Incidence of MRSA infections of the eye, adnexa increases

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Imagine living in the days prior to antibiotics, when a skin and soft tissue infection was as feared as the diagnosis of cancer. In the pre-antibiotic era, a staph wound infection would frequently progress to septicemia, carrying a mortality rate of 82% (Skinner and Keefer). Now, imagine a time when there is bacterial resistance to all available antibiotics.

One organism that has gained much attention in recent years for its resiliency to multiple classes of antibiotics is Staphylococcus aureus. Most commonly referred to as MRSA, methicillin-resistant S. aureus is believed to be responsible for more deaths annually than AIDS.

According to a report issued by the U.S. Centers for Disease Control and Prevention, MRSA was responsible for an estimated 94,000 life-threatening infections and 18,650 deaths in 2005. That same year, about 16,000 people died from AIDS (Klevens and colleagues).

Antibiotic resistance – a historical perspective

In 1928, Alexander Fleming noticed a zone of inhibition on a discarded culture plate inoculated with S. aureus. He realized that it was penicillium mold that was inhibiting the growth of this bacterium. He would later name this active substance penicillin and determine that it had antibacterial properties even at very dilute (1/800) concentrations. Thinking this penicillin might make a good antiseptic, he tried to find a way to extract it. His efforts were ultimately unsuccessful and he would later move on to other projects.

About 10 years later, Ernst Chain, Howard Flory and a team of scientists at Oxford University would expand on the ideas proposed by Fleming and make human antibiotic chemotherapy a reality. In 1939, they developed a way to isolate penicillin and used it to treat bacterial infections during World War II. For these discoveries, Fleming, Chain and Florey were awarded the Nobel Prize in 1945.

It was not long after the first patient was treated in 1941 that penicillin would be considered a “miracle” cure in the fight against infectious disease. By the end of WWII, penicillin would save countless lives and limbs for allied soldiers. In 1946, penicillin became available to the general public and was used maximally for any and all cases of staph or Streptococcus infections. The antibiotic era had arrived, and the average human life expectancy would increase by at least 8 years.

Unfortunately, it was within only a few years of its introduction to humanity that cases of penicillin-resistant S. aureus would be reported. The same would hold true when the semi-synthetic penicillin, methicillin, was introduced in 1960. MRSA would be reported in the United Kingdom just 1 year later.

History shows us that the development of resistance is inevitable following the introduction of a new antibiotic. Typically, one can estimate an initial rate of resistance of 1% per year. However, with overuse of antibiotics, some strains are becoming multidrug resistant in as little as 8 to 12 years. There are some “super bugs” that have become resistant to all known available antibiotics. With respect to S. aureus, some strains of this organism have become resistant (vancomycin-resistant S. aureus) (CDC, Chang and colleagues) or vancomycin intermediately resistant S. aureus (VISA) (Hiramatsu and colleagues, Fridkin and colleagues) to one of the most historically effective antibiotics against staph over the years, vancomycin.

Emergence of resistance

Antibiotic resistance, simply put, is a type of drug resistance where a bacterium is able to survive exposure to an antibiotic. According to Kenneth Todar, PhD, “Antibiotic resistance in bacteria may be an inherent trait of the organism (e.g., a particular type of cell wall structure) that renders it naturally resistant, or it may be acquired by means of mutation in its own DNA or acquisition of resistance-conferring DNA from another source.”

Spontaneous mutation in a bacterium’s DNA

Bacteria may evolve by selective changes to their DNA caused by genetic recombination or mutations. Mutations come from errors made during the replication of DNA or from exposure to mutagens. Mutation rates vary widely among different species of bacteria. Under optimal conditions, S. aureus divides and replicates every 30 minutes. Therefore, a single S. aureus bacterium can exponentially multiply so that in only 10 hours, a single bacterium has turned into bacteria totaling 1 million in number. In that same 10-hour time frame, it is estimated that more than 300 mutations will have occurred somewhere in the 2.8 million nucleotides that make up their genome and, in 30 hours, every nucleotide base pair will have mutated at least 30 times, according to Pray.

