francesco Bandello, MD; Giorgio Marchini, MD; Mauro Fioretto, MD; and Sunir Garg, MD
 

Ophthalmic surgery is thought to be a “clean” surgery and, as a result, antimicrobial prophylaxis for ophthalmic surgery is not discussed in prominent infectious disease textbooks.1

In a recent review, we coined the term odontoiatric model, based on the Italian odontoiatria—in English, dentistry. We aimed to emphasize that modern ophthalmic surgery, like dental surgery, can be 1-day or office-based surgery. We noted the incidence of endophthalmitis (nosocomial infection) has remained stable for the past 5 years.2

For years, the ocular surface was thought to be sterile due to the presence of lysozyme, antimicrobial peptides, immunoglobulin A complement, and other substances. A group led by Rachel Caspi at the US National Eye Institute, using an animal model, found that local bacteria on the ocular surface maintain ocular immunity and that transient disruption of bacteria via antibiotics results in a reduction in immune-related mechanisms.3 These authors demonstrated that a specific commensal organism, Corynebacterium mastitidis, stably colonized the ocular surface and stimulated the host’s ability to resist pathogenic fungal and bacterial infections. This demonstration of the role of a living, resident ocular microbiome will, hopefully, lead to more appropriate and judicious prescription of antibiotics.3,4

AT A GLANCE

• Bacteria on the ocular surface help to maintain ocular immunity. Transient disruption of bacteria via antibiotics results in a reduction in these immune-related mechanisms.

• If a patient’s own eye flora are the source of most postprocedural endophthalmitis, and the use of postinjection antibiotics leads to increased resistance, then the indiscriminate use of antibiotics will lead to more resistant organisms in endophthalmitis.

• The natural history of endophthalmitis suggests that we should rethink the scheduling of postoperative visits in routine cases. Postoperative visits on day 2 or 3 after the injection, if performed at all, may make more sense than a return the next day.

ANTIBIOTIC PROPHYLAXIS IN OPHTHALMIC SURGERY

Some principles regarding antibiotic prophylaxis in ophthalmic surgery are well established. First, microbiologic surveillance should guide the choice of antibiotics.5,6 That is, knowing the organisms that are highly prevalent in one’s region can help determine which agents will be most effective as infection prophylaxis.

Second, topical povidone-iodine is an effective monotherapy against infection for intravitreal injections and vitreoretinal surgery. It has broad-spectrum microbicidal activity (against bacteria, viruses, spores), no reported resistance, and a fast kill time. All physicians should perform surgical prophylaxis with povidone-iodine preparation. Ocular surface preparation for intravitreal injection using 5% povidone-iodine alone, in the absence of postinjection topical antibiotics, does not seem to induce bacterial resistance or change conjunctival flora.7-10

Third, antibiotic resistance is a global public health issue. Ocular surface organisms are becoming more resistant (with increased minimum inhibitory concentration [MIC] values based on systemic susceptibility standards) to antibiotics. Up to 30% of cultured ocular isolates now demonstrate resistance to fluoroquinolones.11-16

MICROBIOLOGIC EPIDEMIOLOGY

We have analyzed 10 years of microbiologic data (2003-2013) from the Torino Eye Hospital. The top five bacteria isolated in the hospital’s territory after postsurgical endophthalmitis were as follows:

• coagulase-negative staphylococci

Staphylococcus aureus

• viridans group streptococci

Pseudomonas aeruginosa

Streptococcus pneumonia

Interestingly, 3 cases of Acinetobacter lwoffii and 23 cases of Peptostreptococcus spp. were also reported.

There is increasing evidence that coagulase-negative staphylococci show multiple antibiotic resistance mechanisms. The Bacillaceae deserve special attention because, compared with the past, this family of Gram-positive bacteria have become more aggressive, they grow rapidly, and they cause colliquative necrosis in tissues.5,6,17-19

Sometimes, it seems that microbiologic surveillance does not help physicians make appropriate choices of antibiotics. Up to 30% of vitreous taps are negative. However, in an apparently culture-negative endophthalmitis, it may be that S. epidermidis or some other indolent organism, including a virus that has already been sterilized by the body, is present. In rabbit eyes with experimental S. epidermidis endophthalmitis, culture results were negative after 48 to 72 hours, even though the entire vitreous of the enucleated eyes was cultured.20

We have tested in vitro susceptibility to different topical ophthalmic antibiotics of bacteria isolated from patients with endophthalmitis (Table) with the following findings:

• Fusidic acid is effective only against Staphylococcaceae;

• Tobramycin shows a high profile of resistance;

• Netilmicin is effective against a wide spectrum of bacteria, with the exception of Streptococcaceae (S. pneumoniae and alpha-hemolytic Streptococcus);

• Fluoroquinolones are effective, except against coagulase-negative staphylococci;

• Moxifloxacin shows only moderate effectiveness against prevalent bacteria; and

• Chloramphenicol is a static antibiotic that is effective against all bacteria with the exception of Gram-negatives.

