Chapter 65
Antimicrobial Resistance in Ophthalmology
DAVID G. HWANG
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HISTORICAL BACKROUND
MECHANISMS OF ANTIBIOTIC RESISTANCE
GENETIC TRANSMISSION OF RESISTANCE
EPIDEMIOLOGY OF RESISTANT INFECTIONS OF THE EYE
CLINICAL IMPLICATIONS OF ANTIMICROBIAL RESISTANCE
REFERENCES

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.
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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,5–7 chloramphenicol,8–12 tetracycline,13,14 actinomycin,15 erythromycin,16–18 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.26–28 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.26,30–37

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.

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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


MechanismExample
Modification of bacterial component targeted by antimicrobial agentAltered penicillin-binding protein in Staphylococcus aureus
Reduction in antimicrobial uptake into bacterial cellImipenem resistance in Pseudomonas aeruginosa
Increased efflux of antimicrobial agent out of bacterial cellFluoroquinolone resistance in S. aureus
Inactivation of antimicrobial agent by bacterial enzymeBeta-lactamase production by S. aureus

 

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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GENETIC TRANSMISSION OF RESISTANCE
Bacteria contain four basic types of DNA: chromosomal, plasmid, bacteriophage, and mobile genetic elements (insertion elements, transposons). Plasmids and transposons encode a number of characteristics including resistance to antibiotics. Bacteriophages provide one of several vehicles for transmission of antibiotic resistance from resistant to susceptible strains.

CHROMOSOMAL MUTATION

Spontaneous chromosomal mutations occur relatively infrequently (10-5 to 10-9/generation),42 but the mutation rate is strikingly increased following bacterial exposure to various external factors such as irradiation, heat, or chemical agents.43 The probability of an induced mutational event is dependent on the strength and duration of exposure of the external factor, with a greater number of events occurring whenever the inducing factor is applied at a suboptimal level over a protracted period.

One example of antibiotic resistance resulting from one or more chromosomal gene mutation is acquired bacterial resistance to the fluoroquinolones through mutation of the gyrA or parC genes encoding for the α subunits of DNA gyrase and topoisomerase IV, respectively. Mutations in the gyrA or parC gene have been detected in E. coli, Salmonella typhimurium, P. aeruginosa, Enterobacter cloacae, Campylobacter jejuni, Mycobacterium tuberculosis, and S. aureus.40 In E. coli, the quinolone-resistance determining region of gyrA has been located to an area between nucleotides 199 and 318, encoding the amino acids at positions 67 to 106 in the α subunit of DNA gyrase, which is close to its active site at tyrosine-122. The most common mutation sites in E. coli are at nucleotides 247 to 249, where serine in position 83 is usually substituted for leucine, which results in a moderate increase in the in vitro minimum inhibitory concentration (MIC) value from 0.015 to 0.5 mg/L for ciprofloxacin. If an additional mutation were to occur in this region (substitutions at both Ser-83 and Asp-87), then the ciprofloxacin MIC value is markedly increased to 64 mg/L.

GENETIC TRANSFERENCE

Most bacteria become resistant to antibiotics not through a mutation in the chromosomal genome but by acquiring a gene residing in extrachromosomal genetic material (plasmid or transposon) from another organism.2 Plasmids are double-stranded circular DNA molecules containing 7 to 200 genes that replicate autonomously, integrate into chromosomal DNA, and encode for special phenotypic traits, the most clinically important of which are antibiotic resistance and pathogen virulence.42 Transposons are smaller DNA-containing elements that carry various genes including those associated with antibiotic resistance. Although not autonomously replicating, transposons are capable of inserting into chromosomal, plasmid, and bacteriophage genomes.

