Regis P. Kowalski

Emerging fluoroquinolone resistance in bacterial keratitis: A 5-year review1

OBJECTIVE To identify resistance patterns to the fluoroquinolones for patients with bacterial keratitis. DESIGN Retrospective observational case series. PARTICIPANTS All cases of bacterial keratitis presenting to the Charles T. Campbell Ophthalmic Microbiology Laboratory at the Eye and Ear Institute of Pittsburgh from January 1993 to December 1997 were reviewed. A total of 1053 ocular isolates from 825 cases of bacterial keratitis were identified. MAIN OUTCOME MEASURES In vitro laboratory susceptibility testing of ocular isolates to ciprofloxacin and ofloxacin was determined by the Kirby-Bauer disk diffusion method and interpreted using the National Committee for Clinical Laboratory Standards serum standards. RESULTS The number of cases of bacterial keratitis per year decreased from 284 in 1993 to 75 in 1997. The ratio of gram-positive to gram-negative organisms changed from 81.8%:18.2% in 1993 to 51.4%:48.6% in 1997 (chi-square, 66.00; degrees of freedom, 4; P < 0.000001). Resistance of Staphylococcus aureus to ciprofloxacin significantly increased annually from 5.8% in 1993 to 35.0% in 1997 (chi-square, 19.80; degrees of freedom, 4; P < 0.0001) and for ofloxacin from 4.7% to 35.0% over the same period (chi-square, 21.32; degrees of freedom, 4; P < 0.001). Streptococcus species and coagulase-negative Staphylococcus species showed significant resistance to both fluoroquinolones but no change in resistance over the study period. The gram-negative organisms showed good susceptibility to the fluoroquinolones. CONCLUSIONS This in vitro study shows a significant increased resistance of S. aureus to the fluoroquinolones from 1993 to 1997. In addition, gaps in fluoroquinolone coverage for Streptococcus and coagulase-negative Staphylococcus species raise concern for the use of monotherapy in treating bacterial keratitis. Contrary to what might be expected, the distribution of gram-positive to gram-negative organisms has shifted, with a decrease in the number of gram-positive organisms identified, while the number of gram-negative isolates has remained stable.

Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates

PURPOSE We compared the in vitro susceptibility patterns and the minimum inhibitory concentrations (MICs) of gatifloxacin (GAT) and moxifloxacin (MOX) (fourth-generation fluoroquinolones) to ciprofloxacin (CIP) and ofloxacin (OFX) (second-generation fluoroquinolones) and levofloxacin (LEV; third-generation fluoroquinolone) using bacterial keratitis isolates. The goal was to determine whether the fourth-generation fluoroquinolones offer any advantages over the second- and third-generation fluoroquinolones. DESIGN Experimental laboratory investigation. In contrast to an epidemiologic prevalence study, this study was designed to compare the relative susceptibility of each bacterial group to different fluoroquinolones by deliberate selection of representative isolates that were both susceptible and resistant to second-generation fluoroquinolones. METHODS In retrospect, the MICs of 177 bacterial keratitis isolates were determined to CIP, OFX, LEV, GAT, and MOX using E tests. A relative susceptibility analysis was performed for each bacterial group that included separate bacterial groups that were resistant to second-generation fluoroquinolones. The NCCLS susceptibility patterns and the MICs were compared statistically. Comparing MICs, the antibiotic with the lower MICs has greater antibacterial activity. RESULTS For most keratitis isolates, there were no susceptibility differences among the five fluoroquinolones. The fourth-generation fluoroquinolones did, however, demonstrate increased susceptibility for Staphylococcus aureus isolates that were resistant to CIP, LEV and OFX. In general, CIP demonstrated the lowest MICs for gram-negative bacteria. The MICs for fourth-generation fluoroquinolones were statistically lower than the second-generation fluoroquinolones for all gram-positive bacteria tested. Comparing the two fourth-generation fluoroquinolones, MOX demonstrated lower MICs for most gram-positive bacteria, whereas GAT demonstrated lower MICs for most gram-negative bacteria. CONCLUSIONS Based on in vitro testing, the fourth-generation fluoroquinolones may offer some advantages over those currently available for the treatment of bacterial keratitis. Clinical studies will be required to confirm these results.

Vitreous Cultures in Suspected Endophthalmitis: Biopsy or Vitrectomy?

BACKGROUND Isolation of bacteria from vitreous biopsy often guides therapy in suspected endophthalmitis. Therapeutic vitrectomy provides an additional source of culture material. The authors compared the ability of these two techniques to isolate organisms from patients with acute endophthalmitis. METHODS In a large ophthalmic microbiology laboratory during a 4-year period, the authors analyzed 206 microbial culture results from patients with suspected endophthalmitis. RESULTS Two hundred six cases were evaluated. While cultures of vitreous biopsy specimens obtained using a needle and syringe were positive in 91 (53.8%) of 169 patients, culturing the contents of the vitrectomy cassettes produced positive cultures in 29 (74.8%) of 39 patients. Both techniques were performed on 23 patients. Vitreous biopsy allowed isolation of the causative organism in 43% of these patients, whereas vitrectomy was 76% successful. Both comparisons were significant at the P < 0.01 level. No positive vitreous biopsy cultures had associated negative vitrectomy cultures. CONCLUSION Culturing the contents of the vitrectomy cassette significantly increases the likelihood of obtaining a positive culture compared with merely culturing a vitreous biopsy.