With that said, not all mutations are harmful. Nor do all mutations confer resistance. In fact, most do not. However, once a resistance gene or genes have developed, they are transferred directly to that bacterium’s progeny during DNA replication. This is known as vertical gene transfer. In a selective, nutrient-rich environment, rapid exponential growth of this new resistant organism is then likely. While this rapid vertical growth in bacteria is concerning, of greater concern is their ability to share resistant genes laterally among bacterial species.

Horizontal gene transfer is a mechanism by which genetic material is transferred between the same or different species of bacteria. This is done in three different ways: conjugation, transformation and transduction.

Conjugation is where there is cell-to-cell contact. Plasmids containing genetic material are transferred from one bacterial cell to the other. Some scientists speculate that this is the primary mechanism by which resistant genes get transferred. Transformation is where segments of free DNA material in the extracellular space are acquired by a living bacterium. Transduction involves bacteriophages actively transferring DNA between two bacteria.

External selection pressure

You may have heard the phrase “that which does not kill us makes us stronger.” Any use of antibiotics can increase selective pressure in a population of bacteria to allow the resistant bacteria to thrive and the susceptible bacteria to die off. If a resistant pathogenic strain survives, and the nonpathogenic bacteria are no longer present to compete in a nutrient-rich environment, then the risk of infection or illness from a drug-resistant organism increases. According to Chen and colleagues, through natural selection, bacteria may develop one or more resistance mechanisms that protect them from antimicrobials:

• They may produce enzymes that render the antibiotic ineffective.
• They can alter or eliminate the an-tibiotic target site so there is less affinity.
• They can decrease antibiotic up- take or increase efflux of the drug.
• They can develop bypass pathways around target sites.

S. aureus, most commonly found on the skin and mucous membranes, is very adaptable to external selection pressure. It first exhibited resistance to penicillin by using an enzyme, beta-lactamase, to inactivate the antibiotic. When methicillin was introduced, strains of S. aureus became encoded with the mecA gene, which allowed for the alteration of the penicillin target site (penicillin binding protein), decreasing the affinity for that antibiotic. There are also strains of S. aureus that have undergone serial mutations at key sites (topoisomerase 2 and 4), allowing for the development of an efflux mechanism for fluoroquinolones.

Common practices that lead to antibiotic resistance

History has shown us that antibiotic resistance is an inevitable consequence of antibiotic use, and that the more you use them, the faster resistance will develop. Given this, the inappropriate use of antibiotics in human and veterinary medicine as well as the agricultural industry have been implicated in the spread and more rapid development of resistance and multiresistant bacteria.

The most obvious example of physician misuse of antibiotics is in the management of cold or flu-like symptoms consistent with a viral upper respiratory infection. According to the CDC, 85% of all upper respiratory infections are viral in nature, and the use of antibiotics is unwarranted. Nonetheless, they estimate that patients with viral infections receive prescriptions for oral antibiotics more than 30% of the time. Not only is there no direct benefit of using the antibiotic, but the exposure to the antibiotic increases the chances of that antibiotic being less effective in the future should a bacterial infection occur. According to the U.S. Department of Health and Human Services, the three primary reasons cited by doctors for overprescribing antibiotics are diagnostic uncertainty, time pressure on physicians and patient demand.

The last reason listed above emphasizes the importance of societal education programs on the appropriate use of antibiotics. With proper education, a parent may be less insistent that his or her child receive antibiotics when the symptoms are more clearly viral in nature. When antibiotics are appropriately prescribed, patients need to be educated on the importance of finishing out the prescribed treatment regimen. According to a survey by Pechère and colleagues, roughly one out of five patients stopped taking their antibiotics earlier than prescribed because they were feeling better.

Misdiagnosis of ocular conditions by primary health care providers has also led to the inappropriate use of antibiotic eye drops. In one retrospective analysis of more than a thousand medical records, Statham and colleagues found that primary health care providers started patients on at least one topical antibiotic 18.7% of the time for a red eye before referring. Of those already on antibiotics, it was determined that more than 50% were being treated inappropriately, and antibiotic therapy was discontinued (Statham and colleagues).

