Antimicrobial Resistance in Ophthalmology
David G. Hwang
Antimicrobial resistance is an advancing problem in ophthalmology. Resistant microorganisms increase the risk of complications and raise the cost of eye care. Understanding the epidemiology and mechanisms of resistance can guide the appropriate use of antibiotics in the management and prevention of microbial conjunctivitis, keratitis, endophthalmitis, and other ocular infections.
HISTORICAL BACKROUND
In the 1930s, chemists in Germany found that a dye (prontosil) could protect mice against streptococcal challenge; the active ingredient was sulfonamide.1 Sulfonamides ushered in the era of antimicrobial therapy, but penicillin was the agent that most changed the treatment of infectious diseases. Discovered in 1928, its large-scale production occurred during World War II; penicillin was considered the first “miracle drug.”2 For 10 years after the end of the war, penicillin and other antibiotics were available without prescription. The advertising message from pharmaceutical companies was that these new drugs would work for many infections and, if ineffective, would at least do no harm.2 Antibiotics were routinely given to patients with the common cold or influenza and were used prophylactically for many surgical procedures.
During the mid-1940s, articles appeared in the medical literature describing strains of Escherichia coli and Staphylococcus aureus that were resistant to penicillin.3,4 A growing list of reports during the 1950s and 1960s extended these observations to other antibiotics: streptomycin,5,6,7 chloramphenicol,8,9,10,11,12 tetracycline,13,14 actinomycin,15 erythromycin,16,17,18 aureomycin,19,20 and methicillin.21 Several microorganisms were found to be resistant to one or more antibiotics, including Enterobacteriaceae,22,23 pneumococci,16,24 Haemophilus,25 Pseudomonas,10 and Bacillus.13,15,17 However, the potential clinical importance of acquired antibiotic resistance among bacterial species was initially ignored by the medical community. The Surgeon General proclaimed to Congress in 1969 that it was time to “close the book on infectious disease.”25
As an increasing list of pathogenic bacteria acquired resistance to multiple antibiotics, the world entered a postantibiotic era.26,27,28 Examples of this phenomenon include the following: (1) S. aureus is now invariably resistant to penicillin and increasingly resistant to methicillin and other semisynthetic penicillinase-resistant penicillins, (2) 15% to 25% of the strains of Streptococcus pneumoniae are relatively resistant to penicillin and an increasing percentage are resistant to many fluoroquinolones, (3) a high percentage of enterococci are resistant to ampicillin and aminoglycosides and some are resistant to vancomycin, and (4) 30% to 40% of Haemophilus influenzae strains and almost all Moraxella are resistant to the β-lactam antibiotics.2,29 Multidrug-resistant strains have become commonplace—Shigella, Salmonella, Escherichia, Enterobacter, Klebsiella, Proteus, Serratia, Pseudomonas, Streptococcus, and mycobacteria are often resistant to multiple.26,30,31,32,33,34,35,36,37
The economic costs of antibiotic resistance are difficult to determine,38 but the Centers for Disease Control and Prevention (CDC) has estimated that the costs related to treatment of infections caused by antibiotic-resistant organisms in the United States is more than $4 billion annually.39 Antimicrobial resistance among ocular infections contributes to substantial economic expenses.
MECHANISMS OF ANTIBIOTIC RESISTANCE
Bacteria have thrived for billions of years in an environment containing naturally occurring antibacterial compounds elaborated by other microorganisms. Several mechanisms have evolved to resist the effects of antimicrobial agents (Table 1). The primary biochemical approaches that mediate bacterial resistance to antibiotics involve genetic mechanisms that allow for altered phenotypic expression and transmission of resistance genes.
Table 1. Mechanisms of Antimicrobial Resistance | ||||||||||
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TARGET MODIFICATION
Many bacteria acquire resistance to antibiotics through modification of an antibiotic-binding protein or nucleic acid target.
β-Lactam antibiotics (penicillins and cephalosporins) bind to transpeptidases and transcarboxypeptidases located on the cell membrane of susceptible bacteria, thereby preventing cross-linking of linear glycopeptides into the peptidoglycan complex and final cell wall assembly.1 In some resistant bacteria (e.g., methicillin-resistant S. aureus), the penicillin-binding proteins are altered, and the β-lactam antibiotic is unable to bind to its target.
The binding of quinolones to deoxyribonucleic acid (DNA) gyrase and topoisomerase IV inhibits normal bacterial replicative and transcriptional activity. Modification of the α (and perhaps β) subunit of DNA gyrase and/or topoisomerase IV through chromosomal mutation prevents quinolone binding and the attendant expression of antibacterial activity.40
Other examples of a modified target and the corresponding antibiotic include ribonucleic acid (RNA) polymerase and rifampin, methylated 23S RNA and erythromycin/clindamycin, dihydropterate synthetase and sulfonamides, and dihydrofolate reductase and trimethoprim.1
REDUCTION IN TARGET EXPOSURE
Target exposure can be reduced through mechanisms that either decrease the uptake of antibiotic and/or increase its rate of efflux. Such mechanisms of resistance, because they may affect permeation or efflux of multiple different antibiotic substrates, may contribute to the phenomenon of multi-drug resistance that has been increasingly observed in recent years.
Gram-negative bacteria have channels (called porins) in their outer lipid membrane through which β-lactam antibiotics pass to reach the penicillin-binding proteins.1 Modification or loss of an outer membrane protein can prevent antibiotic ingress into the bacterium, thus, eliminating binding to the target and averting the bacteriostatic and bactericidal effects. Pseudomonas aeruginosa becomes resistant to imipenem through this mechanism.
Some bacteria (e.g., Haemophilus, Vibrio, Aeromonas, and Moraxella) become resistant to tetracycline by acquiring a gene that encodes for a cytoplasmic membrane efflux protein that can pump a number of antibiotic substrates out of the cell at a rate equal to or greater than its uptake.41 Other species (e.g., Bacillus subtilis) have a single copy of an efflux protein gene but only become resistant when the copy number is increased. Fluoroquinolone resistance in S. aureus can occur by a similar mechanism of increased expression of the NorA efflux pump.
ANTIBIOTIC INACTIVATION
Some bacteria produce enzymes and other products that neutralize the activity of antimicrobial agents.
Within a few years of widespread penicillin G use, most strains of S. aureus were penicillin-resistant, with resistance being mediated by an exoenzyme (β-lactamase) that catalyzes the hydrolysis of the β-lactam ring to an inactive form.1 β-lactamase producing bacteria can also inactivate many of cephalosporins.
Chloramphenicol is susceptible to enzymatic inactivation by certain gram-negative and gram-positive organisms that synthesize chloramphenicol acetyl-transferase.1 Once it has been acetylated, chloramphenicol exhibits substantially less affinity for bacterial ribosomes, and intracellular protein synthesis is no longer suppressed.
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