Purpose
To determine the antibacterial susceptibility profile of bacterial pathogens from ocular infections against relevant aminoglycoside, β-lactam, cephalosporin, chloramphenicol, fluoroquinolone, glycopeptide, lincosamide, and macrolide antibacterial agents.
Design
Laboratory investigation.
Methods
Isolates from patients with bacterial eye infections were collected prospectively by 34 institutions across the United States and were submitted to a central laboratory for inclusion in the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) study. Minimum inhibitory concentrations were determined by microbroth dilution for 200 Staphylococcus aureus ( S. aureus ), 144 coagulase-negative staphylococci, 75 Streptococcus pneumoniae ( S. pneumoniae ), 73 Haemophilus influenzae ( H. influenzae ), and 100 Pseudomonas aeruginosa ( P. aeruginosa ) isolates.
Results
A large proportion of S. aureus and coagulase-negative staphylococci isolates were resistant to oxacillin/methicillin, azithromycin, or fluoroquinolones; 46.5% of S. aureus , 58.3% of coagulase-negative staphylococci, 9.0% of P. aeruginosa , and 9.3% of pneumococcal isolates were nonsusceptible to 2 or more antibacterial drug classes. Only 2.7% of H. influenzae isolates were nonsusceptible to 1 of the agents tested. Methicillin-resistant staphylococci were statistically more likely (all P < .0038) also to be resistant to fluoroquinolones, aminoglycosides, and macrolides.
Conclusions
Resistance to 1 or more antibiotics is prevalent among ocular bacterial pathogens. Current resistance trends should be considered before initiating empiric treatment of common eye infections.
Bacterial infections of the eye can range in severity from mild irritation to sight-threatening infections and frequently are caused by bacteria that inhabit the skin (such as Staphylococcus epidermidis [ S. epidermidis ]) or the upper respiratory tract ( Staphylococcus aureus [ S. aureus ], Haemophilus influenzae [ H. influenzae ], Streptococcus pneumoniae [ S. pneumoniae ], viridans streptococci). Other species, such as Pseudomonas aeruginosa ( P. aeruginosa ), have been associated with ocular infections in contact lens wearers.
Pathogenic bacteria, including those from ocular sources, have become increasingly drug resistant since the introduction of antibiotics. Staphylococci and P. aeruginosa frequently are resistant to β-lactams, macrolides, and fluoroquinolones; pneumococci have shown decreased susceptibility to β-lactams, trimethoprim, and macrolides, whereas H. influenzae isolates have shown resistance to trimethoprim. Resistance to antimicrobial agents is of clinical concern because it can lead to treatment failures, it limits therapeutic choices, and it increases health care costs.
The World Health Organization, United States Food and Drug Administration and the Centers for Disease Control and Prevention have made surveillance studies part of their action plan to combat the thread caused by resistant pathogens. It is hoped that knowledge about the emergence and spread of resistant pathogens will lead to the prevention or control of the resistance problem.
Surveillance studies, such as SENTRY (SENTRY Antimicrobial Surveillance Program), SMART (Study for Monitoring Antimicrobial Resistance Trends), or TRUST (Tracking Resistance in the United States Today) are being conducted to obtain surveillance data nationally or globally from specific sites, for specific pathogens, or both. The ocular TRUST surveillance study, conducted from 2005 through 2006, collected samples of S. aureus , H. influenzae , and S. pneumoniae from ocular infections and determined the resistance profile for commonly used ophthalmic antibiotics. Not surprisingly, the authors found that drug-resistant strains also are common in ocular infections.
The information obtained from surveillance studies is especially relevant when antibacterial drugs are given either as prophylaxis or as part of an empiric therapy and when treatment is initiated in the absence of information about the causative agent or its antibacterial resistance profile. This is, for example, the case for bacterial conjunctivitis, where broad-spectrum antibiotics are administered empirically.
Fluoroquinolones, such as the novel C8-chloro-fluoroquinolone besifloxacin, are bactericidal and have a broad spectrum of activity, which makes them ideal for the treatment of bacterial conjunctivitis. Some ophthalmic formulations combine 2 antibiotics with a narrow spectrum of activity, such as polymyxin B and trimethoprim, to increase the spectrum of activity. Formulations of other classes of antibiotics that are used ophthalmically in the United States (ie, vancomycin), have a more narrow spectrum of activity, restricting them to specific pathogens.
