Corneal Clarity

A battle of biblical proportions

Growing bacterial resistance poses a global problem.

By Thomas John, MD

Since the discovery of antibiotics, the battle between humans and bacteria has been comparable to the one between David and Goliath, as tiny antibiotics have significantly saved human lives by killing bacteria. But the enemy soon learned to take the battle to us: Microorganisms quickly developed resistance to man-made antibiotics.

In 1928, Sir Alexander Fleming discovered penicillin from the mold Penicillium notatum, giving birth to the modern antibiotic era and the mass production of penicillin in 1943.¹ Four years after this victory of man over bacteria, Staphylococcus aureus resistance to penicillin surfaced.²

Neither side has yielded since.

Here, I’ll discuss the current state of bacterial resistance and how it impacts ophthalmology.

OUR COMMON ENEMY

Bacterial resistance to antibiotics may surface by natural selection through random mutation or by the application of an evolutionary stress — namely, evolution through natural selection. Such antibiotic resistance can be attained via horizontal acquisition of resistance genes through plasmids or transposons, by chromosomal mutations or by foreign DNA incorporation into bacterial chromosome.

Bacterial infections cause ocular problems, including corneal ulcers.
COURTESY: THOMAS JOHN, MD

Multi-resistant bacteria, or superbugs, carry several resistant genes, and their impact is broad. Every year, antibiotic-resistant organisms infect more than 2 million people in the United States, and about 23,000 people die as a direct result of such infections.³ Such antibiotic resistance adds $20 billion in excess direct health care costs in addition to productivity losses, costing as high as $35 billion every year.³ In Europe, this number is even higher, as about 25,000 patients die on a yearly basis secondary to drug resistant bacteria, costing at least 1.5 billion euros each year in productivity losses.⁴

OCULAR INFECTIONS

An overall increase in antibiotic-resistant bacteria is reflected in the rise in ocular infections. However, recent reports link the emergence of resistant bacteria in the eye to prior topical antibiotic therapy.⁵ MRSA was found to be increasing in serious ocular infections.⁶ MRSA cultures from serious ocular infections were projected to be more common than methicillin-susceptible S. aureus within two to three years.

The Surveillance Network reviewed data from 200-plus laboratories dated between January 2000 and December 2005 to determine the prevalence of methicillin-resistant S. aureus infections. Researchers found that MRSA cases increased to 41.6% in 2005 from 29.5% in 2000.⁷ Also, pediatric ocular and periocular MRSA cases are increasing.⁸

In the ophthalmic field, we have the advantage of a newer besifloxacin, which has a broad-spectrum of activity and is not used systemically. However, we need to be vigilant since bacteria continue to show resistance over time, even with the development of new antibiotics.

MECHANISMS OF BACTERIAL RESISTANCE

The four major mechanisms by which microorganisms exhibit resistance to antimicrobials are:

1. Direct action on the drug. Drug inactivation or alteration, for example, β-lactamase in penicillin-resistant bacteria causing enzymatic deactivation of penicillin G.

2. Indirect effect on the antibiotic. Target site changes, for example, MRSA altering the penicillin-binding proteins, the binding site of penicillins.

3. Alteration of the metabolic pathway.

4. Decreasing drug accumulation. Either reducing drug entry into the bacterial cell by decreasing the permeability of the drug, or by increasing the efflux or pumping the drugs out of the bacterial cell.

Additionally, bacterial biofilms, which have been detected in contact lenses, scleral buckles, suture materials and IOLs, can provide bacterial protection against antibiotics.⁹ Within biofilms, bacteria can be in the viable but nonculturable (VBNC) state and fail to grow on routine culture media. However, they are still alive and, regardless of the low levels of their metabolic activity, are culturable on resuscitation.⁹ This mode of VBNC state is a bacterial survival strategy. Such biofilm formation adds to bacterial protective mechanisms against antibiotics and the continued existence of the ocular infection.

IMPACT ON THE CORNEA

Corneal infectious keratitis and ulceration are ocular emergencies that require topical antibiotics as a therapeutic mainstay. At the initial examination, it is unclear whether we are dealing with one or more organisms, and if any resistance to antibiotics exists. Hence, a shotgun approach is preferred with a broad-spectrum antibiotic that covers both gram-positive and gram-negative organisms. Newer fluoroquinolone, such as besifloxacin, can be used as a monotherapy with frequent applications around the clock, depending on the severity of the corneal infection.

Corneal cultures and gram stain can assist in our attempts to identify the offending organism(s). Patients should refrain temporarily from contact lens wear until the infection resolves.

Also, frequent clinical evaluation is an integral part of the initial management. Clinical improvement or deterioration is more important than in vitro culture results in directing therapeutic choices. In the event of medical treatment failure, one may need to change the antibiotics or consider surgical intervention in way of therapeutic keratoplasty.

CONCLUSION

Bacterial resistance is a major, continuing threat that requires constant vigilance, monitoring and revenue allotment. We must make every effort to prevent the spread of bacterial resistance and develop new, more effective antimicrobial agents to fight the resistant microorganisms.

If we shy away from this critical issue, human existence will be on shaky grounds and may end as Goliath did. OM

REFERENCES

Thomas John, MD, a world leader in lamellar corneal surgery, is a clinical associate professor at Loyola University at Chicago, and in private practice in Oak Brook, Tinley Park and Oak Lawn, Ill. E-mail him at tjcornea@gmail.com.