Optometry & Vision Science:
Limitations of Current Antibiotics for the Treatment of Bacterial Conjunctivitis
Karpecki, Paul; Paterno, Michael R.; Comstock, Timothy L.
‡OD, MS, FAAO
Koffler Vision Group, Lexington, Kentucky (PK), and Bausch & Lomb, Inc., Rochester, New York (MRP, TLC).
Dr. Paul M. Karpecki: AMO, paid consultant; Allergan Inc, paid consultant; Bausch & Lomb Inc, paid consultant; CZM, speakers bureau; Cyanacon Ocusoft, paid consultant; Eyemaginations, paid consultant; Focus Laboratories, paid consultant; Hoya Surgical, paid consultant; Inspire Pharmaceuticals, paid consultant, shareholder, research grant; Ista Pharmaceuticals, paid consultant; Konan Medical, paid consultant; LCA Vision, LASIK Plus, Advisor; Pixel Optics, paid consultant; Odyssey Medical, paid consultant; OfficeMate/VSP, paid consultant; QLT, research grant; Rapid Pathogen Screening, paid consultant; Science Based Health, paid consultant; Sirion Therapeutics, paid consultant; TearLab Inc., paid consultant, shareholder; Topcon, paid consultant; VMax, paid consultant/shareholder. Drs. Michael Paterno and Timothy Comstock are employees of Bausch & Lomb, Inc.
Received April 22, 2010; accepted July 12, 2010.
Paul Karpecki; Koffler Vision Group; 120 N Eagle Creek Drive, Suite 431; Lexington, Kentucky 40509; e-mail: firstname.lastname@example.org
Bacterial conjunctivitis is a common ocular infection that is generally treated empirically with a broad-spectrum antibiotic. The more common pathogens causing bacterial conjunctivitis include Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus epidermidis, and Moraxella species. Several antibiotics traditionally used to treat bacterial conjunctivitis are no longer widely prescribed because of increased bacterial resistance and/or safety concerns. The introduction of the fluoroquinolone class of anti-infectives offered effective and better tolerated treatment options. Nonetheless, successful therapy for bacterial conjunctivitis continues to be limited by several factors. A primary concern is the development of bacterial resistance that may be impacted not only by widespread antibiotic use but also by antibacterial pharmacokinetics, such as maintenance of insufficient bactericidal concentrations at the site of infection. In addition, poor adherence to prescribed regimens that require frequent administration, along with undesirable adverse events, affects the development of bacterial resistance and the success of treatment regimens. This article reviews current antibacterial agents used to treat bacterial conjunctivitis, factors that limit their successful use in treatment, and options for future development of more effective topical ophthalmic anti-infective agents.
Bacterial conjunctivitis is a disorder that affects all age groups. It is most commonly treated empirically with broad-spectrum antibiotics. Treatment with topical antibacterial drops is considered a standard of care that can shorten the disease course, prevent contagious spread, reduce recurrence of infection, and decrease the risk of vision-threatening complications.1–3
The commonly isolated microbes associated with bacterial conjunctivitis include the gram-positive pathogens Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pneumoniae and the gram-negative pathogen Haemophilus influenzae, which are all considered part of normal lid or nasopharyngeal flora. H. influenzae predominates in children, whereas S. aureus is most commonly found in adults, with Moraxella catarrhalis also frequently isolated.1,4 In recent years, certain microorganisms commonly associated with bacterial conjunctivitis have shown increased resistance to the topical anti-infective agents frequently used in eye care. A greater degree of resistance has been found in the gram-positive bacteria, especially S. aureus, than in the gram-negative bacteria.5
Treatment with topical antibacterial drops is usually empiric, whereas conjunctival culture is reserved for more severe cases in which there may be a risk of severe vision loss or systemic infection.1 Empiric therapy aims to select a topical antibacterial agent with broad spectrum action against both gram-positive and gram-negative organisms. Despite the introduction of new agents over the past 30 years, current choices for topical antibacterial therapy are becoming more limited because of a variety of factors, including, as noted above, resistance among the organisms causing bacterial conjunctivitis. Herein, we review the spectrum of topical antibiotic products introduced in recent years, and the limitations they face today in the treatment of bacterial conjunctivitis.
Agents Used in the Treatment of Bacterial Conjunctivitis
Various classes of topical antibacterial products have been used in the treatment of bacterial conjunctivitis. These include the aminoglycosides, polymyxin B combinations (e.g., polymyxin B/trimethoprim, polymyxin B/bacitracin, and polymyxin B/bacitracin/neomycin), macrolides, and, most recently, the fluoroquinolones (Table 1).6 Some antibiotics traditionally used to treat bacterial conjunctivitis are no longer widely prescribed. The use of chloramphenicol is generally curtailed in the United States because of safety concerns following rare cases of bone marrow toxicity and irreversible aplastic anemia. Bacterial resistance rates of ∼10 to 14% have also been reported.7,8 Sulfacetamide has diminished efficacy, with high resistance displayed by many species of Staphylococci and by H. influenzae, and can be irritating to the eye.1,9,10
The aminoglycosides (e.g., gentamicin and tobramycin) were among the first topical antibiotics used to treat bacterial conjunctivitis.6 Gentamicin and tobramycin are bactericidal, effective primarily against gram-negative bacteria and Staphylococci, but less active against Streptococci (Table 1).6,11,12 A number of early studies demonstrated usefulness in the treatment of bacterial conjunctivitis. (Unless otherwise specified, the clinical studies reviewed in this article include patients of all ages.) Nevertheless, despite their frequent use, weakness in the antimicrobial spectrum against Streptococci contributes to their limitations in broad-spectrum treatment regimens for bacterial conjunctivitis. A double-masked, randomized clinical study in subjects ≤21 years of age with signs and symptoms of conjunctivitis, and cultures positive for H. influenzae or S. pneumoniae, showed similar clinical cure rates with gentamicin 0.3% and polymyxin B/trimethoprim (46% and 45%, respectively) at days 3 to 6 of a 10-day course of therapy (1 drop per eye every 3 h, for a total of 5 to 6 applications per day); the bacteriologic response rate, 2 to 7 days after completion of therapy was higher with polymyxin B/trimethoprim combination (83%) than with gentamicin (68%).13
Three double-masked, randomized, clinical trials, including one study with children and adolescents ≤20 years of age, evaluating bacterial conjunctival infections compared gentamicin 0.3% ophthalmic ointment (0.5 inch ribbon 5 times a day initially, then 3 times a day) and solution (2 drops every 2 h initially, then 4 times a day) with tobramycin 0.3% ophthalmic ointment and solution (same dosages as gentamicin).14–16 The two antibiotics were each administered for at least 10 days in the three studies. In the only study to show a significant difference between the two aminoglycosides, clinical cure rates were 39 to 55% for gentamicin and 46 to 61% for tobramycin (p = 0.038). Conjunctival bacterial eradication/control rates were 77 to 84% for gentamicin and 88 to 91% for tobramycin at day 11 (p = 0.011).15
Clinical cure and bacteriologic eradication/cure rates with gentamicin 0.3% and tobramycin 0.3% ophthalmic solutions compared favorably with the older fluoroquinolones, including ciprofloxacin,17,18 norfloxacin,19 ofloxacin,11,12 and lomefloxacin20,21 in double-masked, randomized, clinical trials. Clinical cure rates of 65 and 71% and bacteriologic cure rates of 76 and 72% were reported for gentamicin and norfloxacin, respectively, following a 7- or 10-day treatment course (day of culture not specified).19 Comparative studies of tobramycin and ciprofloxacin described bacterial eradication rates at day 7 for tobramycin and ciprofloxacin of 91.9 and 94.5%,17 and 84.3 and 90.1%, respectively.18 In both studies, the differences between the two treatments were not statistically significant.17,18
Aminoglycoside ophthalmic solutions require frequent administration (Table 2),6 which may lower patient adherence to prescribed dosing regimens.22 Although the fortified aminoglycoside drops used in the treatment of bacterial keratitis have been associated with ocular irritation,23 non-fortified aminoglycoside ophthalmic solutions are generally well tolerated,18,19,22 with mild to moderate ocular adverse events such as edema, pruritus, burning, and ocular discharge.18,22
Polymyxin B-Based Formulations