Bacteria can gain access to the anterior chamber during the perioperative period. If this happens, it is important to choose an antibiotic that can penetrate the cornea and achieve levels in the aqueous high enough to eliminate the bacteria. Fluoroquinolones can penetrate tissue, but are concentration-dependent, require frequent dosing, and bacteria are becoming more resistant to them.

Choices for prophylaxis vary by region. In Italy, chloramphenicol is used topically but not systemically. Across Europe, broad-spectrum topical antibiotic therapy is the convention following surgery (cataract and vitreoretinal surgery, and post-injection). A fluoroquinolone plus netilmicin or a fluoroquinolone plus chloramphenicol are the most commonly used combinations.

Over the past 5 years, there has been reduced susceptibility of Gram-positive bacteria to levofloxacin (75%), although levofloxacin remains effective against Gram-negative bacteria (95%).

It is important to understand how different antibiotics work. Fluoroquinolones and netilmicin are concentration-dependent. Fluoroquinolones are bacteriocidal, unlike bacteriostatic antibiotics, which only inhibit bacterial growth. A fluoroquinolone’s efficacy is dependent upon its concentration. The higher the concentration, the greater the kill rate. Frequent dosing during a short period of time may be more appropriate than infrequent long-term use.

Chloramphenicol can also be concentration-dependent, depending on the type of bacteria.

The addition of benzalkonium chloride as a preservative may facilitate more rapid killing of bacteria compared with antibiotics without benzalkonium chloride.21-24

ANTIBIOTIC SUSCEPTIBILITY AND RESISTANCE

Most studies of antibiotic use in ophthalmology do not have proper controls because we do not know how many patient eyes are really challenged by bacteria. Also, because endophthalmitis is uncommon, studies must be very large to be adequately powered to detect a change in the rate of endophthalmitis with different regimens.

The problem with studying antibiotic resistance against the topical antibiotics used in ophthalmology is that it may not be directly analogous to antibiotic resistance against their systemic use. Topical antibiotics can obtain very high concentrations compared with systemic antibiotics; therefore, even when an antibiotic may be considered resistant, it may still be effective at killing bacteria, given the high levels of the medication present in the tear film and tissue.

All susceptibility and resistance data are based on systemic treatment standards, so they may not correspond to topical, intracameral, or intravitreal treatments.

True resistance in ophthalmology occurs when (1) an isolate has increased MIC that cannot be treated, topically or by injection; (2) bacteria with elevated MIC are spread to other patients; and (3) the isolate with elevated MIC cannot be treated with antibiotics. No bacterium has met these three conditions in ophthalmology.19

Another limitation to studying antibiotic resistance is the variation in resistance patterns based on geographic location. The TRUST study is a surveillance report of more than 70,000 isolates collected from more than 200 institutions since 1999. This ongoing study does not include important antibiotics that are used in ophthalmology (ie, cephazolin, bacitracin, polymyxin B, neomycin, and sulfacetamide).25

If the patient’s own flora are the source of most postprocedural endophthalmitis, and if the use of postinjection antibiotics leads to increased resistance, then use of topical antibiotics will lead to more resistant organisms in endophthalmitis events. This has been shown in the ARCANE study.14

Schimel et al studied bacterial isolates from endophthalmitis and found a tenfold increase over 10 years in resistance to topical fluoroquinolones and an additional doubling of resistance over a 1-year period as the use of intravitreal injections increased.26

Another study by Milder et al demonstrated that even one drop of peri-injection antibiotics increased the development of bacterial resistance.27

ANTIMICROBIAL STEWARDSHIP

What can be done to stem the rising time of antibiotic resistance? More than 30% of antibiotics are prescribed inappropriately in the community and up to 30% of all surgical prophylaxis is inappropriate (see Antimicrobial Stewardship sidebar).28 The main areas of antibiotic use that seem to affect selection and diffusion of antibiotic resistance are in the food industry and in family medicine.29-31

