Antibiotic resistance among bacterial ocular pathogens is a continued global concern, evidenced by surveillance data from the antibiotic resistance in ocular microorganisms (ARMOR) study.1 The rise in bacterial resistance is largely due to unnecessary overuse of antibiotic therapy, but may also be the result of systematic, evolving resistance of the pathogens themselves. Awareness has improved due to increases in methicillin-resistant Staphylococcus aureus (MRSA) outbreaks in nursing homes and densely populated communities. Due to excessive systemic and, to a lesser degree, ocular use of antibiotics, resistance remains a significant issue.
In this article, we will discuss specific pathogens, the resistance trends being observed and some clinical pearls.
THE PROBLEM WITH ANTIBIOTIC RESISTANCE
Bacterial conjunctivitis is identified by mucopurulent discharge, hyperemia and edema without pre-auricular adenopathy or itching.2 The signs and symptoms may not be so specific and absolute, however, as to always differentiate it from other causes of conjunctivitis.3
Broad spectrum antibiotics, such as the generic fluoroquinolones, or combinations, such as polymyxin B-trimethoprim, (Polytrim), may be used as first-line treatment to decrease the duration and limit the spread of infection of bacterial conjunctivitis, but may not be necessary in uncomplicated cases. Decreased use will help to reduce the selection pressure, encouraging antibiotic resistance. Bacterial conjunctivitis secondary to sexually transmitted diseases, such as syphilis, gonorrhea and chlamydia, however, require both ocular and systemic treatments.4
Many of the common bacterial pathogens, particularly Staphylococcus aureus and coagulase-negative staphylococci (CoNS), are resistant to methicillin with a concurrent resistance to fluoroquinolones, aminoglycosides or macrolides.1 Trends in antibiotic resistance vary across the United States, with the worst cases of MRSA in the East South-Central U.S., at 62% resistance.5 The worst resistance of S. aureus to fluoroquinolones is 55% and 53% in the East South- Central and South Atlantic regions, respectively.5 Fortunately, the ARMOR study showed that S. aureus was susceptible to vancomycin as well as besifloxacin, which is not used systemically.1 Streptococcus pneumoniae was resistant to azithromycin.1 Haemophilus influenzae, which is the most common causative pathogen in children, has minimal resistance to antibiotics.1
Pseudomonas aeruginosa has the least antibiotic resistance, although it is a virulent pathogen typically with a fulminant course that carries a high risk of adverse outcomes.6 It is the most common pathogen present in contact lens-related infections due to its triggering of biofilm growth on both contact lenses and storage cases, and its resistance to certain contact lens solutions.7 The greatest antibiotic resistance of Pseudomonas aeruginosa is in the North-Central U.S.5
According to the American Academy of Ophthalmology Corneal/External Disease Preferred Practice Patterns Panel 2013, culturing and Gram staining is recommended for all recurrent, severe or chronic purulent conjunctivitis, preferably prior to antibiotic use or if there is poor response to treatment.8 This allows for lab-guided treatment and prevents overuse of inappropriate or resistant antibiotics. Rapid antigen testing is available to rule out adenoviral conjunctivitis, which account for 36% of conjunctivitis cases.9
Ocular syphilis – be aware
In March 2016, the Centers for Disease Control and Prevention (CDC) sent out a clinical advisory that ocular syphilis is on the rise in the US.1 Additionally, a paper was published in JAMA Ophthalmology in August 2017 indicating that there is an outbreak of endogenous fungal endophthalmitis (EFE) among intravenous drug users.2 Add these issues to the mix of MRSA and a significant problem emerges. There is an increasing risk of ocular infections among populations who are more likely to experience crowding, abuse drugs and engage in unprotected sexual activity.
Ocular syphilis can occur during any stage of the disease, primarily as uveitis. It results from the spirochete Treponema pallidum. Ocular inflammation is obviously not unique to syphilis which is why it is recommended that patients who present with uveitis be tested for syphilis (and HIV) if there is a remote possibility that they are infected.
Testing includes the nontreponemal tests Rapid Plasma Reagin (RPR) and the Venereal Disease Research Laboratory (VDRL) and treponemal tests Fluorescent Treponemal Antibody Absorption (FTA-ABS) and the Microhemagglutination Treponema pallidum (MHA-TP) tests.3 The CDC recommends analyzing the cerebrospinal fluid (CSF) in patients with ocular syphilis to assess for neurological involvement.1 Management of ocular syphilis is the same as for neurosyphilis with aggressive high dosing of aqueous crystalline penicillin G IV or procaine penicillin IM with Probenecid for 10-14 days.4
- Clinical Advisory: Ocular syphilis in the United States. Centers for Disease Control and Prevention. https://www.cdc.gov/std/syphilis/clinicaladvisoryos2015.htm . Accessed September 27, 2017.
- Relhan N, Schwartz SG, Flynn HW. Endogenous fungal endophthalmitis, an increasing problem among intravenous drug users. JAMA. 2017;318(8):741-742.