Polymyxin B-based combinations (e.g., polymyxin B/trimethoprim, polymyxin B/bacitracin, and polymyxin B/bacitracin/neomycin) are effective for mild cases of bacterial conjunctivitis but are not reliably bactericidal.1,9,10 As the spectrum of action of polymyxin B is limited primarily to gram-negative microbes, the combination formulations add components to polymyxin B that have activity against gram-positive pathogens commonly causing conjunctivitis (Table 1).6
A single-masked, randomized, clinical study compared the efficacy of a corticosteroid, polymyxin B/neomycin, and placebo in patients (n = 143; 207 eyes) with acute conjunctivitis (due to viral or bacterial infections, allergies, or trauma) or blepharoconjunctivitis. The study found that polymyxin B/neomycin had a higher degree of eradication of S. aureus than placebo in patients (52 eyes) with culture-positive bacterial conjunctivitis, whereas the steroid (dexamethasone) alone was more effective than antibiotic monotherapy in reducing signs and symptoms of bacterial conjunctivitis and in physician assessment of patient condition.24 In a double-masked, placebo-controlled study in children and adolescents with culture-positive conjunctivitis, the clinical cure rates with polymyxin B/bacitracin were higher compared with placebo at days 3 to 5 (62 vs. 28%) and days 8 to 10 (91 vs. 72%). Similarly, the bacteriological cure rates were significantly higher compared with placebo at days 3 to 5 (71 vs. 19%) and days 8 to 10 (79 vs. 31%).25 Two separate double-masked, randomized studies comparing different polymyxin B combinations (polymyxin B/trimethoprim/sulfacetamide vs. polymyxin B/neomycin/gramicidin; and polymyxin B/ trimethoprim/sulfacetamide vs. polymyxin B/trimethoprim) administered for 10 days in patients with conjunctivitis or blepharitis reported no significant differences among regimens in bacteriologic cure rates (77 to 90%).26 Although these studies demonstrate the effectiveness of polymyxin B-based formulations in the treatment of bacterial conjunctivitis, a recent study suggested that these formulations may be slower in resolving bacterial conjunctivitis than newer antibacterials.27 Comparing polymyxin B sulfate/trimethoprim with moxifloxacin in 56 patients <18 years of age, this study found that treatment with moxifloxacin led to a significantly (p = 0.001) faster rate of complete resolution of ocular signs and symptoms at 48 h than treatment with the polymyxin B combination.27
Similar to aminoglycosides, polymyxin B combination ophthalmic formulations require administration every 3 to 4 h for 7 to 10 days (Table 2),6 which may decrease compliance with treatment. In reported clinical studies, polymyxin B combination formulations were well tolerated.24,28,29 Topical ophthalmic application of polymyxin B in combination with neomycin and gramicidin was generally safe and tolerable in a corneal ulceration study. No serious adverse events were reported, although 8% of patients reported toxic punctate epitheliopathy or allergic reactions.30 Similarly, combination trimethoprim and polymyxin B was well tolerated in a bacterial conjunctivitis study, with a 7% rate of adverse effects noted.31
The macrolide antibiotics erythromycin and azithromycin are bacteriostatic antimicrobial agents (Table 1).6 Erythromycin ophthalmic ointment has been available since 1982, but, in the treatment of bacterial conjunctivitis, it is generally recommended only for prophylaxis of neonatal conjunctivitis, because activity against S. aureus has diminished.1 Azithromycin is less active against gram-positive organisms than erythromycin but more active against gram-negative organisms, including H. influenzae.32
Azithromycin 1% ophthalmic formulation was evaluated in randomized, double-masked, comparator (vehicle or tobramycin 0.3%) studies in patients with bacterial conjunctivitis.33,34 Both clinical resolution (63.1 vs. 48.7%) and bacteriologic eradication (88.5 vs. 66.4%) rates were significantly higher for azithromycin 1% ophthalmic solution vs. vehicle, respectively, at day 6 or 7 when azithromycin was administered twice daily for 2 days, then once daily for 3 days. Bacteriologic eradication rates with azithromycin 1% for the most common causative pathogens ranged from 83 to 94%.33 Rates of microbial eradication and bacterial infection recurrence were the same with azithromycin 1% and tobramycin 0.3% in studies by Abelson et al.34 and Protzko et al.35
Ocular adverse events with azithromycin include eye irritation, headache, worsening conjunctivitis, and conjunctival hyperemia and edema and are usually well tolerated by patients.33,35 Azithromycin 1% ophthalmic solution offers twice-daily administration for 2 days followed by once-daily administration for 5 days (Table 2).6 Patients tolerated azithromycin 1% ophthalmic solution as well as vehicle in a vehicle-controlled study.33 The most common ocular adverse events associated with azithromycin 1% ophthalmic solution, occurring in <2% of patients in this study, were burning/stinging, eye irritation, conjunctival hyperemia, and worsening bacterial conjunctivitis.33
Fluoroquinolones are broad-spectrum bactericidal anti-infectives with good activity against both the gram-positive and gram-negative pathogens that most frequently cause bacterial conjunctivitis (Table 1).36–38 Fluoroquinolones act by preventing DNA replication via inhibition of DNA gyrase and topoisomerase IV in susceptible organisms.39 Due in part to structural modification leading to more balanced binding of DNA gyrase and topoisomerase IV, the newer fluoroquinolones (e.g., moxifloxacin, gatifloxacin, and besifloxacin) appear to have greater activity against common gram-positive pathogens associated with bacterial conjunctivitis, including some strains of Staphylococci and Streptococci resistant to other antibiotics.36,37,40 (All references in this article to gatifloxacin are to the 0.3% solution.) Of the newer fluoroquinolones, besifloxacin exhibits the most balanced inhibitory activity at concentrations lower than those seen with the other fluoroquinolones.41
Double-masked, randomized, placebo-controlled clinical studies have demonstrated the efficacy of fluoroquinolones for the treatment of bacterial conjunctivitis. Studies using ofloxacin 0.3% ophthalmic solution for 2 days42 and levofloxacin 0.5% ophthalmic solution, which was administered for 5 days every 2 h on days 1 and 2 while patients were awake and then every 4 h on days 3 through 5,43 showed clinical improvement in 64% (ofloxacin)42 and 78% (levofloxacin)43 of patients at the end of treatment. Both drugs were significantly more effective than placebo for clinical improvement. Levofloxacin eradicated 95% (vs. 49% for placebo) of bacteria at days 3 to 5 and 92% (vs. 53% for placebo) at days 6 to 1043 and has also been shown in comparative studies to be more effective than ofloxacin and non-inferior to moxifloxacin.44 In the ofloxacin study, 72% of subjects receiving ofloxacin and 35% of those receiving placebo experienced microbiological cure at day 2.42 In another study, bacterial eradication/reduction at day 3 was 93.6% with ciprofloxacin 0.3% ophthalmic solution administered for 3 days (every 2 or 4 h when awake), compared with 59.5% for placebo.17 A study which compared 2 to 4 times daily administration of gatifloxacin 0.3% ophthalmic solution for 5 days showed similar clinical cure rates for bid dosing (86.5%) vs. qid dosing (71.2%).45 Studies of moxifloxacin 0.5% ophthalmic solution administered 3 times a day for 4 days reported clinical cure rates of 66 to 69% at days 5 to 6 and microbiologic eradication rates of 84 to 94%.46,47 Treatment with besifloxacin ophthalmic suspension 0.6% administered 3 times a day for 5 days resulted in clinical resolution rates of 73% at day 8 in one study48 and 45.2% at day 5 in another study.49 Bacterial eradication rates were 90.0 and 91.5%, respectively.48,49
Results of double-masked, randomized studies comparing ciprofloxacin 0.3%18 and ofloxacin 0.3%11,12 with an aminoglycoside (tobramycin 0.3% or gentamicin 0.3%) did not favor one over the other. For example, in a study of pediatric patients with culture-positive acute bacterial conjunctivitis, the clinical cure rates at day 7 were 87.0% for ciprofloxacin and 89.9% for tobramycin (each administered every 2 or 4 h daily), and the respective microbiologic eradication rates were 90.1 and 84.3%.18 The clinical improvement rate (proportion of patients who showed improvement in a cumulative summary score) at day 11 in a comparative study of ofloxacin and tobramycin administered for 10 days was 98.9 vs. 100%, respectively, but the decrease from baseline in the clinical cumulative summary score (sum of scores for 10 key biomicroscopy and symptom variables) was significantly greater with ofloxacin at day 3 to 5.11 The microbiologic improvement rate (reduction in or eradication of bacterial colony count) was similar between both agents at day 11.
