Review of Cornea & Contact 

lenses

Antibiotics in Practice: USE, DON'T ABUSE

Resistant bacterial strains challenge eye doctors to be judicious in treatment. Here are several key trends to heed when setting a regimen.

By Blair Lonsberry, MS, OD, MEd.

Release Date:

September 2016

Expiration Date:

September 1, 2019

Goal Statement:

This course examines the use of current and emerging antibiotics in the treatment and management of ocular related infections.

Faculty/Editorial Board:

Dr. Blair LonsberryDr. Blair Lonsberry, MS, OD, MEd., is a professor at Pacifi c University College of Optometry in Oregon and a diplomate of the American Board of Optometry. He is also a fellow of the American Academy of Optometry, the Optometric Retinal Society, the Optometric Glaucoma Society and the Ocular Surface Society of Optometry.






Credit Statement:

This course is COPE approved for 1 hour of CE credit. COPE ID is is 50851-PH. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.

Joint Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Lonsberry has received honoraria from Alcon and is a consultant to Optovue, Shire Pharmaceuticals and Bausch + Lomb.


Topical and oral antibiotics are the stock-in-trade of most health care pro-fessionals—workhorse drugs likely prescribed every day. For the most part, eye care practitioners traditionally prescribe topical forms, though systemic drugs are increasingly used in eye care. The release of new products and the ever-evolving resistance patterns of the microorganisms responsible for infections also mean that prescribing habits continue to change. Pick up any public health magazine and you’ll notice that one of the top concerns is the increase in resistance to our current armament of antibiotics, as well as the continuing absence of new drugs to counter this ever-present threat. These trends compel us to remain up-to-date on each drug’s properties, interactions, resistance patterns and clinical impact.

RESISTANCE AND R&D

The US Centers for Disease Control and Prevention continues to track reports of systemic methicillin-resistant Staphylococcus aureus (MRSA), noting that 72,000 patients in this country required treatment for a related infection in 2014.1 Most individuals acquired their condition through the health-care system, though the number of cases with community-associated infections—i.e., those in which the patient had no inpatient contact with a medical facility prior to infection—is also on the rise.1

Data from the recent Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) study reveals that methicillin-resistant organisms continue to remain common in ocular isolates and, when resistance is found, most organisms are discovered to be multidrug-resistant.2 Interestingly, however, nationwide antibiotic resistance rates have not increased in the last five years and have in fact decreased in the case of some combinations of antibiotics and pathogens. The first case of a patient with a strain of E. coli resistant to the powerful anti-biotics administered in the United States was reported in May 2016.3

Antibiotic resistance is a big concern, particularly in light of the relatively few new drugs released in recent years.

Microorganisms have several ways to develop resistance to a drug, including the production of enzymes that render the antibiotic ineffective and the alteration or elimination of the antibiotic target site so that there is less affinity. The presence of microorganisms can also decrease antibiotic uptake and/ or increase efflux of the drug, and lead to the development of bypass pathways around target sites, further rendering the administered drug ineffective. Furthermore, during the development of the bacteria’s resistance characteristics, the inappropriate use of antibiotics (e.g., if they are prescribed for viral infections, or if the wrong one is given in a case of misdiagnosis) in both human and veterinary medicine can have a negative effect, as does the widespread use of these drugs in the agricultural industry.4

As of May 2016, there were 33 antibiotics in clinical trials being studied.5 The majority seem to be variations of existing meds or additional members of already-existing group of drugs with few, if any, recently added classes of antibiotics.

Overall, the success rate for clinical drug development is low, with many failing stringent clinical trials. With the expected return for a company to cover the post-trial development and market launch of a new antibiotic unlikely to exceed initial development costs, many companies have shut down their antibiotic research efforts entirely.5

KICKING KERATITIS

Current antibiotics may not be enough to treat corneal infections such as this alpha-hemolytic Streptococcus presentation.

