When MRSA
Threatens Cataract Surgery

This formidable foe requires the ‘shock and awe’ treatment.

Francis S. MAH, MD

Ever since Louis Pasteur made the first scientific observation of what would now be called an antibiotic effect in the 19th century, an ongoing war between bacterial mutations and adaptation against human research and development has been waging. Ophthalmology has played a role in this battle beginning with Carl Crede's pioneering work in the 1800s to battle ophthalmia neonatorum with silver nitrate. As time passed, the ever-mutating bacteria seemed to be just a step ahead, able to select several sentinel colonies that under normal, wild-type, scenarios would go unnoticed. However, when under attack by antibiotics pathogens take on new importance due to protective resistance mutations that enable them to survive and thrive in the otherwise hostile environments. The latest and toughest combatant in the infectious disease arms race is MRSA (methicillin-resistant Staphylococcus aureus). Here is where eye care stands in the struggle against it.

Figure 1. Bacterial keratitis.

The Battle Begins

Staphylococcus aureus was discovered in Scotland in 1880 by the surgeon Sir Alexander Ogston from pus in surgical abscesses.¹ Staph. aureus is frequently found in the nose and skin of a person; about 20% of the population are long-term carriers.² Staph. aureus is one of the most common causes of nosocomial infections, often causing postsurgical wound infections — including after cataract surgery. Each year some 500,000 patients in American hospitals contract a staphylococcal infection.³

Penicillins were the first large class of antibiotics that were effective against a wide range of bacteria, including Staph. aureus. However, due to bacterial mutation, resistance to this class of antibiotic made it ineffective against β-lactamase producing organisms, including many gram-positive organisms such as Staph aureus. The β-lactamase-resistant penicillins (methicillin, oxacillin, cloxacillin and flucloxacillin) were developed to treat penicillin-resistant Staph aureus and are still used as first-line treatment. Methicillin was the first antibiotic in this class to be used (it was introduced in 1959), but only two years later, the first case of methicillin-resistant Staph. aureus (MRSA) was reported in England.³ The mechanism of resistance to methicillin is mediated via the mec operon, part of the staphylococcal cassette chromosome mec (SCCmec).

The mecA gene confers resistance. This gene codes for an altered penicillin-binding protein (PBP2a or PBP2′) that has a lower affinity for binding β-lactams (penicillins, cephalosporins and carbapenems). This allows for resistance to all β-lactam antibiotics and obviates their clinical use during MRSA infections. As such, the glycopeptide, vancomycin, is often deployed against MRSA.⁴ Glycopeptide resistance is mediated by acquisition of the vanA gene. The vanA gene originates from the enterococci and codes for an enzyme that produces an alternative peptidoglycan to which vancomycin will not bind.⁵

A Force to be Reckoned With

Despite this, MRSA generally remained an uncommon finding even in hospital settings until the 1990s, when there was an explosion in MRSA prevalence in hospitals. It is now endemic in that setting.⁶ In the United States, 95 million people carry S. aureus in their noses; of these, 2.5 million (2.6% of carriers) carry MRSA.⁷ These statistics actually mirror the findings in ophthalmic infections as well. In our laboratory, The Charles T. Campbell Ophthalmic Microbiology Laboratory at the University of Pittsburgh, approximately 70% of post surgical cataract infections are coagulase negative Staph. Approximately 11.4% are Staph aureus, and of these, almost 34.6% are MRSA. In other words, about 3% of all endophthalmitis is MRSA.

Another way to look at this issue in cataract surgery is what percentage of MRSA infections are found following cataract surgery. A University of California, San Francisco, study found that 2.4% of all ocular MRSA infections are postsurgical endophthalmitis cases.⁸

While this hardly constitutes a pandemic, obviously, MRSA infections are a problem and something of which all cataract surgeons need to be aware.

Who Could Be a Carrier?

In one hospital in Texas, 12% of staff were carriers of MRSA.⁹ In an Illinois emergency department, it was found that 15% of the ED staff were carriers.¹⁰ Researchers at Stanford looked at those cataract surgery patients who cultured positive for a resistant bacteria. Diabetes, asthma, chronic blepharitis, active conjunctivitis, ocular discharge, and immunosuppressive and autoimmune disorders all put patients at higher risk.

In light of these facts, cataract surgeons should be sure to educate patients who fall into these categories about their risks and obtain an informed consent from them. It is best to delay surgery until ocular issues can be cleared.