- Davis J. Ocular syphilis. Curr Opin Ophthalmol. 2014 Nov;25(6):513-518.
- Sexually Transmitted Diseases Treatment Guidelines, 2010. https://www.cdc.gov/std/treatment/2010/std-treatment-2010-rr5912.pdf . Accessed October 8, 2017.
SURGICAL CONSIDERATIONS FOR PROPHYLACTIC ANTIBIOTICS
The external ocular microbiome generally consists of Staphylococcus, Corynebacterium, and Propionibacterium species, with transient and invading species leading to conjunctivitis.10 The intraocular tissues, on the other hand, are sterile, but infection occurs when they are subjected to invasion from outside pathogens.
It is common to use a prophylactic antibiotic for cataract and refractive surgery, as these procedures are invasive and the risk of infection is greater with the potential for significant blinding impact. More surgeons are choosing intracameral antibiotics, such as preservative-free fluoroquinolones, including moxifloxacin or advanced generation cephalosporins, following cataract surgery, over topical anti-infectives.11 This is an off-label use and may require compounding.
Potential adverse effects following intracameral antibiotics include anaphylaxis, retinal detachment and corneal and retinal toxicity.14 Intracameral vancomycin has been implicated in the development of hemorrhagic occlusive retinal vasculitis (HORV) due to a delayed hypersensitivity reaction with potentially bilateral blinding consequences and is no longer recommended.15
New risk factors for increased antibiotic resistance are posed by intravitreal triamcinolone acetate and prophylactic use of antibiotics, used in conjunction with repeated intravitreal injections of anti-VEGF, for the treatment of age-related macular degeneration and diabetic macular edema.16
In 2014, an expert panel updated the guidelines for intravitreal injections, recommending the routine use of povidone-iodine as a topical antiseptic on the lids, lashes and conjunctiva prior to intravitreal injection, with no need to use peri-injections of antibiotics to reduce the risks of endophthalmitis. Additionally, they agreed that multiday administration of topical ophthalmic antibiotics results in the colonization of antibiotic-resistant bacteria with increased virulence and is not necessary.17
AN OUNCE OF PREVENTION IS WORTH A POUND OF CURE
According to the Centers for Disease Control and Prevention (CDC), most cases of bacterial conjunctivitis are spread through eyes coming into direct contact with contaminated hands and objects, as well as respiratory tract droplets. Hand antisepsis to reduce the bacterial load includes either aqueous scrubs (povidone iodine, chlorhexidine) or gel alcohol rubs.18
To prevent cross-contamination during biomicroscopy, a long-wooded cotton-tipped applicator is recommended when examining patients with conjunctivitis.19
Aseptic measures for in-office procedures include sterile gloves and surgical face masks. (The added benefits of an operating room are sterile drapes and the positive pressure ventilated environment.)20 The use of a surgical face mask during intravitreal injections is strongly recommended, as evidence suggests that Streptococcus species from oral droplet contamination is the main culprit in injection-related endophthalmitis.17
Additionally, it is suggested that patients and practitioners refrain from speaking during intravitreal injections, to reduce oral droplet contamination of the surgical field.
TREATMENT OF BACTERIAL CONJUNCTIVITIS
The Ocular TRUST (Tracking Resistance in the US Today) study in 2008 found that despite widespread use of fluoroquinolones in medicine and high resistance, they are still the most effective class of antibiotics.20,21 However, their effectiveness continues to decline.
Besifloxacin ophthalmic suspension 0.6% (Besivance, Bausch & Lomb Inc., Rochester, NY) is a broad spectrum, fourth generation topical chloro-fluoroquinolone with a low minimum, inhibitory concentration that is effective against most bacterial conjunctivitis pathogens, including those strains that are generally antibiotic resistant. It contains a muco-adhesive polymer that helps increase retention time on the ocular surface.22,23 Treatment dosing for bacterial conjunctivitis is one drop, three times per day for seven days.22
Besifloxacin's effectiveness is twofold. It is only formulated for topical ocular use so it has not been overexposed to pathogens. And it contains fluorine and chlorine, making it equally balanced against DNA gyrase and topoisomerase IV. For resistance to develop, two mutations would be required.22,24
Regardless, eye care practitioners will need to remain attentive to overprescribing besifloxacin so that it retains its efficacy. Time and continued surveillance will tell how clever bacteria are at developing resistance.
Ocular bacterial infections and antibiotic resistance are vast subjects, and this article only scratches the surface. Ophthalmic physicians must remain vigilant in adequately preventing and treating ocular bacterial infections while attentively limiting antibiotic resistance.
They must also be aware of the increased risk of infection in the aging population undergoing cataract and other ophthalmic surgeries, as well as receiving intraocular injections, adjusting their surgical procedures and infection control protocols accordingly. OM
- Asbell PA, Sanfilippo CM, Pillar CM et al. Antibiotic Resistance Among Ocular Pathogens in the United States Five-Year Results from the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) Surveillance Study. Ophthalmol. 2015;133:1445-1454.