Considered an ocular emergency, microbial keratitis is of particular concern in contact lens wearers. Staph. aureus is a leading cause of keratitis worldwide, possessing a multitude of characteristics that enhance its adhesion to host tissues, evasion of the human immune system and destruction of host cells.6

Patients who wear contact lenses and those who have suffered ocular trauma with damage to the cor-neal epithelium have an increased chance of developing ulceration as a result of infection by this organism, necessitating antibiotic therapy for adequate resolution.7

One study, in which isolates were found to be susceptible to vancomycin and polytrim, but also resistant to the second-generation fluoroquinolones ciprofloxacin and ofloxacin, identified approximately 31% of isolates taken from keratitis patients as MRSA.8 There was also an increase in the resistance of both MRSA and methicillin-susceptible Staphylococcus aureus (MSSA) to fourth-generation fluoroquinolones detected during the study period from 1993 to 2012.8

The latest ARMOR report noted the global prevalence of MRSA at 42% from Staphylococcus isolates, with the most effective treatment option being vancomycin.2 With respect to minimum inhibitory concentrations (MICs), large differences were still identified among the fluoroquinolone class of antibiotics—namely, the newer fluoroquinolones in the group had a lower MIC compared with the older ones.2 Additionally, the chlorofluoroquinolone Besivance (besi-floxacin, Bausch + Lomb) exhibited the lowest MIC for gram-positive isolates and was as effective as moxifloxacin in treating bacterial conjunctivitis; it was also more effective than the same at eliminating bacteria from the ocular surface prior to cataract surgery.2,9

Besivance contains besifloxacin and the delivery vehicle DuraSite (Insite Vision), a mucoadhesive polymer designed to increase drug retention time on the ocular surface to 4.7 hours.9 This agent’s extended retention time and high concentration on the ocular surface, combined with the low associated MIC values for MRSA, may mark it as a possible first-line choice for patients suspected of having MRSA-related conjunctivitis or keratitis.

The ARMOR report also mentioned other commonly seen infectious isolates: Pseudomonas aeruginosa, Streptococcus pneumoniae and Haemophilus influenzae.2 Almost all S. pneumoniae isolates were susceptible to both chloram-phenicol and the fluoroquinolones tested, with Besivance having the lowest MIC among all of latter considered.2 With respect to the P. aeruginosa isolates, their rates of resistance remained rather low in the face of the antibiotics tested, with good susceptibility to both fluoroquinolones and tobramycin. Additionally, the H. influenzae isolates proved susceptible to all an- tibiotics administered, while azithromycin showed the most resistance against it, with 42% of MSSA and 93% of MRSA isolates remaining unaffected.2 The ARMOR report noted that if an isolate was identified as MRSA, there was also a strong likelihood that it exhibited multidrug resistance.

Interestingly, the isolates in the study, regardless of origin, exhibited susceptibility to vancomycin. In this respect, if a clinician is treating a suspected MRSA-related infection—either the patient with the infection is in a hospital or personal care home, or the infection itself is not responding to initial antibiotic therapy—25mg/ml to 50mg/ml of topical fortified vancomycin is the recommended treatment to ensure appropriate coverage.2 This medication would have to be obtained from a compounding pharmacy, where the pharmacist would reconstitute 500mg of vancomycin powder with 10ml sterile water sans-preservative. Alternatively, they can also use 10ml of artificial tears as a compounding ingredient, which would yield a concentration of 50mg/ml. This formulation should be dosed every hour for the first 24 hours with a re-evaluation and a decrease in dosage frequency if improvement is noted. The compounded vancomycin should be stored in the refrigerator for an additional four days before expiration.10

MRSA infections are of particular concern when considering their relation to the periorbital tissues and adnexa. With Staphylococcus sp. being the most prevalent bacteria on the skin, there is also a higher risk of developing an external MRSA-related infection. A study reviewing the records of patients diagnosed with an ocular-centric MRSA infection over a four-year period at a busy hospital practice found that preseptal cellulitis was the most prevalent.11 Additional conditions that should also be looked for, however, included dacrocystitis, canaliculitis and other periobital lesions and/or abscesses.11

