One of the most serious issues in health care is the growing threat of microbial resistance to antibiotic therapy. Now more than ever, infections from antibiotic-resistant bacteria are becoming commonplace. The ever-changing resistance patterns of bacteria severely cripple the ability of health care providers to manage and treat infections.
Over time, this problem will only continue to worsen. Even today’s most potent antibiotics will diminish in effect as bacteria continue to evolve.
What is the current state of therapy for ocular infection? What advances have been made to combat the rise of resistant bacteria? What does the future hold for the treatment of bacterial infections? What are the clinical implications of resistant bacteria?
To answer these questions, we asked a number of experts to share their thoughts on the current and future state of antibiotic resistance in ocular care.
Contributors
Jimmy D. Bartlett, OD, DOS, ScD, FAAO, is professor emeritus at the University of Alabama at Birmingham.
Aaron Bronner, OD, FAAO, is a staff optometrist at the Pacific Cataract and Laser Institute of Kennewick, Washington.
Blair Lonsberry, OD, MS, MEd, FAAO, is the clinic director and
professor of optometry at the Pacific University College of Optometry in
Portland, Oregon.
Jillian F. Meadows, OD, MS, FAAO, is on staff at the Ocular Surface Institute at the University of Houston in Texas.
Jimmy D. Bartlett, OD, DOS, ScD, FAAO: Systemic use of antibiotics is significantly more correlated to the development of bacterial resistance than is the use of antibiotics administered through the topical ophthalmic route. The quantity of oral antibiotics used by internists, pediatricians and surgeons far outstrips the quantities used for topical ocular therapy by the optometrist and ophthalmologist.
Aaron Bronner, OD, FAAO: Traditionally, medicine and eye care have made the assumption that resistance was, for the most part, a product of cavalier prescribing habits and non-compliance by patients in using oral antibiotics. We now know, however, that topical antibiotics do contribute to resistance, and not just of the local ocular flora, but of the nasopharynx as well.
This is changing recommended practice patterns. Specifically, post-procedural use of topical antibiotics is no longer the preferred approach to prophylaxis for infection with intravitreal injections. Rather, topical pre-procedure use of providone iodine (PI) alone is determined sufficient. It’s doubtful this will impact routine antibiotic use in the setting of more invasive ocular surgeries, however.
The kill time of PI is quite short, and in procedures where stability of the globe is more greatly compromised, iodine will need to be supplemented with a longer duration anti-microbial modality. In cataract surgery, for example, the use of postoperative antibiotics will probably continue to remain the norm.
However, the greater the necessity for repeated intervention, the more likely use of antibiotics will contribute to resistance—e.g., cataract surgery performed once is much less likely to contribute to resistance than 30 intravitreal injections.
Also note that that it’s not just health care providers and patients that cause resistance. Widespread use of broad-spectrum antibiotics within agriculture to prevent infection among livestock has, without a doubt, contributed as well.
Are clinicians better off using broad-spectrum topical agents for prophylaxis? For how long should they be used to prevent infection?
Dr. Bartlett: Broad-spectrum topical agents are generally preferred for prophylaxis. It is impossible to know the probability that a gram-positive or gram-negative bacterium will find the opportunity to invade the ocular tissue. More specifically, the three most commonly encountered bacteria accounting for ocular surface infection are Staphylococcus, Streptococcus and Haemophilus.
The prudent clinician will use a broad-spectrum agent that will most likely cover all three, and more, pathogens.
This is more reasonable than, for example, using topical erythromycin or bacitracin ointment, which are much more selective for gram-positive organisms. In the case of prophylactic use, these agents can be extremely effective when used two to three days before surgery, or for one week post-surgery.
Active ocular MRSA infection. Photo: Paul M Karpecki, OD
It is critically important to recognize that topical antibiotics should never be “tapered,” as one might do with ocular steroids, as this achieves sub-antimicrobial levels of drug, which enhances selectivity for resistant pathogens.
Dr. Bronner: When using prophylactic antibiotics in cases of ocular surface or dermatologic disease, or in preventing super-infection of virally infected tissue, it depends on the extent of tissue compromise and what other modalities are being employed. A sterile epithelial defect requiring use of a bandage soft contact lens (BSCL) probably necessitates concomitant use of topical antibiotics.
The antibiotic does not need to be continued, however, once the defect has closed, despite the fact that you may continue use of the BSCL, in the long-term management of recurrent corneal erosions, for example. The use of prophylactic antibiotics in the setting of viral conjunctivitis or keratitis strikes me as excessive in most cases, and probably should be avoided unless you are faced with significant cornea disease.
For actual microbial infections in the optometric clinic, where most of what we treat with antibiotics does not result in a rapid deterioration or loss of vision, I think there are two things to pay attention to.