Fluoroquinolone ophthalmic solutions have been compared in double-masked, randomized, clinical studies. A subset analysis of pediatric patients (aged 1 to 16 years) from two clinical studies comparing levofloxacin 0.5% ophthalmic solution with ofloxacin 0.3% ophthalmic solution administered every 2 or 4 h daily for 5 days reported similar clinical cure rates (81 vs. 86%, respectively) but higher microbial eradication rates with levofloxacin (85 vs. 68%, respectively), which were significantly better with levofloxacin in children aged 2 to 11 years (87 vs. 62%) at days 6 to 10.50 A study of all age groups (infants to adults) comparing a 5-day regimen of levofloxacin 0.5% ophthalmic solution with ofloxacin 0.3% ophthalmic solution (every 2 or 4 h daily) supported the findings in children: 76% of patients in both treatment groups were considered clinically cured at days 6 to 10, whereas the microbial eradication rates at endpoint were significantly higher for levofloxacin (89 vs. 80%) at days 6 to 10.51 As expected, the clinical cure rate with gatifloxacin 0.3% ophthalmic solution, one of the newer fluoroquinolones, was significantly higher than with ofloxacin 0.3% ophthalmic solution (72.3 vs. 63.5%) in a comparative trial for bacterial conjunctivitis.52 There was no difference in either clinical resolution or bacterial eradication between moxifloxacin ophthalmic solution 0.5% and besifloxacin ophthalmic suspension 0.6% in a recent non-inferiority study.53
The ophthalmic preparations of the fluoroquinolones ciprofloxacin, ofloxacin, levofloxacin, and gatifloxacin require more frequent administration (e.g., every 2 h for 2 days, then four times a day for the next 5 days) than moxifloxacin, which is administered 3 times a day for 7 days, and besifloxacin, which is administered 3 times a day at 4 to 12 h intervals for 7 days (Table 2).6,11,12,54,55 Fluoroquinolone ophthalmic preparations are well tolerated43,45,47,50,51,56 and are associated with less toxicity than older antibiotics.10,11,12,23 Ocular adverse events with topical fluoroquinolones generally are mild and self-limiting and have included conjunctivitis, pruritus, discomfort, transient burning, stinging, and photophobia.11,12,23,43,45,47,50,51,56–58 Although infrequent, eye irritation occurred in fewer eyes treated with besifloxacin ophthalmic suspension 0.6% than in those receiving moxifloxacin ophthalmic solution 0.5% (p = 0.02).53
Bacterial Resistance to Current Antibiotics
Bacterial resistance is probably the most significant limitation of current ocular antibiotic therapy and is a potential cause of treatment failure. Development of bacterial resistance is complex and attributable to factors such as overuse of antibiotics for systemic infections, agricultural use of antibiotics, extended durations of treatment, prophylactic use of antibiotics, use of subtherapeutic dosages of antibiotics by non-compliant patients, and misuse of antibiotics for viral and other non-bacterial infections (Table 3).59,60
Ocular-specific breakpoints have not yet been designated for determining the susceptibility of ocular pathogens to topically administered antibiotics. Instead, susceptibility of ocular pathogens is evaluated using general Clinical and Laboratory Standards Institute procedures and systemic breakpoints, which are based on expected serum, plasma, or cerebrospinal fluid levels of antibiotics.36 These systemic breakpoints may have a limited predictive value in ocular infections, because the concentrations of antibiotic reached in some ocular tissues after topical administration generally exceed the minimum inhibitory concentration (MIC90) for common ocular pathogens.9,61 However, the higher ocular concentrations of topically administered antibiotics are diluted rapidly through tearing, which can reduce by more than half a drug's initial conjunctival volume in 2 to 5 min.9 Further research is needed to clarify the relationships between systemic breakpoints, bacterial resistance, and clinical resolution in ocular infections. At present, these tests remain useful for tracking resistance trends and ranking comparative susceptibilities.36
As discussed above, some older ocular antibiotics, such as sulfacetamide and chloramphenicol, have become limited in their usefulness because of increased bacterial resistance and toxicity. Varying degrees of resistance have also been reported in recent years to many other agents for bacterial conjunctivitis.
Bacterial Resistance to Aminoglycosides and Polymyxin B
Resistance to the aminoglycosides and polymyxin B has been documented in several studies. In a 9-year surveillance study (1990 to 1998) of bacterial keratitis isolates in South Florida, the overall in vitro resistance of S. aureus isolates to gentamicin remained stable at 11%.62 By comparison, 5.4% of S. aureus isolates were resistant to gentamicin in a 10-year surveillance study (1994 to 2003) of bacterial conjunctivitis, which was also conducted in South Florida.5 This study showed that 9.5% of gram-positive isolates and approximately 7.2% of gram-negative isolates were resistant to gentamicin, with no clear trends indicating a rise in resistance.5
A 1997 to 1998 study of pediatric patients with acute conjunctivitis described most isolates of penicillin-susceptible and non-susceptible S. pneumoniae as having intermediate resistance to topical gentamicin and tobramycin and resistance to polymyxin B.63 A European surveillance study of ocular bacterial isolates from 2001 to 2002 showed that overall resistance among 532 pathogens to gentamicin was 24.3%, due primarily to its inactivity against streptococci (94.3% of S. pneumoniae and 75.0% of other Streptococci were resistant). Resistance to gentamicin by methicillin- susceptible S. aureus (MSSA) and coagulase-negative Staphylococcus was 1.6% and 18.8%, respectively.8 A 2004 Brazilian study that reviewed patterns of resistance from 1985 to 2000 found increasing resistance among S. pneumoniae to aminoglycosides. From 1989 to 1992, 100% of S. pneumoniae cultures from the cornea or conjunctiva were shown to be susceptible to tobramycin and gentamicin. From 1997 to 2000, susceptibility among S. pneumoniae corneal and conjunctival cultures had decreased to 43.6 and 46%, respectively, for tobramycin and to 42.3 and 56%, respectively, for gentamicin.64
The aminoglycosides and polymyxin B demonstrate activity against H. influenzae. The ocular Tracking Resistance in U.S. Today (TRUST) study showed a resistance rate of 100% to polymyxin B by S. pneumoniae but no resistance from H. influenzae.65 The most recent surveillance data (1999 to 2006) from the ocular TRUST study showed resistance rates of 73.1% to tobramycin and 100% to polymyxin B by S. pneumoniae but virtually no resistance to either antibiotic by H. influenzae.65
Bacterial Resistance to Macrolides
The increase in resistance to macrolide antibiotics has been documented by monitoring of susceptibility patterns among respiratory isolates such as S. pneumoniae.66–68 Among all respiratory isolates of S. pneumoniae collected between October 2005 and April 2006 (respiratory infection season) in the United States, 34% were resistant to azithromycin, and 80.6% of those resistant to penicillin were also resistant to azithromycin.66
In the 10-year surveillance study conducted in South Florida noted above,5 a two-fold increase in resistance to erythromycin by gram-positive isolates was found, from 22.1% (1994–1995) to 45.1% (2002–2003). A two-fold increase was also found in S. aureus resistance from 23.8 to 48.9%, during the same time period.5
A study of bacterial resistance in 12 pneumococcal strains used daily subculturing of the strains with increasing concentrations of azithromycin. The study found that azithromycin selected for resistant clones in four of seven strains of Pneumococci. Azithromycin exhibited resistant clones after 50 sequential subcultures and had a seven-fold increase in MIC from 0.016 μg/mL to 2 μg/mL for the parent strains and an eight-fold increase, from 0.25 to ≥64 μg/mL, for the mutant strains.69 (In comparison, the Clinical and Laboratory Standards Institute breakpoints for Staphylococcus species are MICs of ≤8 μg/ml for susceptible bacteria and ≥16 μg/ml for resistant bacteria.65) Moderate to very high resistance to azithromycin was seen in a study of isolates from patients with bacterial conjunctivitis: the MIC90 for H. influenzae was three-fold higher than the resistance breakpoint (see below) for azithromycin, S. pneumoniae was 16-fold higher, and S. aureus and S. epidermidis were ≥128-fold higher.70
Data from the TRUST surveillance study (1999 to 2006) indicated that 74.1% of S. pneumoniae isolates were resistant to azithromycin (cross resistance with penicillin-resistant isolates was 75%), whereas H. influenzae isolates were sensitive to azithromycin.65 However, other studies have shown an increasing degree of resistance among H. influenzae isolates to macrolide antibiotics,63,70,71 with 76 and 78% of isolates exhibiting resistance to azithromycin70 and erythromycin,71 respectively. In the October 2005 through June 2006 TRUST time period, 45.5% of MSSA isolates were resistant to azithromycin. Resistance to macrolide antibiotics is attributed to widespread usage, bacteriostatic effect, and, especially for azithromycin, long elimination half-life.72,73 The inclusion of DuraSite vehicle in the azithromycin 1% ophthalmic formulation may increase the duration of exposure to the high concentration delivered topically and help to offset the selective pressure for resistance development.74
Bacterial Resistance to Fluoroquinolones
Resistance to fluoroquinolone antibiotics may result from either a single-step mutation or multistep mutations. A single-step mutation confers so-called “low-level” resistance and may not lead to clinical treatment failure if the concentration in the eye remains above the MIC90 for the isolated pathogen.38 Multistep mutants or “high-level” resistance results when bacterial isolates have acquired two or more mutations, often leading to clinical treatment failure. Multistep mutations are thought to result from repeated dosing with less than bactericidal doses.38
The primary targets of fluoroquinolones are the DNA replication enzymes DNA gyrase and topoisomerase IV.75 Resistance to older fluoroquinolones such as ciprofloxacin or ofloxacin, which preferentially target one of these enzymes over the other, is reported to be increasing, particularly among gram-positive organisms.75 A retrospective, cross-sectional study of patients with bacterial conjunctivitis found a three-fold increase in resistance for gram-positive pathogens overall (11.7 to 35.6%; p < 0.001). S. aureus isolates resistant to ciprofloxacin increased between the periods of 1994 to 1995 and 2002 to 2003 from 13.3 to 36.0%; (p < 0.001).5 Resistance rates of up to 35% for ocular isolates of S. aureus are now reported for ciprofloxacin and ofloxacin.62,76,77 Resistance to ciprofloxacin among S. aureus isolates from bacterial conjunctivitis and keratitis cases more than doubled between the periods of 1990 to 1995 and 1996 to 2001 from 8 to 20.7%.77 Approximately one third of ocular isolates of coagulase-negative Staphylococcus were resistant to ciprofloxacin and ofloxacin.8,76,78 In contrast, 1.4 and 0% of S. pneumoniae ocular isolates from an 18-month study8 and 0 and 1.8% from a 5-year study75 were resistant to ciprofloxacin and ofloxacin, respectively.
