Steven J. Lichtenstein

Speed of Bacterial Kill With a Fluoroquinolone Compared With Nonfluoroquinolones : Clinical Implications and a Review of Kinetics of Kill Studies

It is important to rapidly eradicate bacteria in patients with bacterial conjunctivitis in order to decrease disease transmission, shorten symptom duration, and minimize the emergence of resistant bacteria. This paper presents the results of kinetics of kill studies on 3 commonly isolated pathogens in bacterial conjunctivitis. A more rapid speed of kill with moxifloxacin compared with other nonfluoroquinolone antibiotics (tobramycin, gentamicin, polymyxin B/trimethoprim, or azithromycin) was observed inStaphylococcus aureus, Streptococcus pneumoniae, andHaemophilus influenzae infections. Moxifloxacin achieved a 99.9% kill at approximately 1 h for Saureus, 2 h for Spneumoniae, and 30 min forH influenzae. In comparison, other nonfluoroquinolone therapies took longer to achieve a bactericidal (3-log) kill and some demonstrated no change or an increase in bacterial growth. Based on these findings, it is concluded that moxifloxacin kills bacteria more rapidly than nonfluoroquinolone topical ocular antibiotics.

Perception and quality of life associated with the use of olopatadine 0.2% (Pataday™) in patients with active allergic conjunctivitis

This 28-d, open-label, multicenter, single-arm clinical study was designed to evaluate perceptions of olopatadine 0.2% in patients with active ocular allergic signs and symptoms. The study enrolled 330 patients, 5 to 94 y of age, who had previously used olopatadine 0.1% for active allergic conjunctivitis. Most patients were white (n=230; 70.1%) and female (n=239; 72.9%). Of all enrolled patients, 328 were evaluable for analysis. Throughout the study, patients instilled 1 drop of olopatadine 0.2% into each eye once daily; adverse events were documented and ocular evaluations were conducted to ensure patient safety. Direct evaluations of efficacy were not performed. On days 1 and 7, patients completed the Rhinoconjunctivitis Quality of Life Questionnaire, recorded their perceptions of olopatadine 0.1 % (day 1) or 0.2% (day 7), and had their ocular allergies assessed globally. On each of the first 6 d of treatment, patients also completed a telephone-based perception questionnaire. On day 28, patients returned to the study center, reported their treatment perceptions, had their ocular allergies assessed, and exited the trial. Overall, patients had a positive perception of olopatadine 0.2%. Patients were more satisfied with olopatadine 0.2% than they remembered being with olopatadine 0.1% (289 vs 257 patients; 87.6% vs 77.8%; P< .05). The majority of the 48 patients who wore contact lenses (n=42; 88%) believed that they could wear their contacts as desired. Significant improvement was noted in all categories of the Rhinoconjunctivitis Quality of Life Questionnaire (P< .0001). No unexpected safety findings were reported. Patients perceived olopatadine 0.2% to be effective and well tolerated.

Kinetics of kill of bacterial conjunctivitis isolates with moxifloxacin, a fluoroquinolone, compared with the aminoglycosides tobramycin and gentamicin

Purpose: To compare the kinetics and speed of kill of Streptococcus pneumoniae and Haemophilus influenzae on exposure to three topical ophthalmic antibiotic solutions. Materials and methods: Bacterial conjunctivitis isolates of S. pneumoniae and H. influenzae were exposed to 1:1000 dilutions of moxifloxacin 0.5%, tobramycin 0.3%, gentamicin 0.3%, and water (control). At 15, 30, 60, 120, and 180 minutes after exposure, aliquots were collected, cells were cultured, and viable cell counts were determined using standard microbiological methods. Results: Moxifloxacin achieved 99.9% kill (3-log reduction) at approximately 2 hours for S. pneumoniae and at 15 minutes for H. influenzae. Tobramycin and gentamicin did not achieve 3-log reduction of S. pneumoniae during the 180-minute study period. An increase in bacterial growth was noted for these isolates. Gentamicin took more than 120 minutes to achieve the 3-log reduction of H. influenzae and tobramycin did not reach the 3-log reduction of this pathogen during the 180-minute study period. Conclusion: Moxifloxacin killed S. pneumoniae and H. influenzae in vitro faster than tobramycin and gentamicin, suggesting its potential clinical benefit as a first-line treatment for bacterial conjunctivitis to minimize patient symptoms and to limit the contagiousness of the disease.