Sidebar courtesy R. Murri and M. Fantoni, Fondazione Policlinico Gemelli, Italy

From a public health perspective, certain processes may help limit unnecessary antibiotic use, thus limiting development of resistance. These targets include conversion from intravenous to oral antibiotic use, batching of intravenous antimicrobials, therapeutic substitutions, and formulary restriction. These strategies require fewer resources and less effort than other stewardship activities; are applicable to a variety of health care settings, including limited-resource hospitals; and have demonstrated significant financial savings.32

CHOOSING WISELY

According to the principles of the Choosing Wisely campaign (choosingwisely.org), we should not routinely use antibiotics before or after intravitreal injections. It is quite surprising that we are still talking about issues raised in 2004, with no clear consensus in 2019.33

In a 2004 report, Aiello et al found that postinjection topical antibiotics did not decrease endophthalmitis incidence.33 The clinical presentations and visual outcomes of patients with endophthalmitis were similar, regardless of whether postinjection antibiotics were used. Greater incidence of endophthalmitis with the use of topical antibiotics was also demonstrated.

Regarding vitreoretinal surgery, no antibiotics should be given preoperatively. Routine antibiotics are unnecessary postoperatively after routine (ie, uneventful or uncomplicated) surgery.7,34-37 The guidelines in Europe leave the use of antibiotic prophylaxis to the discretion of the surgeon.

Choosing wisely is also a patient-specific choice. Complicated surgery has a higher risk of postprocedure infection, so antibiotic use should still be considered for selected cases such as: elderly patients with blepharitis; patients with a poor tear film; monocular patients or those with a prothesis in the fellow eye, a history of ocular trauma, or previous surgery; immunosuppressed patients for local or systemic reasons; and patients with diabetes, multiple diseases, multiple medications, or cancer. These patients may be more prone to infection and, therefore, good candidates for additional preventive measures, such as use of intracameral or preoperative antibiotics.

HOW DO THESE DATA AFFECT CLINICAL PRACTICE?

The natural history of endophthalmitis suggests that we should rethink the scheduling of postoperative visits in routine cases. We must shift the standard of care in a more patient-friendly direction without compromising safety.

Regarding injections, in many parts of the world, patients do not return for safety monitoring in the days following an injection. Instead, patients are given written instructions to call immediately if redness, pain, decreased vision, or other issues develop.

Regarding vitreoretinal surgery, while many routine cases should be reviewed on day 2 or 3 postoperative, it is the general legal consensus that a postoperative day 1 visit is required.38

MEDICOLEGAL CONSIDERATIONS

From a medicolegal standpoint, we are safest when we adhere to the community standard. Unfortunately, the standard of care in many communities requires antibiotic use, even though, as suggested above, it may not be necessary. This makes it difficult for surgeons to go against the current standard.

It is difficult to prove definitively that antibiotics are unnecessary. For postinjection antibiotics, there are good data from both prospective and large retrospective trials that topical antibiotics are not helpful and may even be harmful particularly because, unlike cataract surgery or vitrectomy, which are likely to be performed only once per eye, intravitreal injections are often repeated numerous times per eye. There is little data to suggest that use of antibiotics before or after injection reduces endophthalmitis risk. Nonetheless, use of antibiotics in these situations may continue to be the standard of care until better data are obtained.

KEY MESSAGES

A multidisciplinary approach is important, and local microbiologic surveillance is mandatory. We should not give topical or oral antibiotics for intravitreal injection. We should prescribe broad-spectrum topical therapy following surgery based on local microbiologic surveillance. Antibiotic resistance in ophthalmology is necessarily applicable to systemic resistance defined because topical antibiotics obtain concentrations higher than oral antibiotics. Risk assessment is the key process to combat defensive medicine. In selected patients, additional preventive measures may be necessary.

1. Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia: Elsevier Saunders; 2015.

2. Grosso A, Ceruti P, Scarpa G, et al. Choosing wisely and the use of antibiotics in ophthalmic surgery: there is more than meets the eye. Eur J Ophthalmol. 2018;28(6):625-632.

3. St Leger AJ, Desai VJ, Drummond RA, et al. An ocular commensal protects against corneal infection by driving an interleukin-17 response from mucosal γδ T cells. Immunity. 2017;18;47(1):148-158.

4. Kugadas A, Gadjeva M. Impact of microbiome on ocular health. Ocular Surf. 2016;14(3):342-349.

5. Attisano C, Cibinel M, Strani G, et al. Severe ocular bacterial infections: a retrospective study over 13 years. Ocul Immunol Inflamm. 2017;25(6):825-829.