The prophylactic use of antibiotics around ocular surgery or in-office procedures may also select for resistant strains of bacteria. Researchers from Vanderbilt University School of Medicine found that repeated exposure of topical antibiotics (fluoroquinolones and azithromycin) after Avastin injections (bevacizumab, Genentech) for macular degeneration was associated with increased multi-drug resistance in coagulase-negative staphylococci when compared to controls (Kim and Hassain). It was also determined that more than 80% of the isolates of coagulase-negative staphylococci were resistant to at least three antibiotics, while more than 65% were found to be resistant to at least five.

Before we lay blame on the shoulders of physicians, it is important to understand that the majority of the antibiotic load introduced to the environment does not come from the treatment of infectious disease in humans.

According to data released by the U.S. Food and Drug Administration in 2009, more than 36 million pounds of antibiotics were sold in the U.S. Approximately 80% of it was used in the agricultural industry. Unfortunately, the majority of antibiotics that are given to livestock are done so to promote growth and prevent infection rather than treat infection.

Irresponsible use of antibiotics in farm animals can lead to the development of resistance in bacteria associated with the animals or in people who consume their meat or byproducts. Such resistance can then be passed on to human pathogens by mechanisms of horizontal gene transfer. Additionally, antibiotics used in feed can run off in dilute concentrations, concentrations that promote resistance, into local streams and groundwater that eventually may find its way into municipal water systems and into our drinking water.

Consider the consequences

According to the CDC, there are a handful of antibiotic classes still showing effectiveness against most strains of community-acquired MRSA (CA-MRSA): clindamycin, tetracycline, doxycycline, minocycline, trimethoprim-sulfamethoxazole, linezolid and vancomycin.

The CDC discourages the use of fluoroquinolones and macrolides for skin and soft tissue infections because of increased resistance. For years, avoparcin, a glycopeptide related to vancomycin, had been used in Australian farm animals to promote growth. It is believed that this is what has led to the emergence of vancomycin-resistant

Enterococcus in humans. As you can see from the FDA report on page 18, doxycycline is being used in significant amounts in the American farming industry. How long will it be before highly virulent strains of CA-MRSA, through external selection pressure and horizontal gene transfer, become resistant to these drugs?

Case report

A 60-year-old Caucasian male presented with a chief complaint of a swollen, tender right lower lid, which had been worsening over the past week. He reported a history of recurrent lid and sinus infections and was now complaining of a mild frontal headache. The patient was using hot compresses with minimal response. He noticed some mucopurulent discharge, but claimed the excessive tearing was more bothersome. He was hoping we would prescribe him some antibiotics to fight the infection.

As an established patient to our practice, his medical and ocular history was reviewed. His medical history was positive for hypertension, sleep apnea, asthma and depression. His systemic medications included lisinopril, Tricor (fenofibrate, Abbott), Zetia (ezetimibe, Merck) and Vicodin (hydrocodone bitartrate and acetaminophen, Abbott) for chronic back pain. He was also on a BiPAP machine nightly.

The patient’s ocular history was positive for refractive amblyopia in both eyes due to high hyperopia and uncorrected astigmatism. He was pseudophakic with open capsules in both eyes. He also had a history of mild floppy eyelid syndrome with secondary lid and lash ptosis in both eyes.

He reported no known drug or medication allergies.

It was also noted that about 20 months prior, the patient was diagnosed by a colleague with a right-side preseptal cellulitis and underwent treatment with oral Augmentin XR (amoxicillin/clavulanate potassium, Dr. Reddy’s Labs), 1,000 mg twice daily for 2 weeks. While the infection responded to treatment, it returned 2 weeks after discontinuing the Augmentin. The patient was switched to oral Keflex (cephalexin, Middlebrook Pharmaceuticals), 500 mg three times daily for 10 days, which appeared to effectively quell the infection.

At the current visit, the patient’s best corrected visual acuity was stable at 20/50 OU. Motilities were full without restriction or discomfort. Pupils were equally round and reactive to light and full fields were normal to confrontation. The patient had dermatochalasis, ptosis and lash ptosis in both eyes.

Slit lamp exam showed right lower lid edema and erythema involving the puncta and canaliculis, minimal discharge from punctum of the right eye, right lower lid punctal ectropian with epiphora, mild mattering and stage 1 meibomian gland dysfunction (frothy tear film) in both eyes, inferior superficial punctate keratitis in both eyes with angular staining in the right eye and trace conjunctival injection in the right eye.