The mechanisms by which plasmid and transposon antibiotic-resistant-encoding DNA can be transferred from one bacteria to another include transformation (naked DNA transfer), transduction (transfer via a viral vector), and conjugation (unidirectional transfer through cell-cell contact).42 Of the three, the most important is the latter that occurs in five distinct stages: (1) specific pair formation—initial interaction between the donor's conjugation pilus and the recipient's cell surface to form a stable mating pair, (2) effective pair formation—joining of donor and recipient cellular envelopes, (3) chromosomal mobilization—initial processing of plasmid/transposon DNA, (4) chromosomal transfer—transfer and simultaneous replication of plasmid/transposon and chromosomal DNA, and (5) recombination—pairing of homologous segments of donor and recipient DNA.

Plasmids and transposons can confer resistance to either a single antibiotic or multiple antibiotics. Bacteria that are resistant to three or more antibiotics, each with a different mechanism of action, are said to be multidrug resistant.2 The list of microorganisms that have acquired plasmids that mediate antibiotic resistance is extensive and includes virtually all bacteria of ophthalmic interest (e.g., S. aureus, Staphylococcus epidermidis, Enterococcus faecalis, Clostridium species, Bacteroides species, H. influenzae, Neisseria gonorrhoeae, Acinetobacter species, Aeromonas species, E. coli, Klebsiella species. Proteus species, Providencia species, Serratia marcescens, and P. aeruginosa).1

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EPIDEMIOLOGY OF RESISTANT INFECTIONS OF THE EYE
Widespread resistance among ocular infections began to be recognized during the last quarter of the 20th century. During the 1980s, the aminoglycosides gentamicin and tobramycin were considered to be the treatment of choice for ocular infections.44 By 1985 to 1990, however, it was apparent that bacteria infecting the eye were becoming resistant to this family of antibiotics; 8% of P. aeruginosa isolates obtained from patients with ulcerative keratitis were resistant to gentamicin (MIC equal to or greater than 32 mg/L).45 At approximately the same time, aminoglycoside resistance among gram-positive organisms was also noted.46 Increasing resistance to chloramphenicol also was reported during this time.47

A similar scenario, from widespread susceptibility to the development of resistance, occurred with ciprofloxacin and other fluoroquinolones. In 1990, quinolones were introduced into ophthalmology and were proposed as an alternative for resistant infections.44 These agents were highly active against a broad array of gram-positive and gram-negative bacteria and were effective against aminoglycoside-resistant strains.48 Within 2 years, however, the first cases of quinolone-resistant bacterial keratitis were reported.49 Fluoroquinolone-resistant ocular infections are now recognized worldwide.50–52 A trend toward progressively higher frequencies of fluoroquinolone resistance has been observed both in gram-positive pathogens (e.g., S. epidermidis endophthalmitis isolates) and gram-negative bacteria (e.g., P. aeruginosa keratitis isolates). Newer fluoroquinolones have improved activity against gram-positive cocci resistant to earlier generation fluoroquinolones, but unfortunately they appear to have no activity against P. aeruginosa resistant to earlier generation quinolones.

β-Lactam resistance has also become prevalent among ocular isolates. Longitudinal surveillance data indicate a progressively increasing prevalence of methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, and β-lactamose producing H. influenzae. Among pneumococci isolated from 1988 to 1995 in Florida,53 14% were resistant to penicillin, with the highest proportion found in intraocular fluid (20%), followed by blepharoconjunctival (15%) and corneal (9%) lesions. In a series from Japan between 1992 and 1995,54 penicillin resistance was found in 15% of pneumococci. A 20-year longitudinal study of penicillin-resistant S. pneumoniae demonstrated the emergent nature of bacterial resistance in Texas55; only 2% of pneumococci recovered between 1976 through 1991 were penicillin-resistant in contrast to 20% obtained between 1992 and 1995 (Fig. 1).