Peripheral retinal nonperfusion in septo-optic dysplasia (de Morsier syndrome)

tocoagulation was applied and the worm was successfully killed (Figure 1F). The patient reported significant subjective improvement, and his visual acuity measured 20/40 OS 1 month and 20/25 OS 3 months following the initial visit. Spectraldomain OCT showed disruption of the photoreceptors in the papillomacular region secondary to prior photocoagulation but progressive restoration of the normal inner segment/outer segment junction and photoreceptor architecture in the fovea (Figure 2B and C).

Fluoroquinolones compared to 1% azithromycin in DuraSite for bacterial conjunctivitis.

In a recent issue of Clinical Ophthalmology, Friedlaender and Protzko (2007) review the development and efficacy of 1% azithromycin in DuraSite® (AzaSite™, Inspire Pharmaceuticals, Inc., Durham, NC) for the treatment of bacterial conjunctivitis. The authors conclude that 1% azithromycin in DuraSite offers a simplified dosing regimen with sustained bactericidal levels that decrease resistance development. While 1% azithromycin in DuraSite is a new formulation of azithromycin that allows topical ocular use, azithromycin and DuraSite have been around for many years. Evidence demonstrates a greater potential for emerging resistance with azithromycin, an older drug, especially when formulated in a vehicle that prolongs low levels of antibiotic exposure over time. Azithromycin is derived from the parent class of macrolides, known to be bacteriostatic. The ability of azithromycin to achieve high intracellular concentrations compared with other macrolides is credited for its bactericidal activity. However, in clinical practice, given the high level of Gram-positive resistance patterns, azithromycin demonstrates time-dependent, bacteriostatic kill against most bacteria within its clinical spectrum. DuraSite technology allows azithromycin to stay in contact with the ocular surface longer than conventional aqueous eye drops; a potential concern for resistance that led to a US Food and Drug Administration (FDA) warning on their package insert regarding missing doses: “Skipping doses or not completing the full course of therapy may … increase the likelihood that bacteria will develop resistance and will not be treatable by AzaSite (azithromycin ophthalmic solution) or other antibiotic drugs in the future.” (Azasite 2007). In contrast, potent, rapid-killing, broad-spectrum topical anti-infectives are less likely to promote resistance and do not carry such an FDA warning. Among these agents are the ophthalmic fourth-generation fluoroquinolones (FQs) that demonstrate concentration-dependent bactericidal kill and are not reliant on time as suggested by the authors. The authors state that changing trends in the activity of newer-generation FQs demonstrate increased resistance among common bacterial conjunctivitis pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. However, within the article, all 3 cited references (Goldstein et al 1999; Venezia et al 2001; Ambrose et al 2004) document resistance patterns in older-generation FQs instead of newer fourth-generation agents such as moxifloxacin 0.5% and gatifloxacin 0.3%. The distinction is critical. The development of resistance to older FQs develops through a single-step topoisomerase mutation (topoisomerase II or topoisomerase IV). However, resistance to newer FQs requires 2 spontaneous mutations at both topoisomerase II and topoisomerase IV and occurs much less frequently (Hwang 2004). In fact, in isolates of S. aureus, S. pneumoniae, and H. influenzae from conjunctivitis patients seen in a community practice setting, resistance to a fourth-generation agent, moxifloxacin, was not observed (Ohnsman et al 2007). This study showed that only when combined with extra vehicle drops (likely containing preservative) for a total of 4 applications per day could 1% azithromycin in DuraSite (dosed twice daily for the first 2 days, then daily for 3 days) achieve a success profile similar to tobramycin dosed four times daily for 5 days. Since the clinical resolution rate of 1% azithromycin in DuraSite dosed in combination with 13 drops of vehicle (total of 20 drops) in the comparative tobramycin study was higher (79.9%) than reported in the comparative vehicle study (63.1%) with only 7 drops of azithromycin, it is probable that the numerous extra drops of vehicle created a washout effect or provided some antibacterial activity. In fact, given that the 2 arms of the study were performed simultaneously, the data indicate that without the 13 extra washout drops of vehicle, azithromycin would not have even reached equivalence to tobramycin. Furthermore, a numerical advantage and statistical trend toward greater bacterial eradication with 0.3% tobramycin (94.3%) compared with 1% azithromycin in DuraSite (88.1%) (p = 0.073) was observed, although there was no overall difference in the rate of clinical resolution at the test-of-cure visit on Day 6 between agents; a finding we suggest may be related to the self-limiting nature of the disease. High failure rates of bacterial eradication (ie, resistant isolates of S. aureus and S. pneumoniae 50% and 40%, respectively) were observed as were lower rates of overall clinical resolution (70.6% and 85.5%, respectively) in all patients infected with azithromycin-resistant isolates. Clinicians should consider the speed in which a therapy eradicates infection, the anticipated spectrum of activity, tolerability, compliance, and cost of therapy when choosing empiric antibiotic therapy. While 1% azithromycin in DuraSite offers the perceived advantage of fewer doses, equivalence to tobramycin was only reached by administering 1 drop of 1% azithromycin in DuraSite with 3 drops of vehicle (ie, 4 drops) in the eye each day, questioning the overall efficacy of a true once-daily regimen. Also disconcerting is this agent’s potential to select for resistant pathogens that can be transmitted to the fellow eye of the patient or to other close contacts as warned by the FDA in the package insert. Furthermore, less frequent dosing does not always translate into increased compliance. If a therapy is not tolerable, the benefit of less frequent dosing may not be realized. In a recently completed study, the fourth-generation FQ, moxifloxacin 0.5%, was found to be more comfortable, resulted in less blurring, and was preferred (84% to 16%) over 1% azithromycin in DuraSite (Granet et al 2007). After reviewing the data from the authors presented in their article we must disagree that 1% azithromycin in DuraSite “appears more favorable than the currently available choices in the UK and US.” When clinicians consider all factors related to therapy (eg, bacterial resistance, blurriness, dosing compliance, and comfort) we suggest rapid-killing bactericidal agents such as ophthalmic fourth-generation fluoroquinolones are better options for the treatment of conjunctivitis.

