Comparison of azithromycin and moxifloxacin against bacterial isolates causing conjunctivitis

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1 Current Medical Research and Opinion Vol. 23, No. 9, 2007, LibraPharm Limited doi: / x All rights reserved: reproduction in whole or part not permitted ORIGINAL ARTICLE Comparison of azithromycin and moxifloxacin against bacterial isolates causing conjunctivitis Christina Ohnsman a, David Ritterband b, Terrence O Brien c, Dalia Girgis c and Al Kabat d a Wills Eye Institute, Philadelphia, PA, USA b New York Eye & Ear Infirmary; New York, NY, USA c Bascom Palmer Eye Institute, Miami, FL, USA d Nova Southeastern University, Fort Lauderdale, FL, USA Address for correspondence: Christina Ohnsman, MD, 115 Grandview Blvd., Wyomissing, PA 19609, USA. Tel.: ; cohnsman@comcast.net Key words: Azithromycin Conjunctivitis Fluoroquinolone Macrolide Moxifloxacin Resistance A B S T R A C T Objective: To examine in vitro resistance to azithromycin and moxifloxacin in bacterial conjunctivitis isolates. Methods: MIC 90 s (Minimum Inhibitory Concentration) and resistance rates to azithromycin and moxifloxacin were determined based upon microtiter broth dilution and/or antimicrobial gradient test strips in a multicenter phase III study and confirmed externally. Results: The most common isolates collected from bacterial conjunctivitis patients in the phase III study were Haemophilus influenzae (40.6%), followed by Staphylococcus epidermidis (19.3 %), Propionibacterium acnes (17.3%), Streptococcus pneumoniae (16.8%), and Staphylococcus aureus (0.06%). MIC 90 s for all of these organisms were well below established resistance breakpoints for moxifloxacin, indicating no bacterial resistance. On the other hand, the MIC 90 for H. influenzae was 3-fold higher than the resistance breakpoint for azithromycin, 128-fold higher for S. epidermidis, 16-fold higher for S. pneumoniae and 128-fold higher for S. aureus, indicating moderate to very high bacterial resistance to azithromycin. Conclusions: Resistance to azithromycin is more common than resistance to moxifloxacin in clinical isolates causing bacterial conjunctivitis. Introduction Bacterial conjunctivitis is a common childhood illness. A recent study demonstrated the need to exclude children with infectious conjunctivitis from school until it has resolved 1. This requires the selection of the most effective topical antibiotic, so that the child may return to school as quickly as possible. The recent FDA approval of an ophthalmic topical formulation of azithromycin (AzaSite*) 2 requires that the antibiotic choices be re-evaluated. The most common pathogens reported in previous bacterial conjunctivitis literature are H. influenzae, S. pneumoniae, and to a lesser extent, S. aureus 3 5. The introduction of the H. influenzae type b (HiB) vaccine in 1985 has not affected the total number of cases of conjunctivitis caused by non-typeable H. influenzae, but has likely decreased the prevalence of serotype b conjunctivitis 6, as it has decreased systemic infection 7 and preseptal and orbital cellulitis caused by this subtype 8. On the other hand, the introduction of the heptavalent pneumococcal vaccine (Prevnar ) * AzaSite is a registered trademark of InSite Vision, Inc., Alameda, CA Prevnar is a registered trademark of Wyeth, Madison, NJ Paper

2 has decreased the frequency of conjunctivitis due to S. pneumoniae 9. Recent epidemics of conjunctivitis due to non-typeable strains of S. pneumoniae demonstrate that this organism remains an important cause of epidemic conjunctivitis Non-typeable H. influenzae and S. pneumoniae are among the most common respiratory pathogens, and therefore, a large body of literature has addressed correct antibiotic selection for them in respiratory illnesses ranging from otitis media to sinusitis to pneumonia. Clinicians must be more mindful than ever, since cultures are typically not performed in conjunctivitis, of selecting an empiric antibiotic that is effective against the suspected pathogen as well as one that will not induce resistance. For example, antibiotic resistance in non-typeable H. influenzae is more diverse and widespread than previously recognized, with intrinsic efflux resistance mechanisms limiting the activity of the macrolides, azolides, and ketolides 14. Another compelling demonstration of antibiotic resistance to azithromycin and clarithromycin was published in In a randomized, double-blind, placebocontrolled study, healthy volunteers