Fig. 1. Penicillin susceptibility of Streptococcus pneumoniae isolated from ocular infections. (Penland RL, Wilhelmus KR. Emergence of penicillin-resistant Streptococcus pneumoniae ocular infections. Cornea 1998;17:135)

A consortium of 12 laboratories in the United States, Canada, Mexico, and Argentina provided an overview of antibiotic susceptibility among ocular infections.56 Using both disk-diffusion and broth-dilution methods to assess the in vitro antibiotic sensitivity of 1,291 bacterial strains isolated from primarily the conjunctiva (42%) and cornea (24%), eight antibiotics were tested. The smallest number of isolates were found to be resistant to ofloxacin and the largest number to erythromycin (Fig. 2). Comparisons of fluoroquinolone sensitivity for the most common gram-positive and gram-negative organisms recovered revealed a similar profile for ofloxacin, ciprofloxacin, and norfloxacin, although several (e.g., S. pneumoniae, E. faecalis, and viridans-group streptococci) were less resistant to ofloxacin (Fig. 3). Interstrain differences in sensitivity between ofloxacin and gentamicin were similar to the pattern found for the fluoroquinolones (Fig. 4).

Fig. 2. A. Antibiotic susceptibility of all organisms tested. B. Gram-positive bacteria. C. Gram-negative bacteria. (Ofl, ofloxacin; Cip, ciprofloxacin; Nor, norfloxacin; Gen, gentamicin; Tob, tobramycin; Chl, chloramphenicol; Tet, tetracycline; Ery, erythromycin). (Jensen HG, Felix C. In vitro antibiotic susceptibilities of ocular isolates in North and South America. Cornea 1998;17:79)

Fig. 3. Susceptibility of the most common gram-positive (A) and gram-negative bacteria (B) to ofloxacin, ciprofloxacin, and norfloxacin. (StA, Staphylococcus aureus; StE, Staphylococcus epidermidis; StrP, Streptococcus pneumoniae; VStr, Streptococcus viridans; Csp, Corynebacterium species; EF, Enterococcus faecalis; HI, Haemophilus influenzae; PS, Pseudomonas aeruginosa; SM, Serratia marcescens; KP, Klebsiella pneumoniae; KL, Klebsiella oxytoca; PM, Proteus mirabilis; EC, Escherichia coli; ECl, Enterobacter cloacae). (Jensen HG, Felix C. In vitro antibiotic susceptibilities of ocular isolates in North and South America. Cornea 1998;17:79)

Fig. 4. Susceptibility of the most common gram-positive (A) and gram-negative bacteria (B) to ofloxacin and gentamicin. (StA, Staphylococcus aureus; StE, Staphylococcus epidermidis; StrP, Streptococcus pneumoniae; VStr, Streptococcus viridans; CSp, Corynebacterium species; EF, Enterococcus faecalis; HI, Haemophilus influenzae; PS, Pseudomonas aeruginosa; SM, Serratia marcescens; KP, Klebsiella pneumoniae; KO, Klebsiella oxytoca; PM, Proteus mirabilis; EC, Escherichia coli; ECl, Enterobacter cloacae). (Jensen HG, Felix C. In vitro antibiotic susceptibilities of ocular isolates in North and South America. Cornea 1998;17:79)

The selection of antimicrobial therapy for ocular infections must account for the presence of resistant strains.57 Among vitreous isolates, over half of enterococci are resistant to gentamicin or cefazolin, and up to a third or more of staphylococci are methicillin-resistant, leading to the recommendation for use as part of the empiric vancomycin treatment of postoperative endophthalmitis.58 The absence of vancomycin resistance in a multicenter study of endophthalmitis therapy59 is noteworthy, but surveillance data from systemic infections indicating increasing vancomycin resistance is of concern. Because vancomycin is often a treatment option of last resort, its use as routine prophylaxis during ophthalmic surgery should be avoided whenever possible.60

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CLINICAL IMPLICATIONS OF ANTIMICROBIAL RESISTANCE
Surveillance programs2,39,61 are required for the early recognition of emergent antibiotic-resistant strains. Several ocular microbiology laboratories in North America, Europe, Asia, and Australia monitor regional patterns of antimicrobial resistance. A similar effort to obtain and regularly report international surveillance data on the antimicrobial susceptibility profile of ocular isolates would be highly beneficial.