First, for blepharitis and conjunctivitis cases that are thought to be bacterial in etiology, a broad-spectrum antibiotic is a reasonable starting point. In my opinion, dosing strategy may be more important than the actual antibiotic. To achieve biologically effective concentrations within tissue, most topical antibiotics will need to be used several times per day.
Using an antibiotic with recommended dosing four times per day, once or twice per day as prophylaxis, or even for suppression of chronic infection, over long periods of time is simply allowing concentrations within tissue to drop below effective levels, and often does nothing more than kill the highly susceptible colonies and select out for the more strongly resistant colonies.
Second, for microbial keratitis, which constitutes a more immediate threat to visual function, we need to be cognizant that as resistant organisms become more and more common we are moving out of the era of easy empiric treatment of these pathologies with broad-spectrum topicals. As this shift continues, culture and sensitivity guided treatment paradigms will likely once again become standard of care.
What persistent challenges remain in therapy for ocular infection?
Dr. Bartlett: I think the answer to this question depends upon the level of services provided by the clinician. Does the clinician provide only entry-level, primary eye care, or is the clinician a tertiary specialist who deals with rare and potentially disastrous infections?
At the primary care level, I believe most clinicians are relatively happy with the degree to which their patients are responding to topical and oral antibiotic therapy. It is a relatively rare patient with infectious conjunctivitis, blepharitis, preseptal cellulitis and most microbial keratitis who does not respond adequately to topical or oral therapy.
On the other hand, the tertiary specialist in ophthalmology, is still presented with some significant and lasting challenges. These include the treatment of fungal keratitis, bacterial or fungal endophthalmitis, and some cases of microbial keratitis.
These cases often require compounded or extemporaneously prepared medications, which are frequently expensive and sometimes difficult to use.
Dr. Bronner: Without a doubt in my mind, severe neurotrophic disease presents the most long-term challenge to avoiding infection, while at the same time not contributing to resistance.
In these cases, the clinician is forced to choose between the potential for contributing to resistance vs. the potential for microbial keratitis in the face of chronically compromised ocular surface, often with concomitant use of bandage soft contact lenses.
What are some new bugs (bacterial and otherwise) on the horizon?
Dr. Bartlett: From an ophthalmic perspective, there are several newly identified pathogens that pose a relatively serious risk at the tertiary level. These conditions include fluconazole-resistant Candida keratitis, multidrug-resistant Pseudomonas aeruginosa keratitis, methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Streptococcus pneumoniae and vancomycin-resistant Staphylococcus aureus (VRSA).
Dr. Bronner: Microsporidiosis is another interesting infection we’ve seen in our clinic. While not necessarily displaying an increased trend towards resistance, it is changing previously defined patterns of infectivity.
Microsporidia are a family of intracellular parasites that share some qualities with fungi, though their exact taxonomy is not well defined. For years it was thought that infection with microsporidia was confined to AIDS patients, where intestinal disease could cause repeated bouts of diarrhea. As time has passed, though, our knowledge of the disease has suggested one of two possible natural histories.
Immunocompetent patients may develop acute microsporidiosis, which is generally a mild bout of gastrointestinal distress. It’s unclear at this point if the organism then goes into a chronic, suppressed state, similar to herpetic infections and only during bouts of immune stress does the disease process re-emerge, or whether we are effectively able to clear the organism and subsequent recurrences of the disease represent actual re-infection.
Regardless, what was once thought to be a disease of the immunosuppressed has become more and more common in immunocompetent patients, with particular predilection for the ocular surface. Its ocular form has two distinct appearances.
In the superficial form, which is more commonly described in immunocompromised patients (though was present in the less involved eye of our immunocompetent patient), conjunctivitis and an unusual cystic epithelial keratitis with mild sub-epithelial infiltration are the primary findings.
The deeper form of the disease is more frequently described in immunocompetent individuals and involves stromal keratitis, which mimics herpetic stromal disease.
Despite being a unique phylum, microsporidia are susceptible in many cases to the antibiotic moxifloxacin. Other treatments, such as fumagillin, also exist, but there are several reported cases of ocular microsporidiosis proceeding to penetrating keratoplasty.
What recent improvements have we seen in fighting these pathogens? What can be used to combat them? And what specifically is happening on the pharmaceutical industry's efforts to combat antibiotic resistance?
Dr. Bronner: Novel antibiotics, such as besifloxicin, with no systemic equivalent, are a good start, and may be reasonably employed as a first-line therapy for microbial ocular surface disease. Also, what was once old is new again. It’s been fairly well determined that many MRSA strains are susceptible to older generations of antibiotics like bacitracin and polymixin b/trimethorprim (Polytrim).
Barring absolute resistance, another older approach may still be valid in many cases. Fortified antibiotics may allow tissue concentrations to build up to levels that can exert a treatment effect that is not attainable with commercially available antibiotics.