were given a 3-day course of azithromycin, and their pharyngeal carriage of macrolide-resistant streptococci was measured. Results from this study demonstrated a large increase in the mean proportion of macrolide-resistant streptococci in the treated groups, but not in the placebo group, peaking at 4 days and persisting for more than 6 months after the 3-day course of therapy was discontinued. This study demonstrated the direct effect of antibiotic exposure on resistance in the pharyngeal streptococcal flora. Considering the vast popularity of azithromycin in the US, the results of this study highlight the likelihood of pre-existing macrolide resistance in patients, raising the question of the suitability of topical azithromycin for the treatment of conjunctivitis. A recent study of current susceptibility/resistance profiles of bacterial pathogens in conjunctivitis demonstrates the superiority of the bactericidal fluoroquinolones, with no resistance to this class of antibiotics among Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus conjunctival isolates. In contrast, resistance to other classes of antibiotics, including bacteriostatic macrolides such as erythromycin and azithromycin as well as sulfamethoxazole, ranged from 30% to 90% for these organisms 9. Likewise, unpublished data from New York Eye and Ear Infirmary indicate that despite the preferential use of the fluoroquinolone class of antibiotics in ophthalmology over the past decade, moxifloxacin maintains a favorable in vitro susceptibility profile, with lower Minimum Inhibitory Concentration (MIC) values as compared to azithromycin, in representative conjunctival strains of S. aureus, S. epidermidis, alpha-hemolytic streptococci, and nontypeable H. influenzae. The purpose of the current study is to examine resistance rates in clinical isolates from bacterial conjunctivitis. Azithromycin was compared to moxifloxacin in both a bacterial conjunctivitis phase III trial in as well as at a tertiary care center (Bascom Palmer Eye Institute, BPEI) in Methods Conjunctival isolates were collected from 625 patients with typical signs and symptoms of bacterial conjunctivitis at 32 clinical centers across the US in enrolled in Phase III trials of moxifloxacin (study sites extended from the west coast, through the Midwest and up to New England). Of these patients, 56% were 12 years of age or less. Fifty-three percent (53%) of the patients were culture-positive. Samples were collected by the physicians using a conjunctival swab, stored, and shipped to a clinical laboratory. These isolates were then tested for in vitro susceptibility to a variety of antibiotics, using microtiter broth dilution methods as recommended by the Clinical and Laboratory Standards Institute (CLSI) 16 to measure the MIC, except in the case of azithromycin, for which they were not available and in which antimicrobial gradient test strips [Etest (AB Biodisk, Piscataway, NJ, USA)] were therefore used. In an independent and confirmatory study, isolates of H. influenzae, S. pneumoniae, and methicillin-resistant (MRSA) and methicillin-sensitive S. aureus (MSSA), which had been collected from patients with bacterial conjunctivitis at Bascom Palmer Eye Institute from 2004 to 2007, were tested for in vitro susceptibility to moxifloxacin and azithromycin using antimicrobial gradient test strips. Institutional Review Board (IRB) approval was granted prior to the initiation of all studies. MIC 90 s were determined by ranking the MICs of each bacterial isolate from lowest to highest, and identifying the isolate at the 90% rank position. The corresponding MIC for that isolate was the MIC 90, or the antibiotic concentration that would inhibit the growth of 90% of the tested bacterial isolates. For example, if 10 isolates were studied and ranked, the MIC for the isolate at the 9th position was the MIC 90. If 20 isolates were studied, the MIC 90 was the MIC of the isolate ranked 18th 17. Results The most common isolates collected from bacterial conjunctivitis patients in the phase III data were H. influenzae (40.6%), followed by S. epidermidis 2242 Moxifloxacin and azithromycin for bacterial conjunctivitis 2007 LIBRAPHARM LTD Curr Med Res Opin 2007; 23()

