Questions remain regarding antibacterial therapy

November 1, 2008

Times have changed, and, with them, practices in antibacterial therapy. Questions remain, however. Has progress been made over the decades, and what does the future hold?

Key Points

Sir Duke-Elder also wrote that in acute conjunctivitis of an infective origin, "the ideal preliminary measure is to determine the causal agent and its susceptibility to antibiotic drugs, an appropriate drug being given topically with a frequency depending on the seriousness of the case."1 In this way, infections were treated according to their cause, at least when possible. Times have changed, and, with them, practices in antibacterial therapy. Questions remain, however. Has progress been made over the decades? What does the future hold?

Good and bad of bacteria

Another possible pathway to virulence is the inter-bacteria communication system of quorum sensing: regulation of gene expression in response to increasing cell density.3 Further, refractive and cataract surgery may allow bacteria to infiltrate the innate immunity of the eye, causing iatrogenic infection.

Resistance

Almost as soon as penicillin became available for use in the early 1940s and when it was commercialized for military use during World War II, bacteria responded to the threat on their survival by developing resistance. As more antibacterial agents were developed, numerous (sometimes remarkably complex) molecular resistance mechanisms have emerged in many bacterial pathogens.

Four main mechanisms of resistance are enzymatic inactivation of antibiotic, efflux pumps to physically remove the antibiotic from the cell, modification of the antibiotic target site, and the production of an alternate metabolic pathway to bypass the drug's action.4 Today, methicillin-resistant Staphylococcus aureus (MRSA) is a menacing threat following ophthalmic surgery.

Thought to be the result of evolution from penicillin-resistant strains of S. aureus, MRSA cases were reported as early as 1961 in the United Kingdom.5,6

A recent report now finds that community-associated MRSA infections pose an even more serious threat, with their "remarkable ability to recruit, activate, and subsequently lyse human neutrophils," attacking the innate infection response system of human cells.7 With poor visual outcome being a general result of MRSA infection,8 the greatest threat of MRSA may be its growing resistance to antibacterials beyond methicillin.

Currently available antibiotics use different mechanisms of action to produce antibacterial effects. Macrolides, for example, achieve antibiosis through inhibition of mRNA translation, whereas fourth-generation fluoroquinolones disrupt DNA replication by targeting DNA gyrase and topoisomerase IV.4,9 Beyond the mechanisms of antibacterial agents, classes and individual agents exhibit different antibacterial activities.

A highly important parameter for susceptibility measurement is the minimum inhibitory concentration (MIC) value, defined as the minimum concentration to inhibit the growth of a given bacterial strain. Although the translation from in vitro susceptibility to in vivo clinical result is not perfect, the MIC gives us the ability to compare activities of antibiotics against various pathogens.10

In an effort to minimize institutional and regional bias, the Ocular Tracking Resistance in the U.S. Today (Ocular TRUST) program incorporates isolate susceptibility testing results across the country. The most recent report demonstrates that of all MRSA isolates tested, 85% were resistant to fluoroquinolones (moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin), using the Clinical and Laboratory Standards Institute susceptibility breakpoints. Interestingly, trimethoprim, an older, now rarely used antibiotic (a component of polymixin B/trimethoprim 10,000 units -1 mg/ml) displayed the lowest resistance rate of all anti-infectives tested, in 6.1% of MRSA strains.11

Studies of an antibiotic on the horizon, besifloxacin, demonstrate promising results as well. The intriguing aspects of this new drug include that it never has been used systemically and that its molecular structure has been modified for enhanced antimicrobial activity.

Current therapy

In contrast to Sir Duke-Elder's explanation of the practice in the 1960s, current antibiotic therapy in ophthalmology relies less on culturing and more heavily on prophylaxis. Although Sir Duke-Elder mentions that his "blunderbuss" should only be used if the situation requires it to quickly treat the infection, today's ophthalmologists often use broad-spectrum fluoroquinolones for ophthalmic surgery prophylaxis.

With the severe and sight-threatening nature of endophthalmitis, for example, the desire to avoid infection altogether is well-grounded. Unfortunately, with increasing resistance rates and the challenges of determining efficacy of prophylactic antibiotic treatment in an infection occurring in approximately 0.05% to 0.286% of cataract extractions, it is difficult to definitively state whether prophylaxis is the best practice.12,13

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