Community-acquired MRSA a growing problem in ophthalmology

Infection caused by methicillin-resistant Staphylococcus aureus, or MRSA, is a growing concern in medicine, and ophthalmology has not been spared.

Reports of the resistant pathogen are increasing in the medical literature, including in ophthalmology, and there is growing evidence to suggest that the increased attention is reflective of increased incidence. Studies have noted a higher risk among certain patients and after certain surgical procedures.

For ophthalmologists, the potential for MRSA infection after refractive or cataract surgery represents a rare but potentially serious complication. In addition, the natural anatomy of the eye puts soft tissue surfaces, namely the lid and conjunctiva, in contact with the environment.

Pathogenically, MRSA has been implicated both in innocuous infections such as conjunctivitis as well as in potentially sight-threatening complications such as endophthalmitis.

“What the epidemiologic studies have shown is that the most reported MRSA infection is conjunctivitis and the least reported kind of infection related to MRSA is endophthalmitis,” Francis S. Mah, MD, OSN Cornea/External Disease Board Member, said. “It can be the cause of severe morbidity and vision loss.”

Francis S. Mah, MD, notes that although MRSA is becoming more prevalent, it is implicated in proportionately few cases of ophthalmic infections. Image: Smith DL

But while the threat of MRSA infection is prominent, the actual risk of infection with resistant organisms is still relatively low in terms of absolute numbers of infections.

“It’s definitely a growing problem in ophthalmology. Certainly there are pockets we need to be concerned about, but in terms of the absolute numbers, it’s not overwhelmingly the most dominant etiology of bacterial infection that clinicians might imagine,” Dr. Mah said. “We need to be cognizant of the rise of MRSA and try not to make the problem worse by ignoring the potential risk, but we need to also realize there are other pathogens that are probably more likely the cause of infections.”

A troubling aspect of MRSA is that the potential for infection affects empiric or prophylactic antibiotic choices. Still, the front-line antibiotic choice should account for the fact that MRSA may not be the inciting etiology.

“If you get a clue that a patient is at high risk, then you should start thinking about MRSA,” Dr. Mah said. “Otherwise, you should treat empirically, or prophylactically, the pathogens that are the most likely pathogens.”

Ophthalmic MRSA

According to Dr. Mah, treatment in the lay media and medical literature may have aroused concern about the role of methicillin-resistant organisms in systemic and general infection. Numerous studies have implicated methicillin resistance as a significant public health threat in various medical disciplines.

However, Dr. Mah said, best estimates of MRSA prevalence in ophthalmic infections suggest that it is implicated in a proportionally low percentage of cases. For instance, epidemiologic evidence suggests that MRSA is responsible for about 3% of all occurrences of endophthalmitis. However, among S. aureus, it is responsible for about 35% of all endophthalmitis, and this should be considered with the knowledge that endophthalmitis is a relatively rare complication.

“[MRSA] is a growing concern, but it is not the No. 1 cause of endophthalmitis, keratitis, conjunctivitis and typical ocular infections,” Dr. Mah said. “Endophthalmitis is a devastating infection. It can cause significant inflammation and problems, but the coagulase negative staph is more common, and actually the coagulase negative staph that is resistant to methicillin is probably a bigger volume of a problem than MRSA is.”

In the ophthalmic setting, the greatest concern with MRSA surrounds postsurgical complications after cataract removal or LASIK. However, according to Dr. Mah, only about 2.5% of the general population carries MRSA as reported in the literature, and so the risk of infection is relatively low. Where extra caution might be necessary, he said, is in the context of certain high-risk patients.

The percentage of MRSA carriers among health care workers is around 15% to 20%, and given the higher penetration of refractive procedures in this patient population, a prospective ocular culture might be an option. Athletes who participate in contact sports are also known to be at higher risk, as are patients who have concomitant risk factors such as diabetes or immune deficiency or who take steroids, which can inhibit immune function.

In terms of MRSA risk, the type of infection may be just as important as the patient history.

“A high percentage of all MRSA infections that are being seen in ophthalmology are in conjunctivitis and blepharitis,” Dr. Mah said. “People with a chronic discharge, such as conjunctivitis or blepharitis, despite anti-infective treatment are at risk for resistant bacteria.”