Blair Lonsberry, OD, MS, MEd, FAAO: The Infectious Disease Society of America (IDSA) has proposed a plan called 10 x ‘20. They want 10 new, novel antibiotics by 2020. To this point, there has only been one systemic antibiotic that has come out since 2010—that is a huge concern with the increased occurrences of MRSA infections.
The website (
http://www.idsociety.org/10x20/) lists all initiatives proposed to encourage to stimulate antibiotic development. But, from what I can see, there isn’t much in the pipeline.
Besivance has an “indication” for Pseudomonas and proven eradication activity for MRSA. The standard of care for a confirmed MRSA infection is topical vancomycin, but that has to be compounded, so I think many practitioners are using Besivance if they suspect MRSA may be a component to an infection. Besivance doesn't have a systemic counterpart, so the chance of developing resistance with this antibiotic may be lower.
What are the strategies to be employed for the future, as our current antibiotics are failing with increased frequency? What might be on the near horizon?
Dr. Bartlett: Four key strategies can be employed to prevent antibiotic resistance.
First, prevent infections in the first place. This reduces the amount of antibiotics that must be used and reduces the likelihood that resistance will develop during therapy. Ways in which drug-resistant infections can be prevented might include immunization, safe food preparation, frequent hand washing and using antibiotics only as directed, and only when necessary. Preventing infections reduces the spread of resistant bacteria.
Second, track antibiotic-resistance patterns in your community, causes of infections and their risk factors. This information can lead to development of specific strategies to prevent those infections, and to prevent resistant bacteria from spreading.
Third, improve antibiotic prescribing stewardship among clinicians. This is perhaps the single most important action needed to reduce the development and spread of antibiotic-resistant infections. It has been estimated that up to half of antibiotic use in humans and much of antibiotic use in animals is unnecessary and inappropriate. Practitioners should be committed to always using antibiotics appropriately and safely, and only when needed to treat infectious disease.
Fourth, develop new drugs and diagnostic tests. Antibiotic resistance occurs as part of a natural process as bacteria evolve, and this evolution can be slowed but not stopped. Thus, we will always need new antibiotics to keep up with resistance patterns, and new diagnostic tests can simplify and improve the clinician’s diagnosis, so as to avoid unnecessary antibiotic prescribing.
Is there anything you would suggest to clinicians and patients to help reduce the number of infections, or to help in the ongoing fight against these resistant strains?
Dr. Bartlett: For clinicians, the single most important piece of advice is to use antibiotics prudently. That is, be diligent in the patient history and clinical examination so that an accurate diagnosis can be made.
Remember that viral infections rarely, if ever, benefit from antibacterial therapy. When in doubt, it may be more prudent to withhold the drug, although this can be a challenge when patients (or their parents) are expecting an antibiotic to be prescribed. It can be a difficult decision to make in actual day-to-day clinical practice.
For patients, my advice is to be fastidious with hand washing, and do not share towels, handkerchiefs or eye cosmetics with others. It may also be tempting for some patients to share family members’ eye drops, such as artificial tears or contact lens solutions. This practice should be strictly forbidden, as it can directly lead to cross-contamination.
One final point: school-age children with bacterial conjunctivitis should probably be kept at home until the purulent discharge has largely dissipated.
Dr. Lonsberry: I think the big concerns center around ocular surgery, including cataract and refractive surgery. So, I think optometrists have an obligation to make sure that their patients’ lids and lashes are as clean as possible.
Treating any blepharitis and meibomian gland dysfunction prior to surgery is crucial. It is commonly thought that during surgery is a crucial time where potential infections like endophthalmitis develop, so it is imperative that optometrists treat any blepharitis prior to surgery to decrease this potential.
Jillian F. Meadows, OD, MS, FAAO: When an antibiotic is dosed below its minimum inhibitory concentration (MIC), its efficacy in killing bacteria is reduced. This provides opportunity for the numerous remaining microbes to mutate and develop resistance.
Although combined antibiotic-steroid drops can promote patient compliance and can be useful in some conditions, their downfall is that the relative dosing of antibiotic to steroid is fixed. If you want less steroid, you have to deliver less antibiotic.
The problem arises when clinicians feel the need to taper the patient off the steroid, which drops the antibiotic concentration below its optimum bactericidal levels. Remember that a steroid only needs to be tapered if you initially pulse-dose it, or if you dose it longer than about one week.
If you avoid both of these patterns, then a taper is not necessary, and the long-term antibiotic effect will be better preserved.
To circumvent this problem altogether, prescribe separate antibiotic and steroid drops so that you have the liberty to vary the dosages, as you want, when you want. In short, respect the MIC—combo drops are not meant to be tapered!