Here we report the results for the 2009 Antibiotic Resistance Monitoring in Ocular MicRorganisms (ARMOR) study that determined the antibacterial susceptibility profile of S. aureus , coagulase-negative staphylococci (CNS), S. pneumoniae , H. influenzae , and P. aeruginosa from ocular infections. Isolates were tested against relevant aminoglycoside, β-lactam, cephalosporin, chloramphenicol, fluoroquinolone, glycopeptide, lincosamide, and macrolide antibacterial agents.
Methods
Antibiotic Resistance Monitoring in Ocular Microrganisms 2009 Study Design
A total of 3 ocular centers, 22 community hospitals, and 9 academic or university hospitals contributed isolates for this study from January 2009 through December 2009. Participating centers were selected to be geographically diverse and represented the following states: California, Florida, Iowa, Idaho, Indiana, Kansas, Massachusetts, Maryland, Michigan, Missouri, North Carolina, New York, Ohio, Pennsylvania, South Carolina, and Tennessee. Each participating site was invited to submit up to 65 ocular isolates, including 20 S. aureus , 20 CNS, 5 S. pneumoniae , 5 H. influenzae , and 15 P. aeruginosa . Sites were requested to collect clinically significant strains from eye infection sources (excluding endophthalmitis). All isolates were sent to a central laboratory, where the bacterial species was confirmed and the antibacterial resistance profile was determined.
Antibacterial Susceptibility Testing
All isolates were tested by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) defined methodology using frozen commercial microtiter panels (TREK Diagnostics Systems, Inc, Cleveland, Ohio, USA) containing dried antimicrobials. Where breakpoints were available, minimum inhibitory concentrations (MICs) were interpreted as susceptible, intermediate, or resistant according to the 2009 published interpretive criteria. Nonsusceptible isolates were those scored to be either intermediate or resistant. Supplemental Table 1 (Supplemental Material at AJO.com ) lists the antibacterials tested, their CLSI breakpoints, and ranges of drug concentration tested. Besifloxacin is unique among the drugs tested because it has not been developed previously for systemic use, and therefore does not have CLSI interpretive criteria. However, previous work has shown that its potency, based on MIC determinations, is similar to that of moxifloxacin against gram-negative pathogens and exceeds that of moxifloxacin against gram-positive species.
Results for all MIC testing were within the acceptable standards based on the CLSI-recommended quality control ranges for each comparator agent and the appropriate ATCC (American Type Culture Collection) control strains. The following strains were used for quality control: Escherichia coli ATCC 25922, P. aeruginosa ATCC 27853, S. aureus ATCC 29213, E. coli ATCC 35218, S. pneumoniae ATCC 49619, H. influenzae ATCC 49247, and H. influenzae ATCC 49766.
Statistical Analyses
Odds ratios and P values were obtained from logistic regression models, where the probability of having resistant isolates was modeled. Analyses were conducted using SAS software version 9.1.3 (SAS Institute, Inc, Cary, North Carolina, USA).
Results
Overall, a total of 592 isolates from ocular infections were collected for analysis. Samples included 200 S. aureus , 144 CNS, 75 S. pneumoniae , 73 H. influenzae , and 100 P. aeruginosa.
Stratification by patient age ( Table 1 ) showed that more than half of the H. influenzae isolates were obtained from patients younger than 18 years of age. For methicillin-resistant S. aureus (MRSA) and ciprofloxacin-nonsusceptible P. aeruginosa , the volume of isolates obtained increased with the age group of the patients. In contrast, methicillin-susceptible S. aureus (MSSA) and ciprofloxacin-susceptible P. aeruginosa isolates were distributed more evenly among the age groups.