It is impossible to devise a strategy for using antibiotics in clinical ophthalmology that would completely obviate the development of antibiotic resistance, for to do so would violate a basic tenet of evolutionary theory: The exposure of a species (bacteria) to a destructive environmental element (antibiotic) results in the natural selection of those traits (antibiotic resistance) that will allow the species to survive. There are, however, some approaches that collectively could help reduce the severity of this problem.

REDUCED ANTIBIOTIC USE

Antibiotics should be judiciously prescribed to patients for the shortest amount of time possible.29 Antibiotic use policies must be established at local, national, and international levels. Educational and monitoring programs should be developed.2,29,34,39,62 Essential elements of any policy would include the withholding of empiric antibiotic therapy for patients with infections likely to be self-limiting and/or of viral etiology,29 adopting an abbreviated (e.g., 72 hours), high dose (e.g., drops administered at least four times daily) prophylactic regimen for many ophthalmic surgical procedures,34,63–66 and eliminating the practice of using antibiotics as growth enhancers for livestock.2,39,67

HIGH DOSING

Data from several studies support the notion that an antibiotic should be given at the highest dose, consistent with an acceptable product-safety profile. Peak serum antibiotic concentrations less than 10 times the MIC of the organism predispose to the emergence of resistant bacterial subpopulations.68–70 It is unclear, however, whether it is the peak concentration that is the primary pharmacokinetic determinant of antibiotic resistance or the area under the curve (AUC). The AUC is important in monitoring the therapy of pneumonia in which resistant strains are more likely to appear when the area under the inhibitory curve (AUIC) is low. A sufficiently high AUIC would ensure that the achieved drug level exceeds the target organism's MIC for at least 80% of the treatment interval.71 The opportunity for resistance to develop is lowered if the antibiotic is used at a high dose during the early treatment phase.72

A tapering antibiotic regimen is prone to promote the development of resistance by repeatedly exposing bacteria to prolonged levels of antibiotic below the MIC. Thus an important principle of antibiotic prescribing is that antibiotic administration should be dosed never less than the frequency adequate to exceed the MIC of relevant pathogens (e.g., four times daily). At the conclusion of therapy, the antibiotic should be discontinued abruptly rather than tapered.

USE OF NARROW-SPECTRUM AGENTS

A narrow-spectrum antibiotic should always be prescribed if possible,29 because broad-spectrum agents needlessly expose nonpathogenic organisms to the selective pressures that inevitably result in the development of resistance. To illustrate the importance of this phenomenon, suppose an individual has been previously exposed to a broad-spectrum antibiotic under conditions that allow for the acquisition of resistant genes by the normal flora. Subsequent exposure of the individual to a pathogen could conceivably lead to the transfer of resistance genes via plasmids or transposons from the commensal to the pathogenic species and promote the development of an infection intractable to antibiotic therapy.

COMBINATIONS AND CYCLING

The use of antibiotic combinations is a common practice in treating serious ocular infections such as microbial keratitis and endophthalmitis. Besides providing broad-spectrum coverage, combination therapy reduces the emergence of resistant strains. Antibiotic cycling is another strategy for reducing the development of resistance.73,74 Switching from one antibiotic to another every several weeks can be done during long-term prophylaxis.75 The use of biocides that nonspecifically target living cells is a useful option for short-term prophylaxis, such as before ophthalmic surgery.76 Appropriate use of disinfectants in the operating room and eye clinic can also slow the spread of resistant microorganisms77,78 and is an essential adjunct to antimicrobial use in surgical prophylaxis.

IMMUNIZATION

Ultimately, preventing ocular infections through mucosal vaccines may prove feasible. The role of immunization in reducing the global burden of infectious diseases of the eye remains a future challenge.