3 (19.3%), P. acnes (17.3%), S. pneumoniae (16.8%), and S. aureus (0.06%) (percent of the culturepositive patients). None of the bacterial isolates were methicillin-resistant Staphylococcus aureus (MRSA). Table 1 indicates MIC 90 s of both moxifloxacin and azithromycin for the phase III and Bascom Palmer Eye Institute (BPEI) data sets. Note the striking similarities of MIC 90 s for H. influenzae and S. pneumoniae from both studies. Statistical significance could not be determined due to the difference in N values in the two groups. Table 2 indicates resistance breakpoints (greater than these breakpoints indicates bacterial resistance) of both moxifloxacin and azithromycin for the phase III and BPEI data sets. Breakpoints for resistance were defined by Stroman in the Phase III data and defined by the Clinical and Laboratory Standards Institute (CLSI) 16 and in the antimicrobial gradient test strips package insert for the BPEI data. MIC 90 s of moxifloxacin were well below breakpoints for resistance for all organisms except MRSA (found only in the BPEI data). Conversely, MIC 90 s of azithromycin were greater than or equal to these breakpoints for resistance for H. influenzae as well as S. pneumoniae and far exceeded them for S. aureus and S. epidermidis, indicating moderate to high level resistance. Figures 1 and 2 represent Phase III and Bascom Palmer data, respectively. Figure 1 demonstrates there was no resistance to moxifloxacin for S. pneumoniae, H. influenzae, S. aureus and 13% for S. epidermidis. Conversely, the same study demonstrates the following resistance rates for azithromycin: S. pneumoniae (20%), H. influenzae (76%), S. aureus (50%), and S. epidermidis (30%). Figure 2 also demonstrates no resistance to moxifloxacin in S. pneumoniae and H. influenzae compared to azithromycin resistance in 23.7% and zero, respectively. Of note, there is a difference between the phase III data and the Bascom Palmer data in the MIC 90 of azithromycin for H. influenzae. This difference is likely due to the small sample size in the BPEI data. Upon further review, all but two H. influenzae BPEI isolates had a MIC of 4, just barely missing the defined breakpoint for resistance of greater than 4. This group of tertiary care center investigators also presented S. aureus data categorized into methicillin-sensitive (MSSA) and -resistant (MRSA). These results indicate 6.8% and 45.8% MSSA resistance to moxifloxacin and azithromycin, respectively. Similarly, these results indicate 68.5% and 90.7% MRSA resistance to moxifloxacin and azithromycin, respectively. No MRSA isolates were found in the phase III data. Figures 3 and 4 from New York Eye and Ear Infirmary indicate the MIC data from the Phase III studies as well as from Bascom Palmer. Discussion Azithromycin is a bacteriostatic, semi-synthetic derivative of erythromycin which binds to the 50S ribosomal subunit of susceptible bacteria, inhibiting mrna-directed protein synthesis. At its introduction in 1994, azithromycin was welcomed by primary care physicians for its good coverage of respiratory pathogens, its high tissue concentrations, and its dosing schedule, requiring only a single daily dose for a short course. Table 1. MIC 90 comparison of phase III to Bascom Palmer Eye Institute Phase III data μg/ml (N) Bascom Palmer data μg/ml (N) H. influenzae Moxifloxacin 0.03 (145) 0.05 (12) Azithromycin 4 (145) 6 (12) S. pneumoniae Moxifloxacin 0.12 (60) 0.19 (26) Azithromycin 8 (60) 6 (26) S. aureus Moxifloxacin 0.06 (21) 0.15 (MSSA) (59), 32 (MRSA) (54) Azithromycin > 512 (21) 256 (MSSA) (59), 256 (MRSA) (54) S. epidermidis Moxifloxacin 1 (69) N/A* Azithromycin > 512 (69) N/A* *Not available MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-sensitive Staphylococcus aureus 2007 LIBRAPHARM LTD Curr Med Res Opin 2007; 23() Moxifloxacin and azithromycin for bacterial conjunctivitis Ohnsman et al. 2243

4 Table 2. Comparison of MIC 90 resistance breakpoints Phase III data (μg/ml) Bascom Palmer data (μg/ml) H. influenzae Moxifloxacin > 2 > 4 Azithromycin > 2 > 4 S. pneumoniae Moxifloxacin > 2 2 Azithromycin > S. aureus Moxifloxacin > 2 2 Azithromycin > 4 8 S. epidermidis Moxifloxacin > 2 N/A* Azithromycin > 4 N/A* *Not available Resistance defined as same for both MSSA and MRSA Figure 1. Resistance patterns for conjunctival isolates collected from patients with bacterial conjunctivitis at clinical centers across the US in The popularity of systemic azithromycin has a downside, however. Resistance to macrolides results from genetic mutations in the macrolide efflux, or mef, gene, or in the erythromycin-resistant methylase, or erm, gene, which changes the macrolide binding site on the bacterial ribosome 18. The presence of a mef gene confers low-level resistance, while an erm gene gives the