MRSA Makes Its Mark

A 50-year-old white male presented complaining of near vision issues. His medical history was unremarkable except for a possible mosquito or spider bite on the back of his neck. He reported going for a hike the day before and noticing a bump that had begun to form later that evening (Figure 1). He admitted taking two of three pills of oral ciprofl oxacin "left over" from a previous Rx and the remaining pill the morning of the current exam. The patient reported no other serious skin conditions or infections, except that three years prior, he had been visiting a friend in the hospital and later developed an infection on his arm. Testing revealed it was MRSA, and the lesion was surgically drained and treated.

At the present exam, he reported some minor discomfort with the lesion and noted that it had a solid feel to it, much like a knot. It was recommended that he contact his primary care physician to have the lesion assessed, especially since he had had a previous MRSA infection.

Two weeks later, the patient returned to the clinic with an update: he had contacted his PCP and scheduled an appointment for the day after the exam; however, as the day proceeded, he had noticed an increase in pain and discomfort and decided to visit an urgent care clinic, where he was given Bactrim (trimethoprim-sulfamethoxazole, AR Scientifi c) to be taken as a single double-strength pill every 12 hours and also Vicodin (acetaminophen and hydrocodone, Abbott) for the pain. The patient was informed that what he initially believed to be a bite instead now appeared to be several pimples "combined" to form a super pimple.

The day after the urgent care consultation, the patient noted that the lesion in question was becoming increasingly larger and the level of pain was still rising despite his taking the medication as prescribed. Unable to wait for his scheduled PCP appointment, the patient instead went to the emergency room, where a physician attempted to drain the lesion. A cotton wedge was ultimately left in the wound in an attempt to help it drain further, and the patient was directed to continue taking the Bactrim and Vicodin (Figure 2).

The following day, however, the patient indicated that the pain had increased to a point where it was aff ecting his sleep, and so he elected to return to the urgent care clinic and then ultimately the ER, where his lesion was debrided and he was given Ancef (cefazolin, GlaxoSmithKline), a cephalosporin antibiotic given intravenously to treat severe soft tissue and skin infections secondary to MSSA. He was told to continue taking the Bactrim, was given oxycodone and told to return the next day for a follow- up appointment.

At this visit, it was found that his infection was secondary to MRSA, so he was switched from the Bactrim to doxycycline 100mg BID (Figure 3), a course of action confi rmed as valid by susceptibility testing on the MRSA isolate. The patient continued to self-administer the doxycycline for 10 days, at which point the lesion fi nally healed (Figure 4).

Though this case doesn't discuss an ocular infection, it highlights the importance of keeping MRSA as a diff erential when assessing a possible skin issue.


SKIN AND SOFT TISSUE INFECTIONS

High antibiotic tissue concentrations are achieved via frequent dosing and direct access to the affected tissue when treating ocular surface infections. However, when treating skin infections like preseptal cellulitis, systemic antibiotics must travel through the circulatory system to enter into the tissue, reducing their local concentration.6 As such, the use of topical antibiotics is unlikely to cause systemic antibiotic resistance, though the overuse of systemic antibiotics has contributed to systemic and also possibly topical antibiotic resistance.6

Healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) is especially correlated with severe, invasive disease in hospitalized patients, while community-associated methicillin-resistant S. aureus (CA-MRSA) is more often linked to young, healthy individu-als exhibiting a skin or soft tissue infection with no recent exposure to the healthcare system.1 Athletes, daycare and school students, military personnel living in barracks and those who recently received in-patient medical care are at a higher chance for developing this condition; Additional risk factors for CA-MRSA infection include skin trauma (i.e., lacerations, abrasions, tattoos and injection drug use), cosmetic body shaving, incarceration, HIV infection and sharing of uncleaned equipment between multiple users.1