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REFERENCES

1. Neu HC. Invading organisms: Agents that kill invaders. In Wingard LR, Brody TM, Larner J et al. (eds). Human Pharmacology: Molecular to Clinical. St Louis: Mosby Year Book, 1991:611–764

2. Harrison JW, Svec TA. The beginning of the end of the antibiotic era? Part I. The problem: Abuse of the “miracle drugs.” Quintessence Int 1998;29:151

3. Demerec M. Production of Staphylococcus strains resistant to various concentrations of penicillin. Proc Acad Sci 1945;31:16

4. Demerec M. Origin of bacterial resistance to antibiotics. J Bacteriol 1948;56:63

5. Sakakibara E. Studies on the streptomycin resistant variants in bacteria. Acta School Med Univ Kioto 1951;29:72

6. Sakakibara E. Studies on the streptomycin resistant variants in bacteria. Acta School Med Univ Kioto 1951;29:116

7. Flaks JG, Cox EC, Witting ML et al. Polypeptide synthesis with ribosomes from streptomycin resistant and dependent E. coli. Biochem Biophys Res Commun 1962;7:390

8. Cavalli LL, Maccacaro GA. Chloromycetin resistance in E. coli: A case of quantitative inheritance in bacteria. Nature 1950;166:991

9. Merkel JR, Steers E. Relationship between chloramphenicol reductase activity and chloramphenicol resistance in E. coli. J Bacteriol 1953;66:389

10. Kushner DJ. The basis of chloramphenicol resistance in Pseudomonas fluorescens. Arch Biochem Biophys 1955;68:1486

11. Bannic S. Transduction to penicillin and chloramphenicol resistance in Salmonella typhimurium. Genetics 1959;44:449

12. Miyamura S. Relationship between chloramphenicol reductase activity and chloramphenicol resistance. Jpn J Bacteriol 1961;16:115

13. Polsinelli M. Genetic analysis of oxytetracycline resistance in Bacillus subtilis by means of transformation. J Gen Microbiol 1964;36:423

14. Franklin TJ, Godfrey A. Resistance of Escherichia coli to tetracyclines. Biochem J 1965;94:54

15. Polsinelli M, Cifferi O, Cassani G et al. Mechanism of resistance to actinomycin in Bacillus subtilis. J Bacteriol 1964;88:1567

16. Ravin AW, Iyer VN. The genetic relationship and phenotype expression of mutations endowing Pneumococcus with resistance to erythromycin. J Gen Microbiol 1961;26:277

17. Taubman SB, Young FE, Corcoran SW. Antibiotic glycosides. IV. Studies on the mechanism of erythromycin-resistance in Bacillus subtilis. Proc Natl Acad Sci 1963;50:955

18. Weaver JA, Patte PA. Inducible resistance to erythromycin in Staphylococcus aureus. J Bacteriol 1964;88:574

19. Foster JW, Pittillo RF. Metabolite reversal of antibiotic inhibition: Especially reversal of aureomycin inhibition by riboflavin. J Bacteriol 1953;66:478

20. Saz AK, Martinez LM. Enzymatic basis of resistance to aureomycin. 1. J Biol Chem 1956;223:285

21. Sutherland R, Robinson GN. Characteristics of methicillin resistant Staphylococci. J Bacteriol 1964;87:887

22. Harada K, Kameda M, Suzuki M et al. Drug resistance of enteric bacteria. II. J Bacteriol 1964;88:1257

23. Kondo E, Mitsuhashi S. Drug resistance of enteric bacteria. III. J Bacteriol 1964;88:1261

24. Hotchkiss RD. Transfer of penicillin resistance to Pneumococcus by the DNA derived from resistant cultures. Cold Spr Harb Symp Q Biol 1957;16:45