High-risk groups

A study published in 2007 on an interventional case series of post-LASIK infections caused by MRSA found that nine of 13 patients were either health care workers or had known exposure to a health care setting. According to co-author Eric D. Donnenfeld, MD, the study, aside from noting the first cases of infectious keratitis due to MRSA, also pointed to a need for increased vigilance.

Eric D. Donnenfeld

“I think that we know that patients within the health care industry, whether they are doctors, nurses, orderlies, have a greater risk of being colonized by MRSA and S. epidermidis,” Dr. Donnenfeld, an OSN Cornea/External Disease Board Member, said. “When you evaluate a patient who has this background for any type of ocular surgery, you have to presume they are colonized and treat them more aggressively.”

Other high-risk groups have been identified in studies: patients who participate in athletics or who frequent gyms; patients in nursing homes; patients with a history of dialysis, previous colonization with MRSA or immune deficiency; and spouses of patients with relevant health care environmental exposure.

But the potential for MRSA infection is not limited to select groups. The 2007 study also described infectious keratitis after cataract surgery in three patients with no health care exposure. According to Dr. Donnenfeld, this novel finding suggests a need for greater awareness.

“I think we have to presume now that every patient is at risk for having MRSA. And the number of community-acquired infections is increasing a lot more quickly than hospital-acquired,” he said.

MRSA on the rise

Many of the epidemiologic studies to date in the ophthalmic literature have noted increasing prevalence of MRSA in local settings. Taken on the aggregate, these studies would suggest a problem that is not just regional.

Growing evidence points to MRSA, specifically community-acquired MRSA, as a potential threat in the ophthalmic setting. In a poster presented at the 2008 meeting of the American Academy of Ophthalmology that reviewed swabs prospectively collected from refractive surgery candidates at 10 U.S. institutions, 321 of 399 patients had a positive lid culture, and 229 had a positive conjunctiva culture for staphylococcal species. Within the positive cultures, S. epidermis was the predominant strain followed by S. aureus.

Significantly, the study was conducted in patients who were not health care workers. “Approximately half of the staph species that we cultured were methicillin resistant, and there was not an increased risk in health care workers in this study,” Dr. Donnenfeld, a co-author of the poster, said. “That was taken from 10 different institutions around the country, so that tells us it’s not a local entity.”

A report based on data submitted by more than 200 laboratories across the United States to The Surveillance Network also showed a trend in increasing methicillin resistance among S. aureus. That study reported an increase in the proportion of methicillin resistance among S. aureus ocular isolates from 29.5% in 2000 to 41.6% in 2005.

“The prudent course would be to consider the possibility of methicillin or multidrug resistance with any S. aureus ocular infection, even in the absence of recognized risk factors,” the study authors said.

The report concluded that “based on the rate of increase in the [The Surveillance Network] database, MRSA cultures from serious ocular infections could be more common than methicillin-susceptible S. aureus within 2 to 3 years.”

The report also found that MRSA isolates had a high level of multidrug resistance, defined as resistance to three or more antimicrobial agents. Only trimethoprim maintained adequate activity against MRSA (95%), while decreased susceptibility was noted for ciprofloxacin (31.6%), gatifloxacin (29%), levofloxacin (26.5%), moxifloxacin (27.4%) and tobramycin (44.9%).

“Those fluoroquinolones — gatifloxacin, moxifloxacin, levofloxacin — track the same, so if it’s resistant to one, it’s resistant to the others,” Penny A. Asbell, MD, MBA, the lead author of the report said. And if they are resistant to those three, “they are also going to be resistant to azithromycin, penicillin, perhaps reduced sensitivity to tobramycin, and the only one that we found might be effective is trimethoprim.”

Penny A. Asbell

A second report, also written by Dr. Asbell, OSN Contact Lenses Section Editor, found high levels of methicillin resistance among S. aureus isolates. Her report was from a separate nationwide surveillance program, Ocular TRUST (Tracking Resistance in the United States Today), which collected ocular isolates from seven eye hospitals and 28 community hospitals in 19 states.