bacteria high-level resistance, and may also result in resistance to lincosamides, such as clindamycin, and streptogramins, due to the similar binding sites in streptococci and staphylococci Just as azithromycin persists for long periods in other tissues, systemic use leads to prolonged high levels of the antibiotic in the conjunctiva 22. For this reason, Figure 2. Resistance patterns for ocular isolates of H. influenzae, S. pneumoniae, and methicillin-resistant (MRSA) and methicillin-sensitive S. aureus (MSSA), collected from patients with bacterial conjunctivitis at the Bascom Palmer Eye Institute from 2004 to 2007 a single dose of oral azithromycin has been used for community-wide mass treatment of trachoma in some portions of the developing world 23,24. Studies have demonstrated an increase in resistant conjunctival 25 and nasopharyngeal 26 S. pneumoniae carriage in those treated, presumably due to the prolonged persistence in these tissues, exposing the bacteria to slowly decreasing levels of antibiotic. The number of resistant organisms has been shown to return to baseline after 1 year 27, but this was only possible due to the lack of continued exposure to this antibiotic, which was not otherwise available in the developing nations in which it was studied. However, mass treatment of trachoma with a single oral dose of azithromycin is repeated yearly, and in Nepal, macrolide resistance was present in 5% of pneumococci 6 months following the second annual dose of azithromycin 28. The effect of ongoing annual treatment on the prevalence of resistant S. pneumoniae has not yet been studied, but even this small amount of continued macrolide pressure is likely to lead to increasing resistance rates. In the US, as well as in Europe, macrolide use is so widespread that these organisms are under continuous pressure to retain their resistance. Use of a five-day course of azithromycin for Group A Streptococcus infection led to increased prevalence of nasopharyngeal carriage of macrolide resistant S. pneumoniae in schoolchildren in Texas 29. In another study, healthy volunteers receiving a 3-day course of azithromycin had a 60.4% increase in the proportion of pharyngeal macrolide-resistant streptococci at Day 4, decreasing to a 40.9% increase over baseline at 6 weeks, and persisting at a lower level beyond 6 months (Figure 5) 15. These resistant organisms may 2244 Moxifloxacin and azithromycin for bacterial conjunctivitis 2007 LIBRAPHARM LTD Curr Med Res Opin 2007; 23()

5 Figure 3. S. aureus on Mueller Hinton Broth plate Figure 4. S. pneumoniae on Mueller Hinton Broth plate with 5% sheep blood agar serve as a reservoir of potential pathogens, and may be spread to close contacts, who may or may not become ill due to them30. Conversely, late-generation fluoroquinolone resistance among respiratory pathogens, including both S. pneu moniae and H. influenzae, has remained relatively low, at less than 1% Fourth-generation fluoroquinolones target two enzymes, DNA gyrase and topoisomerase IV, both of which are required for bacterial DNA replication. Disruption of these 2007 LIBRAPHARM LTD Curr Med Res Opin 2007; 23( ) enzymes results in rapid bacterial cell death. Fourthgeneration fluoroquinolones bind both DNA gyrase and topoisomerase IV in Gram-positive bacteria, and therefore require a double mutation for resistance to occur. In wild-type bacteria, this occurrence would be quite rare (10 14 in S. pneu moniae)36. Single-step mutants with resistance to earlier-generation fluoroquinolones are generally susceptible to moxifloxacin37,38, although concern about acquisition of the second-step mutation is real39,40. These qualities have caused a change in antibiotic Moxifloxacin and azithromycin for bacterial conjunctivitis Ohnsman et al. 2245

6 Figure 5. Temporal changes in the proportion of macrolide-resistant streptococci after azithromycin and chlarithromycin use (reprinted with permission from Elsevier (The Lancet, 2007, Vol 369, page 485)) prescribing; that is, the most potent agent of a class of antibiotics is typically used first to avoid the development of resistance to the entire class of antimicrobials 41,42. This concept has been further refined to selecting a broad-spectrum agent with a good pharmacokinetic and pharmacodynamic profile against the known or suspected pathogen, avoiding excessive use of any single antibiotic for all indications. Using this approach, moxifloxacin is an excellent therapeutic choice for adult systemic infections in which