25. Hsu YC, Herriott RM. Studies on transformations of Haemophilus influenzae. III. J Gen Physiol 1961;45:197

26. Cohen ML. Epidemiology of drug resistance: Implications for post-antimicrobial era. Science 1992;257:1050

27. Begley S. The end of antibiotics. Newsweek 1994(Mar 28):47

28. Abbasi K. Report calls for actin on antibiotic resistance. BMJ 1998;316;1261

29. Prober CG. Bacterial resistance and the dilemma of antibiotic usage. West J Med 1997;166:337

30. Tauxe RV, Puhr ND, Wells JG et al. Antimicrobial resistance of Shigella isolates in the USA: The importance of international travelers. J Infect Dis 1990;162:1107

31. Appelbaum PC. Antimicrobial resistance in Streptococcus pneumoniae: An overview. Clin Infect Dis 1992;15:77

32. Bartlett JG, Frogatt JW. Antibiotic resistance. Arch Otolaryngol Head Neck Surg 1995;121:392

33. Tomasz A. Pneumococcus at the gates. N Engl J Med 1995;333:514

34. Cunney R, Smyth E. Controlling antibiotic use: Protecting an endangered medical resource. Ir Med J 1998;91:14

35. Arachi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991;72:1

36. Bloom BR, Murray CJL. Tuberculosis: Commentary on a reemergent killer. Science 1992;257:1055

37. Barnes PF, Barrows SA. Tuberculosis in the 1990s. Ann Intern Med 1993;119:400

38. Acar JF. Consequences of bacterial resistance to antibiotics in medical practice. Clin Infect Dis 1997;24:S17

39. Harrison JW, Svec TA. The beginning of the end of the antibiotic era? Part II. Proposed solutions to antibiotic abuse. Quintessence Int 1998;29:223

40. Piddock LJV. Mechanisms of resistance to fluoroquinolones: State-of-the-art 1992-1994. Drugs 1995;49:29

41. Speer BS, Shoemaker NB, Salyers AA. Bacterial resistance to tetracycline: Mechanisms, transfer, and clinical significance. Clin Microbiol Rev 1992;5:387

42. Fralick JA. Microbial genetics. In Hentges DJ (ed). Microbiology and Immunology: An Illustrated Review with Questions and Explanations. Boston: Little Brown and Company, 1995:53–86

43. Holt SC, Progulske A. General microbiology, metabolism, and genetics. In Nisengard RJ, Newman MG (eds). Oral Microbiology and Immunology. Philadelphia: Saunders, 1994:47–114

44. Borrmann LR, Leopold IH. The potential use of quinolones in future ocular antimicrobial therapy. Am J Ophthalmol 1988;106:227

45. Gelender H, Rettich C. Gentamicin-resistant Pseudomonas aeruginosa corneal ulcers. Cornea 1984;3:21

46. Mehta NJ, Webb RM, Krohel GB et al. Clinical efficacy of tobramycin and gentamicin sulfate in the treatment of ocular infection. Cornea 1984-1985;3:228

47. Tuft SJ, Matheson M. In vitro antibiotic resistance in bacterial keratitis in London. Br J Ophthalmol 2000;84:687

48. Cokingtin CD, Hyndiuk RA. Insights from experimental data on ciprofloxacin in the treatment of bacterial keratitis and ocular infections. Am J Ophthalmol 1991;112:25S

49. Snyder ME, Katz HR. Ciprofloxacin-resistant bacterial keratitis. Am J Ophthalmol 1992;114:336

50. Garg P, Sharma S, Rao GN. Ciprofloxacin-resistant Pseudomonas keratitis. Ophthalmology 1999;106:1319

51. Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: A 5-year review. Ophthalmology 1999;106:1313

52. Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology 2000;107:1497

53. Perez EM, Palma LA, Miller D et al. Penicillin resistance among ocular pneumococcal isolates. Invest Ophthalmol Vis Sci 1996;37:S317

54. Ooishi M, Miyao M. Antibiotic sensitivity of recent clinical isolates from patients with ocular infections. Ophthalmologica 1997;211:15–24.