“More than 50% of the isolates that were S. aureus were methicillin resistant,” Dr. Asbell said in reference to the surveillance data. “This pretty much mirrors the information from pneumonia or other sources and types of infections, so I don’t think it’s peculiar to the eye. In fact, it is what we would expect: an increase in all infections across the board, and it’s not just related to eye care, but all microbiology today.”

Community-acquired MRSA

Within the growing incidence of MRSA, community-acquired strains are rapidly becoming the predominant threat. According to a widely cited review of all MRSA infections encountered in the Parkland Health and Hospital System in Dallas, looking specifically at the etiology and epidemiology of ocular infections, Preston H. Blomquist, MD, noted a flatline of nosocomial infections but a rise in the number and proportion of community-acquired strains of MRSA.

According to the analysis, the predominance of community-acquired ophthalmic MRSA strains closely mirrored the pattern of all MRSA infections from 2000 through 2004.

“In the hospital, 70% were community-acquired. For the ophthalmic setting, which accounted for 1.3% of our infections, 76% were community-acquired,” Dr. Blomquist said. “It causes not only non-severe infections, but also some very severe infections that can be sight-threatening.”

Methicillin resistance evolved similarly to penicillin resistance. According to Dr. Blomquist, penicillin resistance emerged in the nosocomial setting within 2 years of its release, but resistance was not noted among strains circulating in the community until decades later.

Similarly, S. aureus strains circulating in the community are increasingly demonstrating beta-lactam resistance patterns.

“In the majority of hospitals, strains of S. aureus are predominantly methicillin resistant, and it’s not just hospitals now, it’s also in the community,” Dr. Blomquist said.

Identifying potential community-acquired MRSA may be a difficult proposition, however. In the Parkland study, patients with nosocomial ophthalmic MRSA tended to be younger than patients with community-acquired (average 24 years vs. 35.6 years, respectively). That finding was in contrast to the general hospital setting where patients with nosocomial MRSA were typically older (40.9 years) than patients with community-acquired MRSA (37.4 years).

Patient history may offer a clue to include community-acquired MRSA in the differential diagnosis. In the study, two patients initially diagnosed with a spider bite were later correctly identified as having preseptal cellulitis caused by MRSA. Other risk factors – including history of contact with a correctional facility either as a prisoner or as a visitor, history of playing sports or contact with a sports facility, and recurrent skin or soft tissue infection – were also identified.

“If you’re treating somebody who keeps coming back, it could be MRSA. People with MRSA colonization are at more risk for developing an infection than people with methicillin-sensitive S. aureus,” Dr. Blomquist said.

Genetics affect expression of disease

More recently, Dr. Blomquist said, there has been a leveling of community-acquired infections in the Parkland system. However, it is difficult to attribute that to less prevalence, and instead, the drop in community-acquired cases may be due to use of empiric therapy that covers for MRSA with less use of primary cultures.

In reviewing ophthalmic MRSA infections, Dr. Blomquist noted that half of all infected patients were started on empiric therapy that was ineffective against MRSA. More recently, the Parkland system has adopted the use of front-line antibiotic agents that are known to be effective against MRSA.

“The good news is that for community-acquired MRSA, you don’t have to go to the big gun because many of the older antibiotics still work, because unlike nosocomial strains of MRSA, community-acquired MRSA usually are sensitive to some of the other antibiotics,” Dr. Blomquist said.

As in earlier studies, the ocular MRSA isolates in the Parkland setting were sensitive to trimethoprim-sulfamethoxazole. Also, MRSA strains endemic to the Dallas area are understood not to develop inducible clindamycin resistance that is sometimes seen in community-acquired strains that are erythromycin-resistant by virtue of the erm (erythromycin ribosome methylase) gene, so clindamycin is also considered a highly effective agent, according to Dr. Blomquist.

Distinct genetic identities of the two pathogens may explain the differences in drug resistance between hospital-acquired and community-acquired strains. Community-acquired MRSA strains are typified by the presence of the SCCmec type IV mobile element, which contains the gene that confers low affinity for beta-lactam antibiotics. The type IV genetic element is smaller than types I, II or III, and so is more easily transferred horizontally from staph to staph.