6. Giardini F, Grandi G, De Sanctis U. In vitro susceptibility to different topical ophthalmic antibiotics of bacterial isolates from patients with conjunctivitis. Ocul Immunol Inflamm. 2011;19(6):419-421.

7. Berkelman RL, Holland BW, Anderson RL. Increased bactericidal activity of dilute preparations of povidone-iodine solutions. J Clin Microbiol. 1982;15:635-639.

8. Wykoff CC, Flynn HW Jr, Rosenfeld PJ. Prophylaxis for endophthalmitis following intravitreal injection: antisepsis and antibiotics. Am J Ophthalmol. 2011;152:717-719.

9. Hsu J, Gerstenblith AT, Garg SJ, et al. Conjunctival flora antibiotic resistance patterns after serial intravitreal injections without postinjection topical antibiotics. Am J Ophthalmol. 2014;157:514-518.

10. Nentwich MM, Ta CN, Kreutzer TC, et al. Incidence of postoperative endophthalmitis from 1990 to 2009 using povidone-iodine but no intracameral antibiotics at a single academic institution. J Cataract Refract Surg. 2015;41(1):58-66.

11. Costello P, Bakri SJ, Beer PM, et al. Vitreous penetration of topical moxifloxacin and gatifloxacin in humans. Retina. 2006;26(2):191-195.

12. Moss JM, Sanislo SR, Ta CN. A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections. Ophthalmology. 2009;116(8): 1498-1501.

13. Yin VT, Weisbrod DJ, Eng KT, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol. 2013;131(4):456-461.

14. Dave SB, Toma HS, Kim SJ. Changes in ocular flora in eyes exposed to ophthalmic antibiotics. Ophthalmology. 2013;1220(5):937-941.

15. Storey P, Dollin M, Pitcher J, et al. The role of topical antibiotic prophylaxis to prevent endophthalmitis after intravitreal injection. Ophthalmology. 2014;121(1):283-239.

16. Fayers T, Loh GK, Cordeiro MF, et al. Overprescribing of antibiotics by UK ophthalmologists. Eye (Lond). 2018;32(2):240-242.

17. Miller D, Flynn PM, Scott IU, et al. In vitro fluoroquinolone resistance in staphylococcal endophthalmitis isolates. Arch Ophthalmol. 2006;124(4):479-483.

18. Gentile RC, Shukla S, Shah M, et al. Microbiological spectrum and antibiotic sensitivity in endophthalmitis. Ophthalmology. 2014;121(8):1634-1642.

19. Kowalski RP. Is antibiotic resistance a problem in the treatment of ophthalmic infections? Expert Review of Ophthalmology. 2013;8(2):119-126.

20. Lee AY, Akileswaran L, Tibbetts MD, et al. Identification of torque teno virus in culture-negative endophthalmitis by representational deep DNA sequencing. Ophthalmology. 2015;122(3):524-530.

21. Wispelwey B. Clinical implications of pharmacokinetics and pharmacodynamics of fluoroquinolones. Clin Infect Dis. 2005;41(suppl 2):S127-S135.

22. Kowalski RP, Kowalski BR, Romanowski EG, et al. The in vitro impact of moxifloxacin and gatifloxacin concentration (0.5% vs 0.3%) and the addition of benzalkonium chloride on antibacterial efficacy. Am J Ophthalmol. 2006;142:730-735.

23. Eser I, Hyon J, Hose S, O’Brien TP. Comparative antimicrobial efficacy of preserved and preservative-free topical fourth generation fluoroquinolones against various strains of Staphylococcus. Paper presented at: ARVO Annual Meeting; April 29, 2004; Fort Lauderdale, FL.

24. Cha SH, Lee JS, Oum BS, Kim CD. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro. Clin Experiment Ophthalmol. 2004;32(2):180-184.

25. Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008;145(6):951-958.

26. Schimel AM, Miller D, Flynn HW. Evolving fluoroquinolone resistance among coagulase-negative Staphylococcus isolates causing endophthalmitis. Arch Ophthalmol. 2012;130(12):1617-1618.

27. 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):1420-1424.

28. Fayers T, Loh GK, Cordeiro MF, et al. Overprescribing of antibiotics by UK ophthalmologists. Eye (Lond). 2018;32(2):240-242.

29. Wilson JA, Loveday HP, Hoffman PN, Pratt RJ. Uniform: an evidence review of the microbiological significance of uniforms and uniform policy in the prevention and control of healthcare-associated infections. Report to the Department of Health (England). J Hosp Infect. 2007;66(4):301-307.