55. Penland RL, Wilhelmus KR. Emergence of penicillin-resistant Streptococcus pneumoniae ocular infections. Cornea 1998;17:135

56. Jensen HG, Felix C. In vitro antibiotic susceptibilities of ocular isolates in North and South America. Cornea 1998;17:79

57. Roth DB, Flynn HW. Antibiotic selection in the treatment of endophthalmitis: The significance of drug combinations and synergy. Surv Ophthalmol 1997;41:395

58. Mao LK, Flynn HW, Miller D et al. Endophthalmitis caused by streptococcal species. Arch Ophthalmol 1992;110:798

59. Endophthalmitis Vitrectomy Study Group: Results of the Endophthalmitis Vitrectomy Study: A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol 1995;113:1479

60. Gordon YJ. Vancomycin prophylaxis and emerging resistance: Are ophthalmologists the villains? The heroes? Am J Ophthalmol 2001;131:371

61. Kowalski RP, Pandya AN, Karenchak LM et al. An in vitro resistance study of levofloxacin, ciprofloxacin, and ofloxacin using keratitis isolates of Staphylococcus aureus and Pseudomonas aeruginosa. Ophthalmology 2001;108:1826

62. Berlin B. Antibiotics with an attitude: Are they working? N Engl J Med 1996;93:25

63. Turnidge J. Antibiotics use of misuse? Med J Aust 1997;167:116

64. Preston SL, Briceland LL. Single daily dosing of aminoglycosides. Pharmacotherapy 1995;15:297

65. Epstein JB. Infective endocarditis: Dental implications and new guidelines for antibiotic prophylaxis. J Can Dent Assoc 1998;64:281

66. McDonald M, Grabsch E, Marshall C et al. Single- versus multiple-dose antimicrobial prophylaxis for major surgery: A systematic review. Aust N Z J Surg 1998;68:388

67. Glenny SF. Antimicrobial prophylaxis in colorectal surgery: A systematic review of randomized controlled trials. Health Technol Assess 1998;2:1

68. Bogaard van den AE. Antimicrobial resistance—Relation to human and animal exposure to antibiotics. J Antimicrob Chemother 197;40:453

69. Gerber AU, Vastola AP, Brandel J et al. Selection of aminoglycoside-resistant variants of Pseudomonas aeruginosa in an in vivo model. J Infect Dis 1982;146:691

70. Pechere JC, Marchou B, Michea-Hamzehpour M et al. Emergence of resistance after therapy with antibiotics used alone or combined in a murine model. J Antimicrob Chemother 1986;17:11

71. Blaser J, Stone BB, Groner M et al. Comparative study with enoxacin and netilmicin in a pharmacokinetic model to determine importance of ratio of antibiotic peak concentration to MIC for bacterial activity and emergence of resistance. Antimicrob Agents Chemother 1987;31:1054

72. Schentag JJ, Birmingham MC, Paladino JA et al. In nosocomial pneumonia, optimizing antibiotics other than aminoglycosides is a more important determinant of successful clinical outcome, and a better means of avoiding resistance. Semin Respir Infect 1997;12:278

73. Jernigan DB, Cetron MS, Breiman RF. Minimizing the impact of drug-resistant Streptococcus pneumonia (DRSP). A strategy from the DRSP working group. JAMA 1996;275:206

74. McGowan JE. Minimizing antimicrobial resistance in hospital bacteria: Can switching or cycling drugs help? J Infect Control 1986;7:573

75. Bonhoeffer S, Lipsitch M, Levin BR. Evaluating treatment protocols to prevent antibiotic resistance. Proc Natl Acad Sci 1997;94:12106

76. Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery. An evidence-based update. Ophthalmology 2002;109:13

77. Swartz MN. Hospital-acquired infections: Diseases with increasingly limited therapies. Proc Natl Acad Sci 1994;91:2420

78. Murray BE. Can antibiotic resistance be controlled? N Engl J Med 1994;330:1229

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