Two of the newest antibiotics for acute bacterial skin and skin structure infections (ABSSSI), a category that includes MRSA, are Dalvance (dalbavancin, Allergan) and Sivextro (tedizolid, Merck). The former inhibits cell wall synthe-sis and is delivered to the patient via intravenous infusion, typically as a single dose of 1500mg or a two- dose regimen of 1000mg initially followed by a 500mg dose one week later. Dalvance is supplied in 500mg vials at an approximate cost of $1,788 per vial.12 Sivextro, in contrast, inhibits protein synthesis, with its use as treatment for ABSSSI conditions being 200mg daily for six days administered either orally (priced at $2,230) or intravenously ($2,961).13

Preseptal cellulitis is the most likely periorbital infection an optometrist would treat. This infection involves the eyelid and/or surrounding tissue anterior to the orbital septum. Signs and symp-toms include tenderness, swelling, unusual warmth, redness and/or discoloration of the eyelid and fever, in some cases.14 Common causes of preseptal cellulitis include hordeolum/chalazion, sinusitis, upper respiratory infection and trauma. The most likely causative agent is S. aureus, with a recommended treatment of an oral antibiotic that covers the most common pathogens the cause sinusitis.14

More specifically, the Infectious Disease Society of America (IDSA) advocates the use of amoxicillin-clavulante 500mg every eight hours (or 875mg every 12 hours) in the treatment of uncomplicated sinusitis, but not the use of amoxicillin alone secondary to increased resistance.4,14 An alternative treatment is cephalexin 500mg every six hours; cephalosporin antibiotics have excellent soft tissue penetration and should be considered as first-line treatments for periorbital infections.14 The IDSA also recommends that treatment for uncomplicated infections in adults be administered for a period no longer than seven days, while in children it can be extended from 12 to 14 days.4 In unresponsive cases, MRSA should be initiated for a seven- to 14-day period.4

At-risk patients may also include those with Pseudomonas infections.

Bactrim/Septra is a combination of sulfamethoxazole and trimethoprim available in two concentrations: either sulfamethoxazole 400mg and trimethoprim 80mg or a “double strength” (DS) dose of sulfamethoxazole 800mg and trimethoprim 160mg. One DS tablet taken twice daily for seven to 14 days is recommended for the treatment of skin and soft tissue infections due to MRSA. Monotherapy with DS trimethoprim-sulfame-thoxazole for the treatment of an uncomplicated skin infection may be reasonable in relatively young patients in the absence of systemic manifestations or comorbid conditions. As this medication contains sulfamethoxazole, it is contraindicated for patients with a known allergy to sulfonamide.15

Another medication option, clindamycin, is a protein synthesis inhibitor that has been demonstrated to have good activity against MRSA that can be administered at dosages of 300mg to 450mg every six to eight hours for seven to 14 days. Clindamycin exhibits excellent tissue penetration, particularly with respect to entering bone and abscesses; however, the drug also has an FDA black box warning, as it has been linked to onset of severe colitis, which may be fatal. Thus, it is reserved for serious infections for which less toxic antimicrobial agents are inappropriate. Furthermore, clindamycin is also not suitable for use in patients with nonbacterial infections, including most upper respiratory tract conditions.16

Doxycycline is another protein synthesis inhibitor option that binds to a different ribosomal subunit than clindamycin. Its recommended dose of 100mg twice daily for seven to 14 days is a treatment option for MRSA, but only fol-lowing performance of susceptibility testing. It should not be started empirically in suspected MRSA infections.17 Additionally, doxycycline is a pregnancy category D medication and is not suitable for use in pregnant or nursing women, or in children under the age of eight. Advise patients who are using this medication to take it more than two hours before going to bed, with food but without calcium, antacids or dairy products.

POST-SURGICAL PROPHYLAXIS

Topical antibiotics are routinely used following cataract surgery and/or intravitreal injections as a means to prevent endophthalmitis.18,19 The latest significant development to date is so-called dropless cataract surgery, which incorporates an intracameral or transzonular intravitreal injection at the time of the procedure to administer the antibiotic drug. The intravitreal transzonular procedure involves the delivery of TriMoxi (Imprimis Pharmaceuticals), a combination of triamcinolone 3mg and moxifloxacin 0.2mg, or TriMoxiVanc, which includes the aforementioned agents plus vancomycin.

