Corneal Clarity

Battle of the Bacteria

By Thomas John, MD

Microorganisms such as bacteria can threaten the very existence of man. While bacterial invasion can involve both human and non-human tissues, our primary interest is on ocular tissue invasion. This type of bacterial invasion encompasses a spectrum from relatively minor infections such as conjunctivitis and blepharitis to more serious infections including keratitis, corneal ulceration and endophthalmitis (See Figure 1) that can be devastating, with possible visual compromise or even blindness. So, what is our ammunition against this enemy?

Figure 1. Bacterial keratitis. IMAGE COURTESY OF THOMAS JOHN, MD

Waging War

In addition to our own immune system, man has created defensive ammunition against this enemy: antibiotics. In order to understand the significance of the battle of the bacteria, it is relevant to review the past, examine the present and look ahead to the future of our ammunition in support of man's existence. Often, such in-vivo battles result in collateral damage to human tissues that adds to the insult of infection.

When penicillin was discovered, that event was thought to be the end of the battle of the bacteria, with some even calling it the magic bullet. Accidentally discovered by Sir Alexander Fleming in 1929, penicillin was mass-produced in 1943, and man's victory over bacteria was celebrated globally. However, the victory was short-lived. Within four years of this new antibiotic launch, bacterial resistance to penicillin emerged, signifying the competence of these microorganisms to survive adversity. The war was not over after all.

The term antibiotic evolved from antibiosis (Greek: anti – “against”; bios – “life”); it represents a chemical substance produced by one organism that is destructive to another organism. Coined by Paul Vuillemin as early as 1889, “antibiotic” denotes a process by which life could be used to destroy life. Antibiotics may be natural or synthetic. The term biocide refers to any substance that is specifically destructive to microbes and results in killing or slowing the growth of microorganisms. Biocide includes antibiotics, antiseptics and disinfectants.

While antiseptics are chemical agents that are used externally on living tissue to suppress growth of bacteria, disinfectants are used on nonliving surfaces to destroy microorganisms. Unlike antiseptics and disinfectants, antibiotic products are highly specialized. Their function is dependent on entry into a metabolically active cell, and is highly selective with specific cellular targets. This high degree of antibiotic specificity permits bacteria to easily develop antibiotic resistance.

Meet the Resistance

Bacterial resistance to antibiotics stems from multiple mechanisms that bacteria employ for their survival by staying ahead of the treatment curve. Antibiotic resistance refers to a microorganism's ability to survive exposure to an antibiotic. If a bacterium carries multiple resistant genes, it is called multiresistant or a “super bug.” Bacterial resistance to antibiotic can be intrinsic or acquired resistance. Intrinsic resistances are well documented. Acquired resistance refers to bacteria that could be inhibited by some standard measure, but that measure has now become ineffective.

Spread of bacterial resistance to antibiotics may be either via a vertical gene transfer (or vertical evolution) or a horizontal gene transfer. Let's look at vertical gene transfer first. A de novo mutation can result in acquired resistance to antibiotics. This spontaneous mutation frequency for antibiotic resistance is about 10⁻⁸ to 10⁻⁹, which means that one in every 10⁸ to 10⁹ bacteria in an infection will develop resistance via mutation. These resistant genes are directly transferred to bacteria's progeny during DNA replication, called vertical gene transfer. In the presence of an antibiotic selective environment, the wild type (non-mutants) is killed by the antibiotic while the resistant mutant bacteria are allowed to grow and multiply.

In contrast, horizontal (or lateral) gene transfer refers to transfer of genetic material between individual bacteria of the same species or between different species via conjugation, transduction or transformation. Conjugation results in the presence of direct cell-to-cell contact between bacteria and transfer of DNA takes place via plasmids. In transformation, the bacteria incorporate parts of DNA from the external environment where this DNA is normally present secondary to death and lysis of another bacterium. Lastly, transduction results when bacteria-specific viruses (bacteriophages) transfer DNA between closely related bacteria.