S. pneumoniae is anticipated to be the most likely pathogen 43. Unlike all other antibiotics, fluoroquinolone resistance is least prevalent in children 44,45. This is not surprising, since systemic fluoroquinolones are not routinely prescribed in pediatrics, and it also suggests that resistant organisms are not being passed to children by adults. Further, it may indicate that clonal spread is not occurring among adults, maintaining the low rates of fluoroquinolone resistance observed in the surveillance studies 46. To date, no head-to-head clinical trials are available comparing azithromycin with the fourth-generation fluoroquinolones for the treatment of conjunctivitis. However, azithromycin (AzaSite) is bacteriostatic and is indicated for five bacterial isolates, while moxifloxacin 0.5% [Vigamox (Alcon Laboratories, Inc., Fort Worth, TX)] is a broad-spectrum, bactericidal antibiotic indicated for 13 bacterial isolates. A recent study demonstrated that moxifloxacin 0.5% produced rapid kill (99.9%) within 1 h for S. aureus while there was a slight increase in bacterial growth with 1.0% azithromycin (1:100 dilutions for both antibiotics; D Stroman, PhD, unpublished data, June 2007). Comparison of azithromycin to tobramycin in a noninferiority trial demonstrated low efficacy for both drugs, with a 29.8% cure rate for azithromycin at Day 3 of treatment compared with 18.6% for tobramycin 47. Similarly, the phase III clinical trial comparing azithromycin with tobramycin demonstrated no statistically significant difference ( p > 0.05) between the drugs in bacterial eradication or clinical resolution of the ocular signs of conjunctivitis 48. Tobramycin itself covered only 67% of all bacterial isolates from conjunctivitis, including none of the S. pneumoniae isolates, in a previous study 49. Tobramycin, as well as gentamicin, polymyxin B-neomycin, polymyxin B-trimethoprim, and sulfamethoxazole, all have shown diminished activity for one or both of S. pneumoniae and H. influenzae, with sulfonamides being similar in efficacy to placebo 5. Therefore, the lack of improved efficacy of azithromycin over tobramycin suggests that the drug may not provide an advantage in the treatment for conjunctivitis. Furthermore, pre-existing bacterial resistance may be encountered. Inappropriate dosing of this macrolide may create additional resistance. This is specified in the FDA package label 2 stating: Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AzaSite (azithromycin ophthalmic solution) or other antibacterial drugs in the future. While this may be true for other antibiotics, such a discussion in the package insert is novel. The previously discussed resistance data referring to respiratory infections with H. influenzae and S. pneumoniae and data specific to ocular isolates show similar trends. For example, in a study by Stroman, 75% of H. influenzae, 18% of S. pneumoniae, and 30% of S. aureus isolated from patients with conjunctivitis were resistant to azithromycin, while none of these three organisms were resistant to moxifloxacin 9. The BPEI results support the absence of resistance to 2246 Moxifloxacin and azithromycin for bacterial conjunctivitis 2007 LIBRAPHARM LTD Curr Med Res Opin 2007; 23()

7 moxifloxacin for H. influenzae and S. pneumoniae, while demonstrating 6.8% resistance among MSSA and 68.5% resistance in MRSA. In addition, the BPEI azithromycin resistance rates for MSSA and MRSA, at 45.8% and 90.7%, were much higher than the Stroman rate of resistance for S. aureus. The high rates of resistance among staphylococci, particularly MRSA, at BPEI likely reflect the severity of disease seen at this tertiary care center, in contrast to that seen at the primary care centers that participated in the Stroman data collection. The BPEI data also correspond fairly well with the azithromycin resistance rates of S. pneumoniae in the Stroman study, revealing 23.7% resistance compared with Stroman s 18%. Interestingly, the resistance rates of H. influenzae, although zero by the defined breakpoint of > 4, would have measured 83.3% if the breakpoint had been defined as equal to 4. Without direct comparative clinical trials, physicians must rely on in vitro studies and package inserts to determine which antibiotic to choose in the treatment of bacterial conjunctivitis. In the past, the CLSI had determined MIC levels that translated into antibiotic susceptibility standards, based on levels of antibiotics in serum. These had limited usefulness in ophthalmology due to