As indicated above, the newer fluoroquinolones are more balanced in their binding to DNA gyrase and topoisomerase enzymes.41 Although this balanced dual-binding mechanism has apparently delayed the development of resistance to the newer fluoroquinolones, resistance is now being reported, probably due in part to the extensive use of these fluoroquinolones for systemic infections.65,79–85 For instance, the October 2005 through June 2006 TRUST surveillance study data reported that 18.9 and 15.9% of methicillin-sensitive S. aureus isolates were resistant to gatifloxacin and moxifloxacin, respectively.65 In a case series of 42 eyes of patients in the United States with acute endophthalmitis, resistance to gatifloxacin and moxifloxacin (MIC of 8 μg/mL) was reported in three cases of coagulase-negative Staphylococcus, one case of S. aureus, and one case of methicillin-resistant S. aureus (MRSA).82 An in vitro susceptibility study of coagulase-negative Staphylococcus isolates recovered over a 15-year period from patients with clinical endophthalmitis found that resistance to gatifloxacin increased from 0% during 1990 to 1994 to 22% during 1995 to 1999 and to 31% during 2000 to 2004. A similar trend for resistance to moxifloxacin was also seen.84 This study also noted that at least 65% of coagulase-negative Staphylococcus isolates resistant to ciprofloxacin were also resistant to gatifloxacin and moxifloxacin. Resistance by S. pneumoniae and H. influenzae isolates to fluoroquinolones, especially newer fluoroquinolones such as gatifloxacin and moxifloxacin, has rarely been reported,65,70,71 although there have been reports of low rates of resistance by these pathogens to ciprofloxacin.64,65
Of particular concern among ocular isolates is the increasing frequency of MRSA and methicillin-resistant S. epidermidis (MRSE). The reported prevalence of MRSA as the cause of bacterial conjunctivitis ranges from 3% in an ophthalmic hospital in the United Kingdom86 to 57% in elderly hospitalized patients in Japan.87 In a 10-year study conducted in South Florida of isolates from conjunctival swabs from patients with bacterial conjunctivitis, recovery of MRSA increased from 4.4% (1994–1995) to 42.9% (2002–2003).5 A surveillance study in six European countries of ocular isolates from 2001 to 2002 reported that 57.1% of MRSA isolates were resistant to gatifloxacin.8 A study of MRSA isolates in the United States obtained from ocular infections (mostly conjunctivitis) reported resistance rates of 68% for moxifloxacin, 71% for gatifloxacin, and 94% for ciprofloxacin and ofloxacin. The reported median MIC50 for these MRSA isolates for the above fluoroquinolones was 8.0 μg/mL.82 The most recent surveillance data from the Ocular TRUST study (October 2005 through June 2006) in 19 states in the United Sates reported high resistance rates by MRSA to nearly all antibiotics surveyed: 63.6%, tobramycin; 100%, polymyxin B; 90.9%, azithromycin; 84.8%, ciprofloxacin; 78.8%, levofloxacin; 81.8%, gatifloxacin; and 75.8%, moxifloxacin.65 The rate of fluoroquinolone resistance by MRSE isolates from endophthalmitis, although lower, was 33% for moxifloxacin and gatifloxacin.79
Most recently, among isolates from three clinical studies conducted in the United States and Asia evaluating the efficacy and safety of besifloxacin ophthalmic suspension 0.6% for the treatment of bacterial conjunctivitis, MRSA constituted 14% of S. aureus isolates, of which 65% were ciprofloxacin resistant. All the ciprofloxacin-resistant isolates were also resistant to levofloxacin, ofloxacin, gatifloxacin, and moxifloxacin.88 In the same analysis, MRSE constituted 46% of S. epidermidis isolates, including 47% that were resistant to ciprofloxacin and other comparator fluoroquinolones tested. Besifloxacin retained potent in vitro activity against ciprofloxacin-resistant MRSA and MRSE.88,89 Besifloxacin is also the first fluoroquinolone developed for topical ophthalmic use only (i.e., besifloxacin has no systemic counterpart), theoretically limiting resistance development based on prior systemic use.
Using Pharmacokinetic/Pharmacodynamic Properties to Predict or Enhance Effectiveness of Ocular Antibiotics
Although susceptibility testing is helpful in the selection of an antimicrobial agent for ocular infections, the pharmacokinetic (PK) and pharmacodynamic (PD) features of each antibiotic will ultimately determine clinical efficacy potential. Furthermore, the PD characteristics of ocular antibiotics have implications for achieving sufficient kill rates and suppressing the development of resistance.
Antibiotics must achieve therapeutic concentrations at the site of infection to be effective. Although topical administration of antibiotics rapidly deposits high local concentrations to the conjunctiva and cornea, antibiotic concentrations are quickly dissipated through spillage onto the skin, dilution by tearing, and drainage through the nasolacrimal ducts.9 To be effective, sustained antibiotic concentrations should be several times higher than the MIC90 of the pathogen.46,59,90,91
Most ocular antibiotics are effective against common pathogens because they can generally achieve adequate concentrations on the surface of the eye. However, there are differences among drug classes and compounds with regard to targeted tissue penetration that becomes relevant to the infection being treated. For example, fluoroquinolones achieve better penetration into ocular tissue than older antibiotics (e.g., tobramycin and trimethoprim), and the newer fluoroquinolones tend to penetrate ocular tissues better than the older fluoroquinolones.46,92–96 Concentrations of moxifloxacin in the conjunctiva (6.6 ± 0.3 μg/g) were found to be two times higher than those achieved with tobramycin; three to four times higher than with ofloxacin, levofloxacin, and gatifloxacin; and more than 16 times higher than with trimethoprim.46
Combined PK and PD data can be used to characterize tissue levels of antibiotics relative to microbial susceptibility characteristics. The relationship allows for a better prediction of clinical efficacy than does reliance on MIC values alone, which do not take into account the dynamics of drug disposition in ocular tissues (Fig. 1).90,91 For antimicrobial agents that act via concentration-dependent bacterial killing (e.g., aminoglycosides and fluoroquinolones), the classic PK/PD measure of activity is the ratio of maximum concentration to MIC (Cmax/MIC). For antimicrobial agents that exhibit time-dependent bacterial killing (e.g., macrolides), the comparative measure often referred to is the length of time during which the drug concentration is above the MIC (T > MIC). Establishing PK/PD measures requires use of in vitro and animal PK/PD models; however, these measures may result in conflicting data and disagreement over which best correlates with clinical outcome.91 The ratio of the area under the concentration time curve to MIC (AUC/MIC), which combines concentration-dependent and time-dependent patterns of bacterial killing, may be the preferred measure for comparisons of different antimicrobial classes.91
In a rabbit model that simulated human systemic PKs in vivo, both AUC0 to 24/MIC and Cmax/MIC significantly correlated with the efficacy of levofloxacin and moxifloxacin against S. pneumoniae.97 Although the bacterial species impacts the AUC/MIC ratio, the following guidelines for PK/PD measures have since been used to predict clinical efficacy for fluoroquinolones: a Cmax/MIC90 ≥10 and AUC(0 to 24)/MIC90 ≥30 to 50 for gram-positive bacteria or ≥100 to 125 for gram-negative bacteria.90,98,99
The PK/PD characteristics of besifloxacin have been extensively studied in animals. The conjunctival Cmax/MIC90 ratio was >10 and AUC(0 to 24)/MIC90 was >100 for clinical isolates, including H. influenzae, S. aureus, coagulase-negative Staphylococcus, and S. pneumoniae. The besifloxacin concentrations were high enough to be predictive of clinical and microbiological efficacy while limiting the development of resistance.88,100,101 In additional animal studies comparing besifloxacin with other fluoroquinolones, besifloxacin achieved an AUC(0 to 24)/MIC90 ratio of 763 in tears, compared with <10 for moxifloxacin and gatifloxacin for methicillin-resistant and ciprofloxacin-resistant S. aureus and S. epidermidis.102 Further, the AUC(0 to 24)/MIC90 ratios for these strains were also greater with besifloxacin than with the other two fluoroquinolones in the conjunctiva, cornea, and aqueous humor.102
PK and PD data can also be used to help minimize the development of resistance. The mutant prevention concentration (MPC) is a PK/PD measure of the drug concentration needed to block the growth of first-step resistant mutants in a bacterial population.59 The MPC allows a comparison of antimicrobial potency based on the likelihood of resistance when a drug is exposed to large inocula of bacteria (Fig. 2).59,90 A comparison of the rank order of potency of four fluoroquinolones based on the MPCs for MSSA strains were moxifloxacin (0.25 mg/l) >gemifloxacin (0.5 mg/l) >gatifloxacin (1 mg/l) = levofloxacin (1 mg/l). Higher MPC values were seen against MRSA strains.89 The MPC is a less fully developed concept than other PK/PD measures and one that has not yet gained clinical applicability, perhaps because the process for determining MPC is more involved than MIC testing.