Many drug-resistant genes reside on plasmids that help facilitate their transfer to another bacteria. Plasmid is a circular strand of DNA within the bacterial cytoplasm that can replicate independent of the bacterial chromosomal DNA. Plasmids are double stranded, circular and occur naturally in bacteria. Some antibiotic-resistant genes are carried on transposons, segments of DNA that can exist within the chromosome or in plasmids. Use of antibiotics against a population of bacteria can result in an increase in the selective pressure to allow the resistant bacteria to thrive, while the susceptible bacteria get killed. Antibiotic resistance, therefore, creates a significant problem for us to deal with.

On the Front Lines

With resistant bacteria invading the ocular tissues, our ability to effectively deal with such infections is being challenged. Over time we can expect to see an increasing number of ocular infections with multi-drug resistant organisms. Methicill-inresistant Staphylococcus aureus (MRSA) among S. aureus conjunctivitis has shown steady recently. There is rising prevalence of MRSA in serious ocular infections as well. Combating this rapid change in the landscape of ocular infections toward resistant organisms requires vancomycin eye drops prepared by compounding pharmacies and used as off-label medication. Trimethoprim found in Polytrim has been shown to be effective against MRSA, but vancomycin continues to be the drug of choice for treating most MRSA infections.

The bad news, though, is that vancomycin-resistant MRSA has emerged and we need to look for alternative therapies. The 2009 ARMOR surveillance data evaluating five agents — ciprofloxacin, tobramycin, moxifloxacin, azithromycin and besifloxacin — against S. aureus, showed that besifloxacin was the most potent agent evaluated against S. aureus, including MRSA. Besifloxacin is the one agent that is available only as an ophthalmic eye drop and it has never been used systemically. The MIC90 of besifloxacin was the same as vancomycin; namely, one.

What About Turncoats?

In addition to pathogenic bacteria invading human tissues, we must consider the typically harmless bacteria that live with their human host as the normal bacterial flora. Can these suddenly change to become potentially deadly to their host and thus risk their own survival? Recent research has shown complex interactions among bacterial species that live in the human body. When differing bacterial species compete for space, this can change one dormant bacterial species into a potentially pathogenic species.

For example, when normally existing S. pneumoniae in the nasal passages (as many as two in five people can carry the organism asymptomatically) are forced to share space with Haemophilus influenzae, this can result in S. pneumoniae becoming more pathogenic with increased proliferation of those strains with a thick sugar capsule. Such transformation from dormant to more harmful bacteria can threaten the human host, especially when these organisms enter the bloodstream. The question to explore is whether such bacterial transformation can occur in the normal conjunctival bacterial flora.

Worth Fighting For

Looking back, the introduction of antibiotics and immunization are thought to have contributed to the increased average life expectancy of man by about 20 years in developed countries instituting these measures. However, a rapidly changing global scene — namely, the crisis of antibiotic resistance — is threatening these gains. Multidrug-resistant bacteria are threatening man's existence globally. Clearly, such resistance to current day antibiotics can have serious consequences.

An increasing prevalence of antibiotic-resistant bacteria, combined with a decline in the number of new antibiotic drugs, raises concern about losing ground in the battle against bacteria, and reverting to a level of medical health that existed prior to the introduction of antibiotics. Corneal and systemic infections with multidrug-resistant organisms require potent ammunition for man's long-term survival and retention of eyesight.

The phenomenon of bacterial resistance raises the question of bacteria possibly being “smarter” than humankind's efforts to fight them. It is crucial that we divert revenue for research and development towards newer, effective antibiotics, that we consider regulations directed towards use of antibiotics in animal feed to promote growth and prevent infections (not treat infections), limit agricultural use of antibiotics, avoid antibiotic prescriptions for viral infections, educate the public about completing antibiotic treatment, and look for newer therapeutic modalities (e.g., corneal cross-linking) that may kill bacteria. Otherwise, this battle of bacteria against man may be lost forever in favor of the bugs! OM

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.