A retrospective chart review of endophthalmitis development post-cataract surgery comparing administration of antibiotics intracamerally with topically found there was a 42% reduction in risk associated with intracameral use; additionally, an approximate doubling of risk in the 4.5% of eyes with no evidence of antibiotic prophylaxis was noted, as was the lack of effectiveness of topical aminoglycosides as prophylactic agents.20 In addition to the po-tential reduction in endophthal-mitis, the use of dropless cataract surgery may have the potential to increase patient compliance of medication use post-surgery and also lead to cost savings.21

The use of intravitreal injections has increased dramatically secondary to the beneficial effects of steroids and anti-VEGF medications in patients with conditions such as exudative macular degeneration and diabetic retinopathy. Traditionally, a topical antibiotic is used after (and sometimes prior to) the injection itself to prevent the development of endophthalmitis, as previously mentioned. One study that compared a 28-month period in which topical antibiotics were prescribed following in-travitreal injections with a nine-month period in which they were not found that the incidence of endophthalmitis after intravitreal injection was low and that the use of postinjection topical antibiotic drops did not reduce the risk; in fact, it was associated with a trend towards higher incidence of the condition.19

ORAL ANTIBIOTICS FOR OSD/MGD

Ocular surface disease (OSD) is one of the most common reasons why patients seek care from an eye care professional, resulting from an unstable or insufficient tear film layer and often leading to ocular irritation, discomfort and visual disturbances.21 Meibomian gland dysfunction (MGD) is an often-underlying cause for the disruption to the tear film, with multiple therapies available including warm compresses, topical lubrication and immunomodulation, omega-3 supplementation, oral antibiotics, laser- and light-based therapies and surgical interventions.21

Oral antibiotic use has also be-come a mainstay therapy for many patients suffering from MGD: oral doxycycline and azithromycin have both been used as part of treatment for MGD, as the condition is thought to occur in part due to increased production of inflammatory mediators such as matrix metalloproteinases and activated B-cells.22 The use of dox-ycycline and azithromycin is be-lieved to act as anti-inflammatory medications, reducing the production of these inflammatory media-tors to soothe the ocular surface. Recommended doxycycline dosag-es for MGD vary in the literature from 20mg to 100mg QD to BID, and for varying lengths of time with results including improved patient comfort, tear film break-up time, inflammatory signs and staining scores.22 Azithromycin, in contrast, is typically prescribed at 500mg/day for three days per week for three to four weeks, with expected improvements in tear film break-up time, patient com-fort and staining scores.22

Interestingly, a recent publication from the American Academy of Ophthalmology on the use of oral antibiotics for the treatment of MGD-related OSD indicated that although oral antibiotics are commonly used in the manage ment of OSD, there is no Level I evidence (defined as three or more randomized clinical trials demonstrating similar results) to support their use in this fashion.22 As such, in reviewing the literature, the report further noted that there are few clinically meaningful studies that demonstrate the benefits of oral antibiotics in the treatment of MGD-associated ocular surface disease; however, the studies that do exist indicate their use may be effective. More randomized controlled trials are required in this area to further confirm this hypothesis, however.22

An increase in therapeutic privileges for optometrists necessitates that they continue to educate themselves regarding the latest topical and oral treatments available for their patients. In particular, the increased presence of MRSA-related infections requires heightened vigilance in keeping track of the signs and symptoms of possible cases, as well as what options are available for resolution.  