Pharmacology, clinical efficacy and safety of olopatadine hydrochloride

Olopatadine is a multimechanism anti-allergic agent that inhibits H1 receptor activation and stabilizes mast cell membranes, blocking the release of allergic and inflammatory mediators. Studies in human conjunctival mast cells clearly demonstrate, in the relevant tissue and species, olopatadine’s inhibition of histamine release, which was subsequently confirmed in allergen-challenged subjects. Its comfort and tolerability may be related to the absence of perturbation of cell membranes, in contrast to many anti-allergics, whose disruption of membranes lead to histamine release even at therapeutically relevant concentrations. In preclinical and clinical studies, olopatadine had greater efficacy and comfort than other anti-allergic agents available today for ophthalmic use.

Topical ophthalmic moxifloxacin elicits minimal or no selection of fluoroquinolone resistance among bacteria isolated from the skin, nose, and throat.

PURPOSE To investigate whether moxifloxacin therapy of bacterial conjunctivitis in children changes the moxifloxacin susceptibility of bacterial isolates in eyes, cheeks below eyes, nares, and throat. METHODS Patients (age: 1 to 12 years, n = 105) with bacterial conjunctivitis were treated topically with moxifloxacin three times a day for 7 days. Gender- and age-matched subjects with normal eyes (age: 1 to 12 years, n = 57) served as the control group. Microbiological specimens were collected on days 1 (prior to therapy), 8 (1 day after end of therapy), and 42 (follow-up). Specimens were processed to recover total bacteria and bacteria that grew on fluoroquinolone-selective media. Bacteria were identified to the species level and susceptibility to moxifloxacin and selected other antibiotics determined. RESULTS The primary pathogens recovered from the infected eyes on day 1 before therapy were Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus. None of the pre-therapy isolates of H. influenzae and S. pneumoniae were resistant to moxifloxacin. Isolates of these two pathogenic species were also recovered primarily from the nose and eyes. Moxifloxacin-resistant S. aureus isolates (minimum inhibitory concentration 1.0 μg/mL or greater) were recovered from the nose and throat prior to topical dosing on day 1. However, there was no change in the frequency of moxifloxacin-resistant isolates of S. aureus following treatment with moxifloxacin. CONCLUSION Treatment of conjunctivitis with topical ophthalmic moxifloxacin did not select for moxifloxacin resistance in H. influenzae, S. pneumoniae, or S. aureus in the eye or distal body sites.