What physicians need to know about bacterial resistance

Reviewed by Francis S. Mah, MD

La Jolla, CA—In vitro antibiotic resistance—defined as the ability for bacteria to exist and multiply despite a normally achievable serum level of drug that had been previously determined to successfully treat a clinical infection—is an increasing problem worldwide.

Resistance is determined based on serum standards, however. Taking into account the high concentrations of antibiotic achievable in ocular tissues, antibiotic resistance does not necessarily correspond with poor clinical efficacy when treating infections in ophthalmology, said Francis S. Mah, MD.

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Regional data on antibiotic minimum inhibitory concentration (MIC) and resistance rates are factors ophthalmologists should consider when choosing antibiotics for prophylaxis and as empiric treatment, said Dr. Mah, director, cornea and external diseases and co-director, refractive surgery, Scripps Clinic Torrey Pines, La Jolla, CA.

Understanding resistance

Antibiotic resistance can be either an intrinsic trait of bacteria or develop as an acquired characteristic. An example of intrinsic resistance, gram-positive bacteria are generally resistant to polymixin B, which causes cell membrane lysis after binding to lipopolysaccharide that is present in the outer membrane of gram-negative bacteria only.

Acquired resistance develops as the result of a genetic mutation or as a post-translational modification, which involves transfer of a chemical group that modifies the antibiotic binding site or the passive or active ability of the antibiotic to enter the bacteria. Acquired resistance spreads when bacteria with these features reproduce and the bacteria then pass on resistance genes to other living bacteria through a process of lateral gene transfer.

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Acquired bacterial resistance to antibiotics can involve several different molecular mechanisms. Genetic changes, in addition to post-translational modification, can confer protection of the antibiotic targets within the bacteria.

Alternatively, bacteria may develop the ability to produce enzymes that degrade an antibiotic. Or, the organism can add chemical groups to the antibiotic that prevent the drug from binding to its bacterial target. As another mechanism, the genetic changes can lead to modifications in the bacteria that interfere with the ability of the drug to reach its intracellular target.  

Role of mutations

Mutations that result in acquired bacterial resistance can occur as spontaneous events. These so-called point mutations are the primary mechanism of acquired resistance for the fluoroquinolones.

Among the fluoroquinolones, resistance is more common with second- and third- generation agents—ciprofloxacin, ofloxacin, levofloxacin, and purified ofloxacin—than with fourth-generation agents—besifloxacin, gatifloxacin, and moxifloxacin. Resistance to the earlier agents develops with only a single mutation in DNA gyrase, whereas resistance to the newer fluoroquinolones requires mutations in both DNA gyrase and topoisomerase IV.

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“Resistance to a second-generation fluoroquinolone can develop when there is a mutation in 1 of 10 million bacteria, but with the fourth-generation fluoroquinolones, it takes a mutation in 1 in 10 trillion organisms,” Dr. Mah said.

“Therefore, resistance is much less likely to occur with the fourth-generation fluoroquinolones,” he added. “Furthermore, through selective pressure, the earlier generation fluoroquinolones increase the population of bacteria that already have a single mutation, and then resistance to the fourth-generation fluoroquinolone can develop more easily.”

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The development of bacterial resistance is promoted by inappropriate use of antibiotics, including overuse and inadequate dosing that favors survival of resistant organisms through selective pressure.

“Ophthalmologists should participate in being stewards of good antibiotic practice by using appropriate antibiotics, appropriate dosing, never tapering the antibiotic, and following the regional antibiotic susceptibility information from local microbiology laboratories,” Dr. Mah said.  

More: Visit the Anti-infectives Resource Center

Francis S. Mah, MD

E mah.francis@scrippshealth.org

Dr. Mah is a consultant to Alcon Laboratories, Allergan, Bausch + Lomb, and Valeant.