the topical administration of antibiotics, which did not correlate with serum levels, although they often seemed to correlate with clinical experience. In bacterial conjunctivitis, the pertinent ocular concentrations of antibiotics for efficacy and potential resistance development are in the conjunctiva, the target tissue, as well as in the tears, since conjunctivitis is spread via contact with the tears and discharge. With data becoming available for tear and conjunctival concentrations of drugs, it may be reasonable to make inferences about in vivo effectiveness using the same in vitro data. In rabbits, the concentration of moxifloxacin in tears measured 366 µg/ml 1 min after a single drop was given, and remained greater than or equal to 1 µg/ml at 6 h 50. Azithromycin tear concentration in rabbits measured µg/ml 30 min following one drop of 1% suspension 51. In the same study by Si and colleagues, conjunctival concentration of azithromycin measured 82.6 µg/g (Maximum concentration, C max ) at 30 min (T max ) with an elimination constant of 0.051h -1. For mono-exponential decay of drug levels post T max, the concentration (C) at some time post T max (t) may be estimated as follows: Even more important than the ability of the selected antibiotic to achieve a cure in the individual patient, the mutant selection window should be avoided. This is the concentration range between the MIC 90 and the MIC of the least susceptible, but not yet resistant, next-step mutant. This upper limit has been named the mutant prevention concentration, or MPC 52, and can be empirically estimated to be 8 10 times the MIC For example, Figure 6 demonstrates the decay of azithromycin concentration over time and the MPC (estimated to be 10 MIC) of susceptible strains. If one considers the MIC for susceptible strains of S. aureus, S. epidermidis, S. pneumoniae, and H. influenzae to be 2 μg/ml, 1.5 μg/ml, 0.1 μg/ml, 0.25 μg/ml, respectively, the MPC would be estimated at 20 μg/ml, 15 μg/ml, 1 μg/ml, 2.5 μg/ml for the respective strains. The modeled decay of concentration over time explains how azithromycin could induce resistance. That is to say, the slow elimination of the product allows low antibiotic concentrations over time when susceptible strains can become resistant. This danger exists above the MIC, in the mutant selection window, as well as below the MIC, where the creation of new mutants is fostered indirectly by allowing the pathogen population to expand and be further enriched by subsequent antibiotic challenge 52. These considerations are important for a concentrationdependent antibacterial such as moxifloxacin and of greater importance for a bacteriostatic, concentrationindependent (i.e. time-dependent) drug such as azithromycin. For azithromycin and other macrolides, the time above the MIC is the pharmacodynamic parameter that correlates best with bacterial inhibition and clinical efficacy, and the time above MPC correlates best with avoiding the selection of resistant bacteria. C(t) = C max exp( 0.693/half-life t) Using these single-dose Si and colleagues data, the following curve was constructed (Figure 6) to demonstrate the slow drug release reservoir of azithromycin in the conjunctiva that could induce bacterial resistance. Figure 6. Single-dose azithromycin conjunctival concentrations modeled over 4 days with estimated mutant prevention concentrations of common bacterial isolates 2007 LIBRAPHARM LTD Curr Med Res Opin 2007; 23() Moxifloxacin and azithromycin for bacterial conjunctivitis Ohnsman et al. 2247

8 Therefore, it is advisable to prescribe a concentrationdependent, broad-spectrum antibiotic with a C max that far exceeds the MIC, is rapidly bactericidal, and is quickly eliminated to avoid the creation of newly resistant organisms 56,57. Using the data from the current studies, it is clear that moxifloxacin meets these criteria. As previously mentioned, the current study is not a head-to-head trial of azithromycin and moxifloxacin, and does not contain clinical efficacy data. Furthermore, it would have been useful to analyze the data with regard to the age of the patient, but this information was not available in both data sets. Finally, the disparate sizes of the data sets from the phase III trial and Bascom Palmer prevented analysis for statistical significance. Conclusions Resistance to azithromycin is more common than to moxifloxacin for clinical isolates causing bacterial conjunctivitis. 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