Healthcare workers, those in nursing homes, prisoners, and those involved in contact sports are at higher risk for being colonized with MRSA.¹¹

Treating Ocular MRSA Infections

The question of systemic treatment for MRSA infections is much easier to answer, despite the difficulty of treatment. Using standard microbiologic testing (MICs, or, minimum inhibitory concentrations) with pharmacokinetic (PK) and pharmacodynamic (PD) scientific evidence, infectious disease experts are able to choose from a handful of agents that could be effective against select MRSA strains. These agents include fluoroquinolones, bacitracin, glycopeptides and oxazolidinones (linezolid), to name a few.

When it comes to the eye, though, the question of how to treat MRSA is a little more open to debate. Ophthalmic standards do not exist for the extremely high concentrations achieved with topical dosing. Clinicians would not be wrong in using the systemic standards as a guide; however, treating physicians could be diverted from finding an effective therapy due to the incorrect assumption that the PK and PD are the same for both systemic infections and ocular disease.

Our laboratory has done several studies, of keratitis¹² and endophthalmitis,¹³ showing that due to the extremely high doses of topical antibiotics called for (10 µg/mL typical serum level of fluoroquinolone after parenteral dose vs. 5000 µg/mL typical concentration of commercially available topical fluoroquinolone) and the ability to administer these high doses much more frequently than parenteral dosing (hourly vs. b.i.d.), it is possible to eradicate MRSA with our typical fourth-generation fluoroquinolones. This is true despite the fact that these would be considered ineffective using typical serum standards. This implies ophthalmologists must use different standards because our concentrations and doses are so much higher than what is expected with oral or IV dosing.

Questions Remain

Another difference in characterizing antibiotics for the eye includes the potential effects of the formulation vehicle. Some evidence indicates that typical preservatives in topical preparations such as the “inactive” BAK (benzalkonium chloride) may have some utility in eradicating bacteria, including MRSA.¹²

These classic preservatives may potentially improve the potency of antibiotic agents, although this has not been proven in clinical trials. Further, some argue that tears have a dilutional effect; in vitro studies show a clinical trial may be warranted.

Can we overcome MRSA in clinical practice? Our laboratory presented findings at ASCRS 2005 demonstrating that compared to methicillin-sensitive Staphylococcus aureus, there is no difference in time to epithelialization and resolution of infiltrate in keratitis patients. This study looked retrospectively at patients using the fourth-generation FQs that were deemed resistant.

We showed that high-frequency dosing and high concentrations were able to overcome systemic standard resistance. Dosing was as follows: cefazolin was 25 µg/mL; tobramycin was 14%, moxifloxacin was 0.5%. Q1 hour dosing range was one day to 200 days, depending on the drug.

However, if there is a culture-proven MRSA infection that is worsening despite frequent, high-dose FQ application, other agents should be strongly considered without delay. Depending on clinical scenario, you might switch antibiotics in as little as one to two days. Some alternate agents include bacitracin, cefazolin, gentamicin, vancomycin and linezolid, among others. It is important to realize regional variations may occur in terms of antibiotic susceptibilities, so close work with local microbiologists and infectious disease experts is recommended.

MRSA is the newest and toughest pathogen ophthalmologists have faced in this ongoing battle of ocular infections. With new standards of treatment, and research into who is at risk, clinicians will be able to reduce the potential for infection from this latest enemy to the eye. OM

References

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11. Mino De Kaspar H, Shriver EM, Nguyen EV, Egbert PR, Singh K, Blumenkranz MS, Ta CN. Risk factors for antibiotic-resistant conjunctival bacterial flora in patients undergoing intraocular surgery. Graefes Arch Clin Exp Ophthalmol. 2003; 241:730-733.
12. Romanowski EG, Mah FS, Kowalski RP, Yates KA, Gordon YJ. Benzalkonium chloride enhances the antibacterial efficacy of gatifloxacin in an experimental rabbit model of intrastromal keratitis. J Ocul Pharmacol Ther. 2008; 24:380-384.
13. Kowalski RP, Romanowski EG, Mah FS, Sasaki H, Fukuda M, Gordon YJ. A comparison of moxifloxacin and levofloxacin topical prophylaxis in a fluoroquinolone-resistant Staphylococcus aureus rabbit model. Jpn J Ophthalmol. 2008; 52:211-216.

Francis S. Mah, MD, is director, Cornea and External Disease and codirector of refractive surgery at Scripps Clinic Torrey Pines, in La Jolla, CA. Dr. Mah is a consultant for and has received research support from Alcon and Allergan. He can be e-mailed at Mah.Francis@Scrippshealth.org.