1. CDC. Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network Methicillin-Resistant Staphylococcus aureus, 2014. Available at: www.cdc.gov/abcs/reports-findings/survreports/mrsa14.pdf. Accessed June 21, 2016.
2. Ophthalmology Times. Antibiotic resistance levels shift among ocular pathogens in 2014 ARMOR data. Available at: www. ophthalmologytimes.modernmedicine.com/ophthalmologytimes/news/antibiotic-resistance-levels-shift-among-ocular-patho-gens-2014-armor-data?page=0,0. Accessed June 21, 2016.
3. Pittsburgh Post-Gazette. Wolf confirms antibiotic-resistant E. coli strain found in Pa. woman. Available at: www.post-gazette.com/news/state/2016/05/26/Gov-Wolf-adminis-tration-confirms-antibiotic-resistant-E-co-li-strain-found-in-Pennsylvania-woman/sto-ries/201605260206. Accessed June 21, 2016.
4. Barlam TF, Cosgrove SE, Abbo LM, et al. Executive Summary: Implementing an Antibi-otic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016 May;62(10):1197-202.
5. PEW Charitable Trusts. Antibiotics Currently in Clinical Development. Available at: www. pewtrusts.org/~/media/assets/2016/05/antibiotics-currently-in-clinical-development.pdf?la=en. Accessed June 21, 2016.
6. Mangan RB. Incidence of MRSA infections of the eye, adnexa increases. Available at: www.healio.com/optometry/cornea-external-disease/news/print/primary-care-optometry-news/%7B0b922672-b9f3-436e-a09d-0663410e2ce0%7D/incidence-of-mrsa-infections-of-the-eye-ad-nexa-increases. Accessed July 1, 2016.
7. Azari AA, Barney NP. Conjunctivitis: a system-atic review of diagnosis and treatment. JAMA. 2013 Oct;310(16):1721-9.
8. Chang VS, Dhaliwal DK, Raju L, Kowalski RP. Antibiotic resistance in the treatment of staphylococcus aureus keratitis: a 20-year review. Cornea. 2015 Jun;34(6):698-703.
9. Deschenes J, Blondeau J. Besifloxacin in the management of bacterial infections of the ocular surface. Can J Ophthalmol. 2015 Jun;50(3):184-91.
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11. Blomquist PH. Methicillin-resistant staphylococcus aureus infections of the eye and orbid (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2006 Dec;104:322-45.
12. UptoDate. Dalbavancin: Drug information. Available at: www.uptodate.com/contents/dalba-vancin-drug-information. Accessed July 2, 2016.
13. UpToDate. Tedizolid: Drug information. Available at: www.uptodate.com/contents/tedizol-id-drug-information. Accessed July 2, 2016.
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15. UpToDate. Trimethoprim-sulfamethoxazole (co-trimoxazole): Drug information. Available at: www.uptodate.com/contents/trimethoprim-sul-famethoxazole-co-trimoxazole-drug-information. Accessed July 2, 2016.
16. UpToDate. Clindamycin (systemic): Drug information. Available at: www.uptodate.com/contents/clindamycin-systemic-drug-information. Accessed July 2, 2016.
17. UpToDate. Doxycycline: Drug information. Available at: www.uptodate.com/contents/doxy-cycline-drug-information. Accessed July 2, 2016.
18. Herrinton LJ, Shorstein NH, Paschal JF, et al. Comparative effectiveness of antibiotic prophylaxis in cataract surgery. Ophthalmology. 2016 Feb;123(2):287-94.
19. Storey P, Dollin M, Pitcher J, et al. The role of topical antibiotic prophylaxis to prevent endoph-thalmitis after intravitreal injection. Ophthalmolo-gy. 2014 Jan;121(1):283-9.
20. Qiao J, Yan X. Emerging treatment options for meibomian gland dysfunction. Clin Ophthalmol. 2013;7:1797-803.
21. Liegner J. A case for dropless cataract sur-gery: A single prophylactic injection is gaining growing support. Ophthalmology Management. Available at: www.ophthalmologymanagement. com/articleviewer.aspx?articleID=111160. Accessed July 2, 2016.
22. Wladis EJ, Bradley EA, Bilyk JR, et al. Oral antibiotics for meibomian gland-related ocular surface disease: a report by the American Acad-emy of Ophthalmology. Ophthalmology. 2016 Mar;123(3):492-6.