- Roat MI. Acute bacterial conjunctivitis. http://www.merckmanuals.com/en-ca/professional/eye-disorders/conjunctival-and-scleral-disorders/acute-bacterial-conjunctivitis . Accessed September 27, 2017.
- Rietveld RP, van Weert CPM, ter Riet G, Bindels PJE. Diagnostic impact of signs and symptoms in acute infectious conjunctivitis: systematic literature search. BMJ. 2003;327:789.
- Azari AA, Barney NP. Conjunctivitis: A Systematic Review of Diagnosis and Treatment. JAMA. 2013; 310:1721–1729.
- Resistance Map United States, The Center for Disease Dynamics, Economics and Policy. https://resistancemap.cddep.org/CountryPageSub.php?country=United+States . Accessed October 8, 2017.
- Silverstein BE, Morris TW, Gearinger LS, DeCory HH, Cornstock TL. Besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis patients with Pseudomonas aeruginosa infections. Clin Ophthalmol. 2012;6:1987–1996.
- Mayrya A. Managing contact lens-related bacterial Infections. Review of Cornea and Contact Lenses. September 15, 2016. http://www.reviewofcontactlenses.com/content/c/62929/ . Accessed October 3, 2017.
- AAO Cornea/External Disease PPP Panel, Hoskins Center for Quality Eye Care. Conjunctivitis PPP – 2013. https://www.aao.org/preferred-practice-pattern/conjunctivitis-ppp--2013 . Accessed September 27, 2017.
- Sambursky R, Tauber S, Schirra F et al. The RPS adeno detector for diagnosing adenoviral conjunctivitis. Ophthalmology. 2006;113:1758–1764.
- Sharma S. Diagnosis of infectious diseases of the eye. Eye (Lond). 2012;26:177–184.
- Daly R. Controversies in Cataract Surgery: Is it time to move to intracameral antibiotics? Ophthalmology News. April 2017. https://www.eyeworld.org/it-time-move-intracameral-antibiotics . Accessed October 4, 2017.
- Shorstein HN, Winthrop KL, Herrinton LJ. Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department. J Cataract Refract Surg. 2013;39:8-14.
- An JA, Kasner O, Samek DA, Levesque V. Evaluation of eyedrop administration by inexperienced patients after cataract surgery. J Cataract Refract Surg. 2014;40:1857-1861.
- Naseri A, Melles RB, Shorstein NH. Intracameral Antibiotics in the Shadow of Hemorrhagic Occlusive Retinal Vasculitis. Ophthalmology. 2017;124:580–582.
- Witkin AJ, Chang DF, Jumper JM et al. Vancomycin-associated hemorrhagic occlusive retinal vasculitis: clinical characteristics of 36 Eyes. Ophthalmology. 2017;124:583-595.
- Schwartz SG, Relhan N, O’Brien TP, Flynn HW Jr. A New Complication Associated with the Use of Prophylactic Intracameral Antibiotics: Hemorrhagic Occlusive Retinal Vasculitis. Ophthalmology. 2017 May; 124:578-579.
- Avery RL, Bakri SJ, Blumenkranz MS, et al. Intravitreal injection technique and monitoring: Updated guidelines of an expert panel. Retina 2014;34(Suppl 12):S1-S18.
- Conjunctivitis for clinicians. Centers for Disease Control and Prevention. https://www.cdc.gov/conjunctivitis/clinical.html . Accessed October 2, 2017.
- Yeung KK, Dahl AA. Bacterial conjunctivitis (Pink Eye) workup. http://emedicine.medscape.com/article/1191730-workup . Accessed October 10, 2017.
- Merani R, Hunyor AP. Endophthalmitis following intravitreal anti-vascular endothelial growth factor (VEGF) injection: a comprehensive review. Int J Retin Vitr. 2015;1:9.
- Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008;145:951-958.
- Khimdas S, Visscher KL, Hutnik CML. Besifloxacin Ophthalmic suspension: Emerging evidence of its therapeutic value in bacterial conjunctivitis. Ophthalmol Eye Dis. 2011;3:7–12.
- Mah FS. A Potent Broad-spectrum Fluoroquinolone for the Treatment of Bacterial Conjunctivitis. April 2013. http://www.ophthalmologyweb.com/134116-A-Potent-Broad-spectrum-Fluoroquinolone-for-the-Treatment-of-Bacterial-Conjunctivitis/ Accessed October 8, 2017.
- Asbell PA. A Powerful Option for the Treatment of Bacterial Conjunctivitis. August 2013. http://www.ophthalmologyweb.com/139526-BESIVANCE-besifloxacin-ophthalmic-suspension-0-6-A-Powerful-Option-for-the-Treatment-of-Bacterial-Conjunctivitis/ . Accessed October 3, 2017.