The corneas were clear and there was no cell or flare. The posterior chamber IOLs were well centered, the capsules were open and there was no vitreous cell.

A funduscopic exam was deferred.My impression was skin and soft tissue infection of the right lower lid, including the punctum and canalicula. I decided to do a lid culture and sensitivity testing and prescribed Maxitrol (neomycin and polymyxin b sulfates and dexamethasone, Alcon) ointment twice daily for the right lower lid and Keflex 500 mg three times daily. The patient was asked to return for follow-up in 3 to 5 days or sooner if necessary.

Three days after the culture swab (BBl CultureSwab) was retrieved by our local hospital for microbial identification and susceptibility testing, a final microbiology report was faxed to our office. The offending organism was identified as MRSA.

Based on the fact that our patient had no apparent risk factors for hospital-associated MRSA (HA-MRSA), and the susceptibility profile was favorable to most classes of antibiotics, excluding the beta-lactams and closely related cephalosporins, a tentative diagnosis of CA-MRSA was made.

A local infectious disease specialist was notified of our findings. Considering the recurrent nature of the patient’s infections, the specialist recommended decolonization. As the susceptibility profile suggested this strain was resistant to ceftriaxone, the patient was contacted and asked to discontinue the Keflex and begin Bactrim DS 800/160 (sulfamethoxazole 800 mg/trimethoprim 160 mg, Roche) twice daily for 10 days. He was asked to keep his scheduled appointment, which was in 3 more days.

At his next visit, the patient felt that his lid infection had improved, but brought to my attention a rash that had developed on his face and neck. He reported not feeling ill and felt the rash coincided with his use of Bactrim and was not related to the decolonization protocol: Bactroban (mupirocin 2%, GlaxoSmithKline) nasal ointment to each nare three times daily and a body wash regimen of 4% aqueous chlorhexidine solution daily, both for 5 days). When asked if he was allergic to sulfa drugs, he indicated no known allergy.

Guided once again by the susceptibility report, the patient was switched to a third antibiotic, oral doxycycline 100 mg twice daily, and within 2 weeks the infection had resolved. He was also instructed on the importance of finishing the decolonization protocol prescribed and that the success or failure of this treatment will be determined over the next 6 to 12 months. He was educated on the importance of good hygiene and proper hand washing technique. Lastly, he was given literature on proper disinfection at home or in the workplace.

S. aureus and MRSA

S. aureus is a non-motile gram-positive bacterium that resides on the skin and mucous membranes of humans. Approximately one-third to one-half of all healthy adults are colonized with S. aureus (Casewell and Hill). MRSA is defined as strains of S. aureus that are resistant to the action of methicillin, or by current lab standards, oxacillin and related beta-lactam antibiotics such as penicillin and cephalosporin. Most notable for being a nosocomial infection, MRSA is now gaining attention and, unfortunately, momentum as a community-acquired super bug.

MRSA infections may be subcategorized as HA-MRSA or CA-MRSA. While there are distinct genetic differences between CA-MRSA and HA-MRSA, clinically, the subcategorization is often based on risk factors, as well as susceptibility testing, as shown in the table.

MRSA infections that occur in otherwise healthy people who have not been recently hospitalized (within the past year) or have not undergone a medical procedure (i.e., surgery, catheter or dialysis) are categorized as CA-MRSA strains. Sometimes resembling a spider bite, approximately 75% of CA-MRSA infections are localized to skin and soft tissue and tend to be resistant to fewer antibiotic classes as compared to HA-MRSA strains. However, CA-MRSA strains display enhanced virulence, spread more rapidly and may cause more severe illness than traditional HA-MRSA infections. If treatment is ineffective or untimely, then CA-MRSA can become invasive, affecting vital organs and leading to widespread infection (sepsis), toxic shock syndrome, musculoskeletal infections, osteomyelitis, and/or pneumonia (Gonzalez and colleagues, Martinez-Aguilar and colleagues).