| No. of Isolates (%) | |||||
|---|---|---|---|---|---|
| Organism (Phenotype) | No. | 0 to 17 y | 18 to 64 y | ≥ 65 y | Unknown Age |
| Staphylococcus aureus (MS) | 122 | 33 (27.1) | 44 (36.1) | 39 (32.0) | 6 (4.9) |
| Staphylococcus aureus (MR) | 78 | 7 (9.0) | 18 (23.1) | 40 (51.3) | 13 (16.7) |
| CNS (MS) | 68 | 8 (11.8) | 25 (36.8) | 22 (32.4) | 13 (19.1) |
| CNS (MR) | 76 | 23 (30.3) | 15 (19.7) | 27 (35.5) | 11 (14.5) |
| Streptococcus pneumoniae | 75 | 25 (33.3) | 19 (25.3) | 25 (33.3) | 6 (8.0) |
| Haemophilus influenzae | 73 | 41 (56.2) | 12 (16.4) | 13 (17.8) | 7 (9.6) |
| Pseudomonas aeruginosa (CIP-S) | 89 | 21 (23.6) | 33 (37.1) | 18 (20.2) | 17 (19.1) |
| Pseudomonas aeruginosa (CIP-NS) | 11 | 0 (0) | 5 (45.5) | 6 (54.6) | 0 (0) |
Staphylococcus aureus
Of the 200 S. aureus isolates collected ( Table 2 ), 78 (39%) were resistant to methicillin or oxacillin. As shown in Figure , these 78 MRSA isolates were statistically more likely also to be resistant to other drug classes when compared with the 122 MSSA isolates, with P values < .0001 for resistance to macrolides, fluoroquinolones, lincosamides, and aminoglycosides. Almost all of the MRSA isolates were resistant to azithromycin, and nearly 80% were resistant to ciprofloxacin. By comparison, azithromycin resistance did not exceed 40% in MSSA isolates, and less than 11% were resistant to ciprofloxacin. All S. aureus and CNS isolates tested were susceptible to vancomycin, whereas less than 6% of isolates were resistant to clindamycin ( Tables 2 and 3 ). For all antibacterials tested except vancomycin, the MICs inhibiting the visible growth of 50% of all isolates (MIC 50 ) and the MICs inhibiting the visible growth of 90% of all isolates (MIC 90 ) were higher for the methicillin-resistant group when compared with methicillin-susceptible isolates, consistent with the higher level of resistance in the former. The fluoroquinolones showed stark differences in their potencies against staphylococcal isolates. Besifloxacin was the most potent fluoroquinolone tested, especially against ciprofloxacin-resistant isolates, followed by moxifloxacin and ciprofloxacin.
| MIC (μg/mL) a | Resistance Profile | ||||||
|---|---|---|---|---|---|---|---|
| Antibacterial | Phenotype | Range | MIC 50 | MIC 90 | % S | % I | % R |
| Besifloxacin | MSSA | ≤0.008 to 2 | 0.015 | 0.25 | NA | NA | NA |
| MRSA | ≤0.008 to 4 | 0.5 | 4 | NA | NA | NA | |
| Ciprofloxacin | MSSA | ≤0.06 to 256 | 0.25 | 4 | 87.7 | 1.6 | 10.7 |
| MRSA | ≤0.06 to >512 | 64 | 256 | 20.5 | 0.0 | 79.5 | |
| Moxifloxacin | MSSA | ≤0.008 to 16 | 0.03 | 1 | 89.3 | 4.9 | 5.7 |
| MRSA | ≤0.008 to 64 | 4 | 32 | 20.5 | 14.1 | 65.4 | |
| Azithromycin | MSSA | ≤0.25 to >512 | 1 | >512 | 60.7 | 0.0 | 39.3 |
| MRSA | 0.5 to >512 | >512 | >512 | 3.8 | 0.0 | 96.2 | |
| Clindamycin | MSSA | ≤0.03 to >16 | 0.06 | 0.12 | 94.3 | 0.0 | 5.7 |
| MRSA | ≤0.03 to >16 | 0.12 | >16 | 65.4 | 0.0 | 34.6 | |
| Oxacillin | MSSA | ≤0.06 to 2 | 0.25 | 0.5 | 100.0 | 0.0 | 0.0 |
| MRSA | 4 to >4 | >4 | >4 | 0.0 | 0.0 | 100.0 | |
| Tobramycin | MSSA | ≤0.06 to >256 | 0.5 | 1 | 95.9 | 0.8 | 3.3 |
| MRSA | 0.12 to >256 | 32 | >256 | 46.2 | 1.3 | 52.6 | |
| Vancomycin | MSSA | 0.5 to 1 | 0.5 | 1 | 100.0 | 0.0 | 0.0 |
| MRSA | 0.25 to 2 | 0.5 | 1 | 100.0 | 0.0 | 0.0 | |
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