Fluoroquinolones in the Treatment of Bacterial Keratitis

PURPOSE We evaluated the potential role of three topical fluoroquinolones in the treatment of bacterial keratitis by means of a laboratory database. METHODS Antibiotic susceptibilities were determined for 153 isolates from patients with bacterial keratitis. Results were analyzed for each fluoroquinolone individually and in combination with cefazolin. RESULTS Predicted susceptibility to each cefazolin-fluoroquinolone combination (98.7%) was superior to that for single-agent therapy with ofloxacin (88.2%), ciprofloxacin (82.3%), or norfloxacin (80.4%) (P = .0002). A cefazolin-fluoroquinolone combination (98.7%) was comparable to a cefazolin-gentamicin combination (97.4%). CONCLUSIONS Combination therapy with cefazolin and a fluoroquinolone offers a reasonable alternative for the treatment of bacterial keratitis. Single-agent therapy with fluoroquinolones for vision-threatening bacterial keratitis is not advised.

Multicenter open-label study evaluating the efficacy of azithromycin ophthalmic solution 1% on the signs and symptoms of subjects with blepharitis.

Purpose: To evaluate the effect of 4 weeks of treatment with azithromycin ophthalmic solution 1% on eyelid bacterial load, tear cytokines, and signs and symptoms of blepharitis. Methods: Twenty-six subjects (mean age 64.2 years; 65% female; 100% white) with moderate to severe blepharitis received azithromycin ophthalmic solution 1% in the absence of warm compresses or eyelid scrubs for 28 days (twice a day on days 1 and 2 and once a day on days 3-28). Blepharitis signs and symptoms were evaluated at baseline (day 1) and compared with end of treatment (day 29) and 2 follow-up visits (2 and 4 weeks posttreatment). Tear collection and eyelid margin bacterial cultures were performed at baseline and end of treatment. Tear cytokines were measured by a multiplex immunobead assay. Results: Four-week azithromycin treatment demonstrated significant decreases from baseline in investigator-rated signs of meibomian gland plugging, eyelid margin redness, palpebral conjunctival redness, and ocular discharge (P ≤ 0.002) at day 29, which persisted 4 weeks posttreatment (P ≤ 0.006). Subject-reported symptoms of eyelid itching, foreign body sensation/sandiness/grittiness, ocular dryness, ocular burning/pain, and swollen/heavy eyelids also demonstrated significant improvement from baseline (P < 0.001 for all symptoms and time points, except P = 0.037 for ocular dryness at visit 4). Eyelid margin culture exhibited significant decreases in coagulase-negative staphylococci and Corynebacterium xerosis bacteria. Changes in tear cytokine concentrations were not observed. Twelve subjects experienced 19 adverse events, 15 of which were ocular and none of which were serious. Conclusions: Azithromycin provided significant improvement in signs and symptoms of blepharitis after 4 weeks of treatment compared with baseline and persisted in the 4-week follow-up period.

Acanthamoeba keratitis: The Persistence of Cases Following a Multistate Outbreak

Purpose: To describe the trend of Acanthamoeba keratitis case reports following an outbreak and the recall of a multipurpose contact lens disinfection solution. Acanthamoeba keratitis is a serious eye infection caused by the free-living amoeba Acanthamoeba that primarily affects contact lens users. Methods: A convenience sample of 13 ophthalmology centers and laboratories in the USA, provided annual numbers of Acanthamoeba keratitis cases diagnosed between 1999–2009 and monthly numbers of cases diagnosed between 2007–2009. Data on ophthalmic preparations of anti-Acanthamoeba therapies were collected from a national compounding pharmacy. Results: Data from sentinel site ophthalmology centers and laboratories revealed that the yearly number of cases gradually increased from 22 in 1999 to 43 in 2003, with a marked increase beginning in 2004 (93 cases) that continued through 2007 (170 cases; p < 0.0001). The outbreak identified from these sentinel sites resulted in the recall of a contact lens disinfecting solution. There was a statistically significant (p ≤ 0.0001) decrease in monthly cases reported from 28 cases in June 2007 (following the recall) to seven cases in June 2008, followed by an increase (p = 0.0004) in reported cases thereafter; cases have remained higher than pre-outbreak levels. A similar trend was seen in prescriptions for Acanthamoeba keratitis chemotherapy. Cases were significantly more likely to be reported during summer than during other seasons. Conclusion: The persistently elevated number of reported cases supports the need to understand the risk factors and environmental exposures associated with Acanthamoeba keratitis. Further prevention efforts are needed to reduce the number of cases occurring among contact lens wearers.