30. Wise R. Antimicrobial resistance: increasing concerns. Br J Gen Pract. 2007;57(543):772-774.

31. Shlaes DM, Gerding DN, John JF Jr, et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Infect Control Hosp Epidemiol. 1997;18(4):275-279.

32. Goff DA, Bauer KA, Reed EE, et al. Is the “low-hanging fruit” worth picking for antimicrobial stewardship programs? Clin Infect Dis. 2012;55(4):587-592.

33. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina. 2004;24(5 Suppl):S3-S19.

34. Parke DW 2nd, Coleman AL, Rich WL 3rd, Lum F. Choosing wisely: five ideas that physicians and patients can discuss. Ophthalmology. 2013;120(3):443-444.

35. Cheung CS, Wong AW, Lui A, et al. Incidence of endophthalmitis and use of antibiotic prophylaxis. Ophthalmology. 2012;119(8):1609-1614.

36. Chandra A, Smith J, Wang BZ, et al. Post-vitrectomy endophthalmitis in Victoria, Australia. Asia Pac J Ophthalmol (Phila). 2017;6(1):104.

37. Yu CQ, Ta CN. Prevention and treatment of injection-related endophthalmitis. Graefes Arch Clin Exp Ophthalmol. 2014;252(7):1027-1031.

38. Zick J, Joondeph BC. Is a postoperative day one examination needed after uncomplicated vitreoretinal surgery? Retina. 2018;38(2):331-333.

Corresponding Author Andrea Grosso, MD
• Retinal Consultant, Centre for Macular Research, San Mauro Torinese, Italy
78andreagrosso@gmail.com
• Financial disclosure: None

Francesco Bandello, MD
• Full Professor and Chair, Eye Clinic, University Vita-Salute San Raffaele, Milan, Italy
bandello.francesco@hsr.it
• Financial disclosure: None

Piero Ceruti, MD
• Consultant, University of Verona, NHS Borgo Roma Hospital, Verona, Italy
piero.ceruti@univr.it
• Financial disclosure: None acknowledged

Giovanni Di Perri, MD
• Full Professor and Chair, Infectious Diseases Clinic, University of Torino, Italy
giovanni.diperri@unito.it
• Financial disclosure: None

Michael Engelbert, MD
• Vitreoretinal Surgeon,Vitreous Retina Macula Consultants of NY, New York
michael.engelbert@gmail.com
• Financial disclosure: None

Mauro Fioretto, MD
• Ophthalmologist in Chief, Santo Spirito Hospital, Casale Monferrato, NHS, Viale Giolitti, Italy
fiorettomauro@libero.it
• Financial disclosure: None

Sunir J. Garg, MD
• Professor of Ophthalmology, Thomas Jefferson University and the Wills Eye Retina Service, and Co-Director of Retina Research and Partner, Mid Atlantic Retina; both in Philadelphia
sgarg@midatlanticretina.com
• Financial disclosure: None

Franco Giardini
• Biologist in Microbiology and Public Health, Past Director Microbiology Lab Torino Eye Hospital, Italy
franco.giardini@libero.it
• Financial disclosure: None acknowledged

Brian C. Joondeph, MD, MPS
• Partner, Colorado Retina Associates, Denver
• Clinical Professor of Ophthalmology, Rocky Vista University College of Osteopathic Medicine, Parker, Colorado
bjoondeph@retinacolorado.com; Twitter: @retinaldoctor
• Financial disclosure: None

Regis Kowalski, MS, M(ASCP)
• Research Professor of Ophthalmology, University of Pittsburgh, Pittsburgh
• Executive Director, Charles T. Campbell Ophthalmic Microbiology Laboratory, University of Pittsburgh, Pittsburgh
kowalskirp@upmc.edu
• Financial disclosure: None acknowledged

Giorgio Marchini, MD
• Full Professor and Chair, Eye Clinic, University of Verona, Italy
giorgio.marchini@univr.it
• Financial disclosure: None

Giuseppe Scarpa, MD
• Ophthalmologist in Chief, Cà Foncello Hospital, NHS, Treviso, Italy
giuseppe.scarpa@aulss2.veneto.it
• Financial disclosure: None

 

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About Retina Today

Retina Today is a publication that delivers the latest research and clinical developments from areas such as medical retina, retinal surgery, vitreous, diabetes, retinal imaging, posterior segment oncology and ocular trauma. Each issue provides insight from well-respected specialists on cutting-edge therapies and surgical techniques that are currently in use and on the horizon.