Rapid bacterial eradication, often evaluated by time-kill studies, may also minimize the emergence of resistant bacteria and curtail disease transmission.103 The results of bactericidal studies showed that moxifloxacin and gatifloxacin achieve complete rapid killing of S. aureus and S. epidermidis (45 min, moxifloxacin; 60 min, gatifloxacin). Moxifloxacin achieved complete kill of S. pneumoniae by 140 min, whereas older antibiotics (gentamicin, tobramycin, and polymyxin B/trimethoprim) showed no kill through 24 h.46 Another study comparing in vitro speed of bacterial kill reported complete killing (3-log kill) of H. influenzae at 30 min, S. aureus at 1 h, and S. pneumoniae at 2 h with moxifloxacin, whereas other types of antibiotics (tobramycin, gentamicin, and polymyxin B/trimethoprim) took longer to achieve bactericidal kill, demonstrated no change, or permitted an increase in bacterial growth.103 A third study compared concentration-dependent time-kill kinetics at 2×, 4×, and 8× MIC of gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin in isolates of S. pneumoniae, M. catarrhalis, and H. influenzae. For S. pneumoniae, the four fluoroquinolones displayed similar time-kill kinetics; for M. catarrhalis, moxifloxacin, levofloxacin, and gatifloxacin had a bactericidal effect at 6 h at 8× MIC, whereas gemifloxacin was not bactericidal; and for H. influenzae, the four fluoroquinolones were similarly bactericidal at 6 h with 8× MIC, although moxifloxacin was the most rapidly and gemifloxacin the least rapidly bactericidal at 2 and 4× MIC.102 Most recently, besifloxacin was shown to be rapidly bactericidal with complete killing of S. aureus, S. epidermidis, S. pneumoniae, and H. influenzae by 2 h (the earliest time point tested) and to have bactericidal activity against bacterial isolates resistant to other fluoroquinolones, β-lactams, macrolides, or aminoglycosides.103
Antibiotics that are primarily bacteriostatic do not demonstrate reductions in bacterial counts in in vitro time-kill studies. In the comparative time-kill study noted above, azithromycin did not exhibit bactericidal kill activity (3-log reduction) for S. aureus, S. pneumoniae, or H. influenzae within the study period of 180 min or in 24 h.101 In another time-kill study, concentrations of azithromycin ranging from 100 μg/mL to 750 μg/mL did not demonstrate bactericidal activity (3-log reduction) against S. aureus, S. pneumoniae, or H. influenzae over 1 h. The rate and extent of in vitro antibacterial activity did not change at higher concentrations, which supports the theory that azithromycin is not a concentration-dependent antimicrobial agent.73
Addition of Benzalkonium Chloride to Ocular Antibiotic Formulations
A topical ophthalmic antibiotic's antibacterial activity and ability to control the development of resistance can also be affected by the use of preservative agents, which are added to the drug to maintain its sterility. Ophthalmic formulations of fluoroquinolones, except moxifloxacin, contain benzalkonium chloride (BAK) as a preservative.6 BAK is a quaternary ammonium compound with activity against gram-positive cocci (e.g., S. aureus and S. epidermidis) and Serratia marcescens but not gram-negative rods.104–107 The antimicrobial activity of BAK may lower the MIC of the drug product against selected pathogens and possibly limit the development of resistance.108 In a study comparing the effect of adding BAK to gatifloxacin and moxifloxacin on the MIC for clinical isolates of MRSA, the MICs for both drugs were lowered markedly for all MRSA strains tested, regardless of fluoroquinolone susceptibility, by the addition of BAK. The MIC90 values were 8 μg/mL for gatifloxacin and moxifloxacin alone compared with 0.063 μg/mL for gatifloxacin with BAK and 0.125 μg/mL for moxifloxacin with BAK.108 The in vitro findings from a time-kill study showed that the killing times of S. aureus and coagulase-negative Staphylococcus were decreased by 3 h with the addition of BAK to either gatifloxacin 0.3% or moxifloxacin 0.5% ophthalmic solution. However, the effect of BAK is not considered synergistic.109 BAK had no antibacterial effect against Pseudomonas aeruginosa and did not affect the efficacy of gatifloxacin 0.3% in a gatifloxacin-resistant, methicillin-resistant S. epidermidis rabbit model of keratitis.110
Although the above studies suggest a potential benefit of BAK, the use of BAK as a preservative has also been associated with ocular toxicity. Both clinical and in vitro studies have identified adverse effects such as chronic cell injury, superficial punctate keratitis, decreased stability of precorneal tear film, reduction of corneal cell viability and proliferation, impairment of corneal healing, and increased corneal cell apoptosis.111–113 However, many studies of BAK-related toxicity identified cellular damage only after long-term use of BAK in glaucoma medications,111–113 whereas ocular treatment for bacterial conjunctivitis is generally administered for 7 or, at most, 14 days.6
Finally, the potential toxicity and enhancement of antibiotic efficacy from the addition of BAK will be mitigated by the same reflex tearing and blinking induced by instillation of a topical antibiotic and that reduces the effect of the antibiotic.110 Dilution by tears has been shown to reduce the concentration of BAK to near 0 within 20 min.114 Therefore, the role of BAK in ophthalmic solutions is being debated. Caution in extrapolating the clinical relevance of in vitro results is always warranted,109 and such findings will require confirmation through clinical studies.
Clinical studies of ocular infections have documented a gradual decline in the effectiveness of many commonly used topical antibacterial agents, creating a continuing demand for newer, effective treatments and better strategies to minimize resistance. The development of several generations of fluoroquinolones reflects those efforts to stay ahead of the resistance curve. The most recently developed ocular fluoroquinolones have, in fact, demonstrated improved clinical efficacy. Even so, surveillance data confirm increasing resistance to these compounds, highlighting the need for continuing development in this field. In response, research is focusing more purposefully not only on the discovery of new compounds but also on the development of compounds for specialized uses. For example, the most recently marketed fluoroquinolone, besifloxacin, was developed exclusively for ocular application.
Developing new antibiotic compounds is not the only strategy for combating ocular pathogen resistance. A greater appreciation is evolving for the importance of manipulating ocular antibiotic PK and PD characteristics to optimize efficacy and minimize resistance. Ocular antibiotic administration represents a unique PK/PD environment relative to systemic antibiotic use, and traditional MIC determinations may have lesser utility in the ocular setting. More sophisticated PK/PD correlations, such as Cmax/MIC90 and AUC(0 to 24)/MIC90 ratios and MPC, are increasingly being applied and may be especially useful in predicting potential ocular efficacy. Continued research could lead to an even greater understanding of the complex interactions between host, antibiotic PK/PD features, pathogen susceptibility characteristics, and the additive effects of preservatives such as BAK. The success of this research will hopefully stimulate even further progress in the management of ocular infections.
We thank the contributions of Sandra Westra, PharmD, and Jessica Umbriac (Churchill Communications) in assisting with preparation of the manuscript.
Koffler Vision Group
120 N Eagle Creek Drive, Suite 431
Lexington, Kentucky 40509
1.Diamant JI, Hwang DG. Therapy for bacterial conjunctivitis. Ophthalmol Clin North Am 1999;12:15–20.