Community-acquired MRSA is also more easily spread from patient to patient, according to James P. McCulley, MD, FACS, and because it produces increased levels of Panton-Valentine leukocidin, it more readily kills the body’s natural defense mechanisms.

“The genetic differences between the two manifest themselves in some very different expressions of disease and behavior of the bacteria,” Dr. McCulley said.

Genetic testing is impractical in the clinical setting. Instead, Dr. McCulley said, patient-specific factors may be telling: a young, otherwise healthy person, especially in the context of potential exposure to other possible carriers such as family members, fellow sports team members or a prison environment. The nature of the disease may also be a clue because community-acquired MRSA most often causes skin and soft tissue infection, so a presentation around the lids may be a sign.

“There are genetic differences between the two, but it’s not practical to do that testing. Plus, it would take so long, it wouldn’t be clinically helpful. It’s helpful epidemiologically and in doing studies, but it doesn’t help in treating patients,” Dr. McCulley said. “If one has a methicillin-resistant infection, one would need to lean on the history for the best ideas on whether it is hospital- or community-acquired. If it’s community, one has to be more concerned about a more rapidly progressive, much more severe infection,” he said.

Antibiotic choices

Recently, vancomycin has demonstrated the greatest bactericidal effect against MRSA, but reports have surfaced of MRSA in the nosocomial setting with resistance to that antibiotic.

“Anytime you overuse antibiotics or use them inappropriately, you are getting a selective pressure for these strains to survive,” Dr. Blomquist said. “The Hospital Infection Control Practice Advisory Committee did come out strongly advising against the routine use of vancomycin for prophylaxis.”

Intracameral prophylaxis may have a role in the ophthalmic surgery setting to help offset risk of postsurgical infection. Based on experiences from a study sponsored by the European Society of Cataract and Refractive Surgeons, there have been calls from some corners of the ophthalmic community to include universal – or at least widespread – intracameral prophylaxis with either a fluoroquinolones or vancomycin, with the goal of reducing postoperative infection, including MRSA.

Critics have countered that intracameral prophylaxis, while effective during the surgical setting, does not stay in the eye long enough to offer protection over the duration of the postsurgical period. As well, cost and the risk of dilution errors may outweigh the benefits of that strategy. In addition, Dr. Blomquist said, widespread vancomycin use is undesirable because it is not as effective against methicillin-sensitive S. aureus (MSSA) as other antibiotics.

“The morbidity of MRSA comes from our inability to treat it with agents that are as efficacious as are available for MSSA,” Dr. Blomquist said.

Newer fluoroquinolones, including gatifloxacin, moxifloxacin and levofloxacin, have broad-spectrum activity and low likelihood of encouraging resistance. According to Dr. Asbell, that may be due to the fact that these newer antibiotics target two separate enzymes that inhibit bacterial growth, as opposed to only one target in earlier fluoroquinolones.

The key to selecting an antibiotic in the face of suspected MRSA, Dr. Asbell said, depends on the agent’s particular concentration, bioavailability, solubility and safety. An agent with a broad spectrum of activity is theoretically useful, but defined minimum inhibitory concentrations determined in an in vitro setting may not account for the unique circumstances in treating ocular infection.

“The concentrations we can get in the eye may be much higher than what we can get in the blood after taking a pill or IV treatment, so topical treatment may not really be equivalent in terms of resistance or sensitivity for systemic treatment. It’s important for information, but it’s only one piece of information,” Dr. Asbell said. “Some antibiotics may be great in the lab, but it may not get into the cornea or whatever the target tissue is, and so they are not going to be effective either.”

Despite the success of more recent fluoroquinolones, ophthalmologists still face a bit of a conundrum due to the stagnancy in antibiotic development, according to Dr. Donnenfeld.

“We need better antibiotics to treat these potential infections because they are the No. 1 cause of infection after refractive surgery and cataract surgery,” he said.

“We know that PRK has an increased risk because of the prolonged epithelium defect. Perhaps we need to be more aggressive in treating PRK patients that we do with LASIK patients because of that increased risk,” he said.

Because of the increased risk for postsurgical infection among patients with presurgical colonization with MRSA, it is standard practice in some medical subspecialties, including orthopedics, to screen universally for the pathogen. But this may not be necessary in the eye care setting.