Because of its predilection for the skin and mucous membranes, CA-MRSA is more likely to present in an eye care setting as a blepharoconjunctivitis or periorbital soft tissue infection, according to Miller and Alfonso. A retrospective analysis of records in the Parkland Health and Hospital System found 3,640 patients that cultured positive for MRSA over a 5-year period. Thirty percent of them were determined to be nosocomial infections, while 70% were considered to be CA-MRSA. Only 49 (1.3%) of the patients had ophthalmic MRSA infections. While the majority of these infections presented as preseptal cellulitis or a lid abscess, sight-threatening infections (corneal ulcers, orbital cellulitis, endophthalmitis and blebitis) were also reported.

Doctors out of northern California reported a similar spectrum of eye disease related to MRSA in their retrospective analysis. Freidlin and colleagues found that the majority of the 88 MRSA isolates recovered were from infections involving the lid or conjunctiva (78%), while 14.6% of cases involved the cornea; and cellulitis, dacryocystitis and endophthalmitis all came in at 2.4% each.

Prevalence and resistance patterns in ocular MRSA infections

Multiple reports from varying geographical regions show increasing prevalence of MRSA infections of the eye and adnexa (Asbell and Sahm, Freidlin and colleagues, Cavuoto and colleagues). According to data from Ocular TRUST (Tracking Resistance in the U.S. Today), the world’s largest collection of surveillance data on eye infections, more than 50% of the S. aureus isolates collected were identified as MRSA (Asbell and colleagues). Ocular Trust 3 data (2008) shows that while fluoroquinolones are still effective (85% susceptibility) against methicillin-susceptible S. aureus, they are far less so (30% susceptibility) against MRSA. Conversely, trimethoprim is still showing high susceptibility against MRSA at 94%.

When managing infectious eye disease, it is important to remember that susceptibility testing is based on minimum inhibitory concentration breakpoints for serum level concentrations of an antibiotic. These are concentration levels achieved with parenteral use. Commercially formulated antibiotic eye drops offer concentration levels that are significantly higher, even at standard dosing. Considering the fact that most topical antibiotic formulations are generally well tolerated with frequent dosing, we may be able to achieve high enough concentrations with say, a fourth-generation fluoroquinolone, so as to effectively treat a peripheral MRSA infiltrate, even though the sensitivity report may come back indicating resistance. If a known MRSA carrier presents, Polytrim (polymyxin B and trimethoprim sulfate, Allergan) would be appropriate prophylactically or in combination with a fluoroquinolone in the case of an ulcer.

The same would hold true for fortified antibiotics. Suppose you started a patient on fortified vancomycin (33 mg/mL) every 30 minutes for a central corneal ulcer suspected to be MRSA. Monitoring the patient daily you notice that the infection is improving. Two to 3 days later the sensitivity report indicates “intermediate” resistance to vancomycin. If the fortified vancomycin appears to be effective clinically, you are justified in sticking with that treatment.

In our case report of an infectious canaliculitis, the culture and sensitivity testing helped guide us in his oral treatment. For any patient who presents with recurring lid or periorbital soft tissue infection, culturing can not only help identify the causative organism, but can save the patient a tremendous amount of time and money from ineffective treatments – treatments that could lead to a greater level of resistance and a more invasive infection in the future.

Bacteria have proven to be much more resilient than ever imagined and continue to develop resistance to antibiotics at a concerning pace. While antibiotic resistance is increasing, research and development dollars used in the discovery or development of new antibiotics is decreasing. When you consider that it takes approximately 10 years and costs about 1 billion dollars to see a new drug through the FDA pipeline, one can understand why pharmaceutical companies place more attention on the development of drugs used for chronic diseases such as hypertension or glaucoma rather than medications that are designed for short-term use.

Leaders in infectious disease, medicine, agriculture, government and the pharmaceutical industry must work together in developing protocols to address this problem of antibiotic misuse. Additionally, incentives should be considered in an effort to increase research and development, not only in antibiotic development but technology – technology that can more rapidly detect the causative agents of infection. This would allow for a more targeted approach in treating infections and may slow trends in resistance that we are seeing firsthand today. Until we recognize that antibiotics are a precious limited resource – and actually do something about it – we could find ourselves with mortality rates that rival the pre-antibiotic era.