2.Morrow GL, Abbott RL. Conjunctivitis. Am Fam Physician 1998;57:735–46.
3.Sheikh A, Hurwitz B. Antibiotics versus placebo for acute bacterial conjunctivitis. Cochrane Database Syst Rev 2006(2):CD001211.
4.Sheikh A, Hurwitz B. Topical antibiotics for acute bacterial conjunctivitis: a systematic review. Br J Gen Pract 2001;51:473–7.
5.Cavuoto K, Zutshi D, Karp CL, Miller D, Feuer W. Update on bacterial conjunctivitis in South Florida. Ophthalmology 2008;115:51–6.
6.Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer; 2008.
7.Tuft SJ, Matheson M. In vitro antibiotic resistance in bacterial keratitis in London. Br J Ophthalmol 2000;84:687–91.
8.Morrissey I, Burnett R, Viljoen L, Robbins M. Surveillance of the susceptibility of ocular bacterial pathogens to the fluoroquinolone gatifloxacin and other antimicrobials in Europe during 2001/2002. J Infect 2004;49:109–14.
9.Leeming JP. Treatment of ocular infections with topical antibacterials. Clin Pharmacokinet 1999;37:351–60.
10.Hammond RW, Edmondson W. Treatment of ocular bacterial infections: an update. J Am Optom Assoc 1997;68:178–87.
11.Gwon A. Ofloxacin vs tobramycin for the treatment of external ocular infection. Ofloxacin Study Group II. Arch Ophthalmol 1992;110:1234–7.
12.Gwon A. Topical ofloxacin compared with gentamicin in the treatment of external ocular infection. Ofloxacin Study Group. Br J Ophthalmol 1992;76:714–8.
13.Lohr JA, Austin RD, Grossman M, Hayden GF, Knowlton GM, Dudley SM. Comparison of three topical antimicrobials for acute bacterial conjunctivitis. Pediatr Infect Dis J 1988;7:626–9.
14.Leibowitz HM, Hyndiuk RA, Smolin GR, Nozik RA, Hunter GJ, Cagle GD, Davis DS. Tobramycin in external eye disease: a double-masked study vs. gentamicin. Curr Eye Res 1981;1:259–66.
15.Cagle G, Davis S, Rosenthal A, Smith J. Topical tobramycin and gentamicin sulfate in the treatment of ocular infections: multicenter study. Curr Eye Res 1981;1:523–34.
16.Timewell RM, Rosenthal AL, Smith JP, Cagle GD. Safety and efficacy of tobramycin and gentamicin sulfate in the treatment of external ocular infections of children. J Pediatr Ophthalmol Strabismus 1983;20:22–6.
17.Leibowitz HM. Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in the treatment of bacterial conjunctivitis. Am J Ophthalmol 1991;112:29S–33S.
18.Gross RD, Hoffman RO, Lindsay RN. A comparison of ciprofloxacin and tobramycin in bacterial conjunctivitis in children. Clin Pediatr (Phila) 1997;36:435–44.
19.Miller IM, Vogel R, Cook TJ, Wittreich J. Topically administered norfloxacin compared with topically administered gentamicin for the treatment of external ocular bacterial infections. The Worldwide Norfloxacin Ophthalmic Study Group. Am J Ophthalmol 1992;113:638–44.
20.Montero J, Casado A, Perea E, Vigo F, Pastor JC, Alio JL, Soler F, Escartin P, Clarke I, Juach A. A double-blind double-dummy comparison of topical lomefloxacin 0.3% twice daily with topical gentamicin 0.3% four times daily in the treatment of acute bacterial conjunctivitis. J Clin Res 1998;1:29–39.
21.Gallenga PE, Lobefalo L, Colangelo L, Della Loggia G, Orzalesi N, Velati P, Bujtar E, Ponte F, Damiani S, Bucci MG, Bonini S, Curatola MR, Palma LA, Bonomi L, Tomazzoli Gerosa L, Pagliarusco A, Milan E, Jauch A. Topical lomefloxacin 0.3% twice daily versus tobramycin 0.3% in acute bacterial conjunctivitis: a multicenter double-blind phase III study. Ophthalmologica 1999;213:250–7.
22.Cochereau I, Meddeb-Ouertani A, Khairallah M, Amraoui A, Zaghloul K, Pop M, Delval L, Pouliquen P, Tandon R, Garg P, Goldschmidt P, Bourcier T. 3-day treatment with azithromycin 1.5% eye drops versus 7-day treatment with tobramycin 0.3% for purulent bacterial conjunctivitis: multicentre, randomised and controlled trial in adults and children. Br J Ophthalmol 2007;91:465–9.
23.O'Brien TP, Maguire MG, Fink NE, Alfonso E, McDonnell P. Efficacy of ofloxacin vs cefazolin and tobramycin in the therapy for bacterial keratitis. Report from the Bacterial Keratitis Study Research Group. Arch Ophthalmol 1995;113:1257–65.
24.Leibowitz HM, Pratt MV, Flagstad IJ, Berrospi AR, Kundsin R. Human conjunctivitis. II. Treatment. Arch Ophthalmol 1976;94:1752–6.
25.Gigliotti F, Hendley JO, Morgan J, Michaels R, Dickens M, Lohr J. Efficacy of topical antibiotic therapy in acute conjunctivitis in children. J Pediatr 1984;104:623–6.
26.Lamberts DW, Buka T, Knowlton GM. Clinical evaluation of trimethoprim-containing ophthalmic solutions in humans. Am J Ophthalmol 1984;98:11–6.
27.Granet DB, Dorfman M, Stroman D, Cockrum P. A multicenter comparison of polymyxin B sulfate/trimethoprim ophthalmic solution and moxifloxacin in the speed of clinical efficacy for the treatment of bacterial conjunctivitis. J Pediatr Ophthalmol Strabismus 2008;45:340–9.
28.van Rensburg SF, Gibson JR, Harvey SG, Burke CA. Trimethoprim-polymyxin ophthalmic solution versus chloramphenicol ophthalmic solution in the treatment of bacterial conjunctivitis. Pharmatherapeutica 1982;3:274–7.
29.Genee E, Schlechtweg C, Bauerreiss P, Gibson JR. Trimethoprim-polymyxin eye drops versus neomycin-polymyxin-gramicidin eye drops in the treatment of presumptive bacterial conjunctivitis, a double-blind study. Ophthalmologica 1982;184:92–6.
30.Bosscha MI, van Dissel JT, Kuijper EJ, Swart W, Jager MJ. The efficacy and safety of topical polymyxin B, neomycin and gramicidin for treatment of presumed bacterial corneal ulceration. Br J Ophthalmol 2004;88:25–8.
31.Behrens-Baumann W, Quentin CD, Gibson JR, Calthrop JG, Harvey SG, Booth K. Trimethoprim-polymyxin B sulphate ophthalmic ointment in the treatment of bacterial conjunctivitis: a double-blind study versus chloramphenicol ophthalmic ointment. Curr Med Res Opin 1988;11:227–31.
32.Drew RH, Gallis HA. Azithromycin, spectrum of activity, pharmacokinetics, and clinical applications. Pharmacotherapy 1992;12:161–73.
33.Abelson MB, Heller W, Shapiro AM, Si E, Hsu P, Bowman LM. Clinical cure of bacterial conjunctivitis with azithromycin 1%: vehicle-controlled, double-masked clinical trial. Am J Ophthalmol 2008;145:959–65.
34.Abelson M, Protzko E, Shapiro A, Garces-Soldana A, Bowman L. A randomized trial assessing the clinical efficacy and microbial eradication of 1% azithromycin ophthalmic solution vs tobramycin in adult and pediatric subjects with bacterial conjunctivitis. Clin Ophthalmol 2007;1:177–82.
35.Protzko E, Bowman L, Abelson M, Shapiro A. Phase 3 safety comparisons for 1.0% azithromycin in polymeric mucoadhesive eye drops versus 0.3% tobramycin eye drops for bacterial conjunctivitis. Invest Ophthalmol Vis Sci 2007;48:3425–9.
36.Kaliamurthy J, Nelson Jesudasan CA, Geraldine P, Parmar P, Kalavathy CM, Thomas PA. Comparison of in vitro susceptibilities of ocular bacterial isolates to gatifloxacin and other topical antibiotics. Ophthalmic Res 2005;37:117–22.
37.Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol 2004;49(Suppl. 2):S79–83.
38.Egger SF, Ruckhofer J, Alzner E, Hell M, Hitzl W, Huber-Spitzy V, Grabner G. In vitro susceptibilities to topical antibiotics of bacteria isolated from the surface of clinically symptomatic eyes. Ophthalmic Res 2001;33:117–20.
39.Mah FS. Fourth-generation fluoroquinolones: new topical agents in the war on ocular bacterial infections. Curr Opin Ophthalmol 2004;15:316–20.