“I don’t think in ophthalmology we need to take those extreme measures,” Dr. Donnenfeld said.

Dr. McCulley agreed with that assessment and suggested a more patient-specific approach to both screening and prophylaxis.

“We typically are not going to screen or culture individuals unless we see something clinically that raises our concern,” Dr. McCulley said. “Otherwise, we’re not going to do anything differently, except that it would be wise to prophylax pre- and postop any intraocular or keratorefractive procedures with an antibiotic that is more apt to be effective.” – by Bryan Bechtel

Should ophthalmology adopt the practice of intracameral prophylaxis during cataract/refractive surgery?

References:

• Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antibiotic susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008;145(6):951-958.
• Asbell PA, Sahm DF, Shaw M, Draghi DC, Brown NP. Increasing prevalence of methicillin resistance in serious ocular infections caused by Staphylococcus aureus in the United States: 2000-2005. J Cataract Refract Surg. 2008;34(5):814-818.
• Blomquist PH. Methicillin-resistant Staphylococcus aureus infections of the eye and orbit (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2006;104:322-345.
• Cavuoto K, Zutshi D, Karp CL, Miller D, Feuer W. Update on bacterial conjunctivitis in South Florida. Ophthalmology. 2008;115(1):51-56.
• Chung JL, Seo KY, Yong DE, et al. Antibiotic susceptibility of conjunctival bacterial isolates from refractive surgery patients [published online ahead of print April 23, 2009]. Ophthalmology. doi:10.1016/j.ophtha.2008.12.064.
• Deramo VA, Lai JC, Winokur J, Luchs J, Udell IJ. Visual outcome and bacterial sensitivity after methicillin-resistant Staphylococcus aureus-associated acute endophthalmitis. Am J Ophthalmol. 2008;145(3):413-417.
• Endophthalmitis Study Group, European Society of Cataract & Refractive Surgeons. Prophylaxis of postoperative endophthalmitis following cataract surgery: Results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007;33(6):978-988.
• Freidlin J, Acharya N, Lietman TM, Cevallos V, Whitcher JP, Margolis TP. Spectrum of eye disease caused by methicillin-resistant Staphylococcus aureus. Am J Ophthalmol. 2007;144(2):313-315.
• Kotlus BS, Wymbs RA, Velozzi EM, Udell IJ. In vitro activity of fluoroquinolones, vancomycin, and gentamicin against methicillin-resistant Staphylococcus aureus ocular isolates. Am J Ophthalmol. 2006;142(5):726-729.
• McKinley SH, Yen MT, Miller AM, Yen KG. Microbiology of pediatric orbital cellulitis. Am J Ophthalmol. 2007;144(4):497-501.
• Solomon R, Donnenfeld ED, Perry HD, et al. Methicillin-resistant Staphylococcus aureus infectious keratitis following refractive surgery. Am J Ophthalmol. 2007;143(4):629-634.
• Witherspoon SR, Blomquist PH. Methicillin-resistant Staphylococcus. Ophthalmology. 2007;114(7):1420-1421.

• Penny A. Asbell, MD, MBA, can be reached at Mount Sinai School of Medicine, One Gustave L Levy Place, Box 118, New York, NY 10029; 212-241-7977; fax: 212-289-5945; e-mail: penny.asbell@mssm.edu.
• Preston H. Blomquist, MD, can be reached at University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390; 214-648-3770; fax: 214-645-9482; e-mail: preston.blomquist@utsouthwestern.edu.
• Eric D. Donnenfeld, MD, can be reached at OCLI, 2000 North Village Ave., Rockville Centre, NY 11570; 516-766-2519; fax: 516-766-3714; e-mail: eddoph@aol.com.
• Francis S. Mah, MD, can be reached at University of Pittsburgh Medical Center, Eye and Ear Institute, 203 Lothrop St., 8th Floor, Pittsburgh, PA 15213; 412-647-2200; fax: 412-647-5119; e-mail: mahfs@upmc.edu.
• James P. McCulley, MD, FACS, can be reached at UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390; 214-648-3407; fax: 214-648-9061; e-mail: james.mcculley@utsouthwestern.edu.