An in vitro resistance study of levofloxacin, ciprofloxacin, and ofloxacin using keratitis isolates of Staphylococcus aureus and Pseudomonas aeruginosa

PURPOSE We compared levofloxacin with ciprofloxacin and ofloxacin using the in vitro susceptibilities of Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) keratitis isolates. DESIGN Retrospective, clinical laboratory study of antibiotic susceptibility among keratitis isolates. PARTICIPANTS Keratitis isolates from 200 patients with either SA or PA keratitis. METHODS Minimum inhibitory concentrations (MICs) were determined for levofloxacin, ofloxacin, and ciprofloxacin for 93 SA keratitis isolates (68 fluoroquinolone-resistant and 25 susceptible, as determined by disk diffusion) and 107 PA keratitis isolates (13 fluoroquinolone-resistant and 94 susceptible). National Committee for Clinical Laboratory Standards susceptibilities were determined and analyzed statistically. Time kill studies were determined for fluoroquinolone-susceptible and -resistant isolates to all antibiotics at 8 microg/ml. The killing rates were determined by regression, and the colony count decreases were analyzed. MAIN OUTCOME MEASURES The susceptibilities and potencies of levofloxacin, ciprofloxacin, and ofloxacin to SA and PA were determined from the MICs. Time kill studies determined the killing rates and decreases in colony counts. RESULTS The fluoroquinolone-resistant SA susceptibilities to levofloxacin, ofloxacin, and ciprofloxacin were only 22%, 10%, and 3%, respectively. The fluoroquinolone-susceptible SA were 100% susceptible to all antibiotics, with levofloxacin demonstrating the best potency. The fluoroquinolone-resistant PA were resistant to all antibiotics. The fluoroquinolone-susceptible PA isolates were highly susceptible to levofloxacin, ofloxacin, and ciprofloxacin, with ciprofloxacin demonstrating the highest potency. For fluoroquinolone-susceptible SA and PA, the time kill studies determined that the killing rates and decreases in colony counts were equivalent for all three antibiotics tested. The time kill studies demonstrated no colony count decreases for the fluoroquinolone-resistant SA and PA. CONCLUSIONS Taken together, our susceptibility and time kill data failed to demonstrate convincing differences in the susceptibility of SA and PA keratitis isolates to levofloxacin, ciprofloxacin, and ofloxacin. In general, bacterial isolates that were resistant to ciprofloxacin and ofloxacin were also resistant to levofloxacin.

An in vitro comparison of the susceptibilities of bacterial isolates from patients with conjunctivitis and blepharitis to newer and established topical antibiotics

This retrospective study compared new and established topical antibiotics with regard to the in vitro susceptibility of bacterial isolates recovered from patients with conjunctivitis (n=385) and blepharitis (n=173) using the National Committee for Clinical Laboratory Standardsapproved disk diffusion method. The percent susceptibility of recovered isolates to single antibiotic agents or combinations were ranked from greatest to least: chloramphenicol, bacitracin/polymyxin B, ofloxacin, sulfa, ciprofloxacin, trimethoprim/polymyxin B, norfloxacin, gentamicin, bacitracin, trimethoprim, tobramycin, neomycin, erythromycin, and polymyxin B. We determined that none of the available topical antibiotics provided 100% broad spectrum coverage in vitro. Established antibiotics often provided coverage comparable to the newer drugs. Due to the unproven value of in vitro testing as a predictor of clinical outcome in bacterial blepharitis and conjunctivitis, the ophthalmologist should choose therapy based on clinical experience, ongoing critical evaluation of available antibiotics, and cost-effectiveness.

Infectious disease: changing antibiotic susceptibility

The field of ophthalmology is fortunate to have an array of antibiotics to treat bacterial infections. Because many of the older antibiotics are no longer useful for treating systemic infections, their use and associated acquired resistance have been reduced. These antibiotics, therefore, likely will continue to be effective for treating ophthalmic infections. The bacteria that cause recurrent infections (e.g., blepharitis) may acquire antibiotic resistance because of the repeated use of one particular agent for therapy (e.g., erythromycin). Recurrent pathologies and those that are treated with antibiotics that have varied broadspectrum activities should be cultured routinely to confirm infection and to institute appropriate therapy. Resistant trends of Staphylococcus aureus to the second-generation fluoroquinolones have been confirmed, and new trends of resistance for Pseudomonas aeruginosa have emerged. These antibiotics are effective but should be used judiciously to avoid bacterial resistance to them and to ensure their future potency.

Prolonged Recoverability of Desiccated Adenovirus Type 19 from Various Surfaces

Epidemic keratoconjunctivitis is a highly contagious disease whose transmission has been linked to the ophthalmologists office. The authors studied the ability of adenovirus 19 (ADV 19) to survive on surfaces commonly found in the office setting. An initial in vitro laboratory experiment demonstrated that ADV 19 in a desiccated state could be recovered up to 8 days from paper, and up to 10 days from cloth, metal, and plastic. The amount of recovered ADV 19 was significantly greater (analysis of variance, P less than 0.0001) from nonporous surfaces (plastic, metal) compared with porous surfaces (cloth, paper). A second experiment demonstrated that 35 days was the maximum length of time that desiccated ADV 19 could be recovered from a nonporous surface (plastic). The authors conclude that despite drying, ADV 19 is a hearty virus that remains potentially infectious for a long time on various surfaces that may be found in an ophthalmologists office.