40.Schlech BA, Blondeau J. Future of ophthalmic anti-infective therapy and the role of moxifloxacin ophthalmic solution 0.5% (VIGAMOX). Surv Ophthalmol 2005;50(Suppl. 1):S64–7.
41.Cambau E, Matrat S, Pan XS, Roth Dit Bettoni R, Corbel C, Aubry A, Lascols C, Driot JY, Fisher LM. Target specificity of the new fluoroquinolone besifloxacin in Streptococcus pneumoniae
, Staphylococcus aureus
and Escherichia coli.
J Antimicrob Chemother 2009;63:443–50.
42.Rose P. Management strategies for acute infective conjunctivitis in primary care: a systematic review. Expert Opin Pharmacother 2007;8:1903–21.
43.Hwang DG, Schanzlin DJ, Rotberg MH, Foulks G, Raizman MB; Levofloxacin Bacterial Conjunctivitis Placebo-controlled Study Group. A phase III, placebo controlled clinical trial of 0.5% levofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis. Br J Ophthalmol 2003;87:1004–9.
44.Keating GM. Levofloxacin 0.5% ophthalmic solution: a review of its use in the treatment of external ocular infections and in intraocular surgery. Drugs 2009;69:1267–86.
45.Yee RW, Tepedino M, Bernstein P, Jensen H, Schiffman R, Whitcup SM. A randomized, investigator-masked clinical trial comparing the efficacy and safety of gatifloxacin 0.3% administered BID versus QID for the treatment of acute bacterial conjunctivitis. Curr Med Res Opin 2005;21:425–31.
46.O'Brien TP. Evidence-based review of moxifloxacin. Int Ophthalmol Clin 2006;46:61–72.
47.Alfonso E, Crider J. Ophthalmic infections and their anti-infective challenges. Surv Ophthalmol 2005;50(Suppl. 1):S1–6.
48.Karpecki P, Depaolis M, Hunter JA, White EM, Rigel L, Brunner LS, Usner DW, Paterno MR, Comstock TL. Besifloxacin ophthalmic suspension 0.6% in patients with bacterial conjunctivitis: a multicenter, prospective, randomized, double-masked, vehicle-controlled, 5-day efficacy and safety study. Clin Ther 2009;31:514–26.
49.Tepedino ME, Heller WH, Usner DW, Brunner LS, Morris TW, Haas W, Paterno MR, Comstock TL. Phase III efficacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis. Curr Med Res Opin 2009;25:1159–69.
50.Lichtenstein SJ, Rinehart M; Levofloxacin Bacterial Conjunctivitis Study Group. Efficacy and safety of 0.5% levofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis in pediatric patients. J AAPOS 2003;7:317–24.
51.Schwab IR, Friedlaender M, McCulley J, Lichtenstein SJ, Moran CT; Levofloxacin Bacterial Conjunctivitis Active Control Study Group. A phase III clinical trial of 0.5% levofloxacin ophthalmic solution versus 0.3% ofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis. Ophthalmology 2003;110:457–65.
52.Tepedino ME, Jensen HG. Efficacy and safety of gatifloxacin 0.3% ophthalmic solution compared with ofloxacin 0.3% for treatment of acute bacterial conjunctivitis. Poster presented at the Annual Meeting of the American Academy of Ophthalmology (AAO), October 20–23, 2002. Orlando, FL.
53.McDonald MB, Protzko EE, Brunner LS, Morris TW, Haas W, Paterno MR, Comstock TL, Usner DW. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5% for treating bacterial conjunctivitis. Ophthalmology 2009;116:1615–23.
54.Vigamox [package insert]. Fort Worth, TX: Alcon Laboratories, Inc; 2008.
55.Besivance [package insert]. Rochester, NY: Bausch & Lomb Inc.; 2009.
56.Comstock TL, Paterno MR, Decory HH, Usner DW. Safety and tolerability of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis: data from six clinical and phase I safety studies. Clin Drug Investig 2010;30:675–85.
57.Silver LH, Woodside AM, Montgomery DB. Clinical safety of moxifloxacin ophthalmic solution 0.5% (VIGAMOX) in pediatric and nonpediatric patients with bacterial conjunctivitis. Surv Ophthalmol 2005;50(Suppl. 1):S55–63.
58.Roberts C. Comparison of the ocular comfort of ofloxacin 0.3% ophthalmic solution and lubricant eye drops. Clin Pediatr (Phila) 2002;41:151–4.
59.Blondeau JM, Hansen G, Metzler K, Hedlin P. The role of PK/PD parameters to avoid selection and increase of resistance: mutant prevention concentration. J Chemother 2004;16(Suppl. 3):1–19.
60.Harbarth S, Samore MH. Antimicrobial resistance determinants and future control. Emerg Infect Dis 2005;11:794–801.
61.Varaldo PE. Antimicrobial resistance and susceptibility testing: an evergreen topic. J Antimicrob Chemother 2002;50:1–4.
62.Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology 2000;107:1497–502.
63.Block SL, Hedrick J, Tyler R, Smith A, Findlay R, Keegan E, Stroman DW. Increasing bacterial resistance in pediatric acute conjunctivitis (1997–1998). Antimicrob Agents Chemother 2000;44:1650–4.
64.Chalita MR, Hofling-Lima AL, Paranhos A Jr, Schor P, Belfort R Jr. Shifting trends in in vitro antibiotic susceptibilities for common ocular isolates during a period of 15 years. Am J Ophthalmol 2004;137:43–51.
65.Asbell PA, Colby KA, Deng S, McDonnell P, Meisler DM, Raizman MB, Sheppard JD Jr, Sahm DF. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol 2008;145:951–8.
66.Critchley IA, Brown SD, Traczewski MM, Tillotson GS, Janjic N. National and regional assessment of antimicrobial resistance among community-acquired respiratory tract pathogens identified in a 2005–2006 U.S. Faropenem surveillance study. Antimicrob Agents Chemother 2007;51:4382–9.
67.Halpern MT, Schmier JK, Snyder LM, Asche C, Sarocco PW, Lavin B, Nieman R, Mandell LA. Meta-analysis of bacterial resistance to macrolides. J Antimicrob Chemother 2005;55:748–57.
68.Drago L, De Vecchi E, Nicola L, Legnani D, Prenna M, Ripa S. In vitro selection of resistance to clarithromycin in Streptococcus pneumoniae
clinical isolates. J Chemother 2005;17:161–8.
69.Clark CL, Kosowska-Shick K, Ednie LM, Appelbaum PC. Capability of 11 antipneumococcal antibiotics to select for resistance by multistep and single-step methodologies. Antimicrob Agents Chemother 2007;51:4196–201.
70.Ohnsman C, Ritterband D, O'Brien T, Girgis D, Kabat A. Comparison of azithromycin and moxifloxacin against bacterial isolates causing conjunctivitis. Curr Med Res Opin 2007;23:2241–9.
71.Buznach N, Dagan R, Greenberg D. Clinical and bacterial characteristics of acute bacterial conjunctivitis in children in the antibiotic resistance era. Pediatr Infect Dis J 2005;24:823–8.
72.Bergman M, Huikko S, Huovinen P, Paakkari P, Seppälä H; Finnish Study Group for Antimicrobial Resistance (FiRe Network). Macrolide and azithromycin use are linked to increased macrolide resistance in Streptococcus pneumoniae
. Antimicrob Agents Chemother 2006;50:3646–50.
73.Dorfman MS, Wagner RS, Jamison T, Bell B, Stroman DW. The pharmacodynamic properties of azithromycin in a kinetics-of-kill model and implications for bacterial conjunctivitis treatment. Adv Ther 2008;25:208–17.
74.Friedlaender MH, Protzko E. Clinical development of 1% azithromycin in DuraSite®, a topical azalide anti-infective for ocular surface therapy. Clin Ophthalmol 2007;1:310.
75.Chen FJ, Lo HJ. Molecular mechanisms of fluoroquinolone resistance. J Microbiol Immunol Infect 2003;36:1–9.
76.Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology 1999;106:1313–8.
77.Marangon FB, Miller D, Muallem MS, Romano AC, Alfonso EC. Ciprofloxacin and levofloxacin resistance among methicillin-sensitive Staphylococcus aureus
isolates from keratitis and conjunctivitis. Am J Ophthalmol 2004;137:453–8.
78.Kunimoto DY, Sharma S, Garg P, Rao GN. In vitro susceptibility of bacterial keratitis pathogens to ciprofloxacin. Emerging resistance. Ophthalmology 1999;106:80–5.
79.Miller DM, Vedula AS, Flynn HW Jr, Miller D, Scott IU, Smiddy WE, Murray TG, Venkatraman AS. Endophthalmitis caused by Staphylococcus epidermidis
: in vitro antibiotic susceptibilities and clinical outcomes. Ophthalmic Surg Lasers Imaging 2007;38:446–51.
80.Jhanji V, Sharma N, Satpathy G, Titiyal J. Fourth-generation fluoroquinolone-resistant bacterial keratitis. J Cataract Refract Surg 2007;33:1488–9.
81.Kotlus BS, Wymbs RA, Vellozzi EM, Udell IJ. In vitro activity of fluoroquinolones, vancomycin, and gentamicin against methicillin-resistant Staphylococcus aureus
ocular isolates. Am J Ophthalmol 2006;142:726–9.
82.Deramo VA, Lai JC, Fastenberg DM, Udell IJ. Acute endophthalmitis in eyes treated prophylactically with gatifloxacin and moxifloxacin. Am J Ophthalmol 2006;142:721–5.
83.Epstein SP, Bottone EJ, Asbell PA. Susceptibility testing of clinical isolates of Pseudomonas aeruginosa
to levofloxacin, moxifloxacin, and gatifloxacin as a guide to treating Pseudomonas ocular infections. Eye Contact Lens 2006;32:240–4.
84.Miller D, Flynn PM, Scott IU, Alfonso EC, Flynn HW Jr. In vitro fluoroquinolone resistance in staphylococcal endophthalmitis isolates. Arch Ophthalmol 2006;124:479–83.
85.Brown L. Resistance to ocular antibiotics: an overview. Clin Exp Optom 2007;90:258–62.
86.Shanmuganathan VA, Armstrong M, Buller A, Tullo AB. External ocular infections due to methicillin-resistant Staphylococcus aureus
(MRSA). Eye (Lond) 2005;19:284–91.
87.Fukuda M, Ohashi H, Matsumoto C, Mishima S, Shimomura Y. Methicillin-resistant Staphylococcus aureus
and methicillin-resistant coagulase-negative Staphylococcus ocular surface infection efficacy of chloramphenicol eye drops. Cornea 2002;21:S86–9.
88.McDonald MB, Blondeau JM, DeCory HH, Usner DW, Brunner LS, Haas W, Morris TW. Multidrug-resistant strains in clinical trials of besifloxacin in the treatment of bacterial conjunctivitis. Poster presented at the Annual Meeting of the American Academy of Ophthalmology, November 8–11, 2008. Atlanta, GA.
89.Haas W, Pillar CM, Zurenko GE, Lee JC, Brunner LS, Morris TW. Besifloxacin, a novel fluoroquinolone, has broad-spectrum in vitro activity against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 2009;53:3552–60.
90.Metzler K, Hansen GM, Hedlin P, Harding E, Drlica K, Blondeau JM. Comparison of minimal inhibitory and mutant prevention drug concentrations of 4 fluoroquinolones against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus
. Int J Antimicrob Agents 2004;24:161–7.
91.Schentag JJ. Pharmacokinetic and pharmacodynamic predictors of antimicrobial efficacy: moxifloxacin and Streptococcus pneumoniae
. J Chemother 2002;14(Suppl. 2):13–21.
92.Robertson SM, Curtis MA, Schlech BA, Rusinko A, Owen GR, Dembinska O, Liao J, Dahlin DC. Ocular pharmacokinetics of moxifloxacin after topical treatment of animals and humans. Surv Ophthalmol 2005;50(Suppl. 1):S32–45.
93.Price FW Jr, Dobbins K, Zeh W. Penetration of topically administered ofloxacin and trimethoprim into aqueous humor. J Ocul Pharmacol Ther 2002;18:445–53.
94.Wagner RS, Abelson MB, Shapiro A, Torkildsen G. Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin, ofloxacin, and levofloxacin concentrations in human conjunctival tissue. Arch Ophthalmol 2005;123:1282–3.
95.von Keyserlingk J, Beck R, Fischer U, Hehl EM, Guthoff R, Drewelow B. Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous humours of patients by different topical application modes. Eur J Clin Pharmacol 1997;53:251–5.
96.Donnenfeld ED, Schrier A, Perry HD, Aulicino T, Gombert ME, Snyder R. Penetration of topically applied ciprofloxacin, norfloxacin, and ofloxacin into the aqueous humor. Ophthalmology 1994;101:902–5.
97.Xuan D, Zhong M, Mattoes H, Bui KQ, McNabb J, Nicolau DP, Quintiliani R, Nightingale CH. Streptococcus pneumoniae
response to repeated moxifloxacin or levofloxacin exposure in a rabbit tissue cage model. Antimicrob Agents Chemother 2001;45:794–9.
98.Allen GP, Kaatz GW, Rybak MJ. In vitro activities of mutant prevention concentration-targeted concentrations of fluoroquinolones against Staphylococcus aureus
in a pharmacodynamic model. Int J Antimicrob Agents 2004;24:150–60.
99.Wright DH, Brown GH, Peterson ML, Rotschafer JC. Application of fluoroquinolone pharmacodynamics. J Antimicrob Chemother 2000;46:669–83.
100.Proksch JW, Chappa A, Haas W, Morris TW. Besifloxacin, moxifloxacin, and gatifloxacin ocular tissue AUC/MIC ratios for fluoroquinolone-resistant organisms. Invest Ophthalmol Vis Sci 2009;50:E-abstract 2673.
101.Lichtenstein SJ, Wagner RS, Jamison T, Bell B, Stroman DW. Speed of bacterial kill with a fluoroquinolone compared with nonfluoroquinolones: clinical implications and a review of kinetics of kill studies. Adv Ther 2007;24:1098–111.
102.Boswell FJ, Andrews JM, Jevons G, Wise R. Comparison of the in vitro activities of several new fluoroquinolones against respiratory pathogens and their abilities to select fluoroquinolone resistance. J Antimicrob Chemother 2002;50:495–502.
103.Haas W, Pillar CM, Hesje CK, Sanfilippo CM, Morris TW. Bactericidal activity of besifloxacin against Staphylococci, Streptococcus pneumoniae
and Haemophilus influenzae.
J Antimicrob Chemother 2010;65:1441–7.
104.McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev 1999;12:147–79.
105.Majtán V, Majtánová L. Antibacterial efficacy of disinfectants against some gramnegative bacteria. Cent Eur J Public Health 2002;10:104–6.
106.Mamoru S, Reiko U, Nobuhiro I, Naoaki H, Ellchi O, Hisashi O. Studies of antibacterial activity of benzalkonium chloride as preservative for ophthalmic solutions against gram-positive cocci and negative rods. Jpn J Pharm Health Care Sci 2003;29:341–5.
107.Dantas PE, Uesugui E, Nishiwaki-Dantas MC, Mimica LJ. Antibacterial activity of anesthetic solutions and preservatives: an in vitro comparative study. Cornea 2000;19:353–4.
108.Blondeau JM, Borsos S, Hesje CK. Antimicrobial efficacy of gatifloxacin and moxifloxacin with and without benzalkonium chloride compared with ciprofloxacin and levofloxacin against methicillin-resistant Staphylococcus aureus
. J Chemother 2007;19:146–51.
109.Kowalski RP, Kowalski BR, Romanowski EG, Mah FS, Thompson PP, Gordon YJ. The in vitro impact of moxifloxacin and gatifloxacin concentration (0.5% vs 0.3%) and the addition of benzalkonium chloride on antibacterial efficacy. Am J Ophthalmol 2006;142:730–5.
110.Mah FS, Romanowski EG, Kowalski RP, Yates KA, Gordon YJ. Does topical 0.3% gatifloxacin need BAK (benzalkonium chloride) to treat gatifloxacin-resistant, methicillin-resistant Staphylococcus epidermidis
in the NZW rabbit keratitis model? Invest Ophthalmol Vis Sci 2007;48:E-abstract 4743.
111.Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 2002;86:418–23.
112.Pauly A, Meloni M, Brignole-Baudouin F, Warnet JM, Baudouin C. Multiple endpoint analysis of the 3D-reconstituted corneal epithelium after treatment with benzalkonium chloride: early detection of toxic damage. Invest Ophthalmol Vis Sci 2009;50:1644–52.
113.Nakamura T, Teshima M, Kitahara T, Sasaki H, Uematsu M, Kitaoka T, Nakashima M, Nishida K, Nakamura J, Higuchi S. Sensitive and real-time method for evaluating corneal barrier considering tear flow. Biol Pharm Bull 2010;33:107–10.
114.Friedlaender MH, Breshears D, Amoozgar B, Sheardown H, Senchyna M. The dilution of benzalkonium chloride (BAK) in the tear film. Adv Ther 2006;23:835–41.
antimicrobial resistance; bacterial conjunctivitis; ophthalmic antibacterials; fluoroquinolones
© 2010 American Academy of Optometry
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read