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Newer Fluoroquinolones demonstrate success

ByFrancis S. Mah, MD

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Fluoroquinolones are considered an effective class of antibiotics. Many ophthalmologists choose them because they possess several characteristics required to treat and prevent infections. Fluoroquinolones are rapidly bactericidal and safe, as demonstrated through a 12-year history of use.^1,2 They are broad-spectrum antibiotics with low toxicity.^1-8 Additionally, fluoroquinolones have excellent pharmacokinetics with good penetration of ocular tissues. ^1-10 Fluoroquinolones also have excellent pharmacodynamics in terms of eradicating bacteria rapidly.^1-10

Zymar (gatifloxacin 0.3%, Allergan, Inc.) and Vigamox (moxifloxacin 0.5%, Alcon Laboratories, Inc.) are the newest agents in this class of antibiotics and were developed specifically to improve gram-positive efficacy, especially against systemic infections. ^1,7-11 Gram-positive coverage is increased because the newer generation’s mode of action includes two enzymes, the DNA gyrase and topoisomerase-IV, with equal binding affinity. With earlier fluoroquinolone generations, there was one strong binding site, and now there are two. Because a double mutation is required for resistance to newer generation fluoroquinolones, resistance development is delayed as well.

In vitro testing and MICs

The minimum inhibitory concentration (MIC), or the lowest concentration required to inhibit bacteria growth, can predict theoretically which antibiotic is less likely to induce resistance and potentially which antibiotic will more effectively kill bacteria. The most potent antibiotics have the lowest MICs.¹

Gatifloxacin and moxifloxacin demonstrate a greater advantage in covering resistant endophthalmitis isolates than other fluoroquinolones such as levofloxacin, ofloxacin and ciprofloxacin, according to a study conducted by my laboratory, the Charles T. Campbell Eye Microbiology Laboratory at the University of Pittsburgh Medical Center (Figures 1, 2).² Additionally, my colleagues and I published three in vitro studies that showed the efficacy of newer generation fluoroquinolones against endophthalmitis, keratitis and conjunctivitis isolates.^3-5

Newer generation fluoroquinolones have improved activity against gram-positive organisms due to the molecular structure’s 8-methoxy group. Gram-positive pathogens that are resistant to other fluoroquinolones are susceptible to newer generation fluoroquinolones. In addition, we have documented that the new fluoroquinolones have retained activity over gram-negative organisms.

Over reporting resistance

Surgeons should be cautioned that, in terms of in vitro testing in ophthalmology, no ophthalmic or ocular susceptibility standards for resistance are set in place. Clinicians must rely on serum standards or the systemic break points for resistance. Therefore, resistance might be over reported, and break points for resistant and susceptible bacteria are unknown. More importantly, surveillance reports show trends of increasing MICs, indicating less effective antibiotics.

To test this theory, my colleagues and I observed a patient who had a methicillin-resistant Staphylococcus aureus (MRSA) infection. The smear showed gram-positive cocci in clusters. A newer generation fluoroquinolone, such as gatifloxacin or moxifloxacin, was proving effective on the patient, based on the patient’s apparent improvement. A laboratory report, however, indicated that the bacteria were resistant to both gatifloxacin and moxifloxacin. The patient remained on the newer generation fluoroquinolone due to clinical improvement, and the infection resolved despite the laboratory report’s assertion that the bacteria were resistant.

In vivo rabbit model

In vitro resistance is based on serum standards, and antibiotic concentrations are higher in ocular tissue. In an in vivo situation, dosing can be performed every 5 minutes, every 15 minutes or every hour, resulting in high levels of antibiotic concentrations in the tissues that can be much higher than that achieved by systemic administration. My colleagues and I wondered, therefore, if in vitro antibiotic resistance could be overcome in the eye in an in vivo situation with frequent dosing.

We developed a rabbit model with MRSA bacteria to attempt to answer that question.¹² MRSA bacteria are theoretically resistant to levofloxacin, ciprofloxacin and cefazolin, and newer fluoroquinolones, such as gatifloxacin, seem to be ineffective as well. Vancomycin should have been the only effective treatment in the rabbit model. Surprisingly, gatifloxacin caused a bactericidal effect and demonstrated an advantage. More surprisingly, gatifloxacin and cefazolin each eradicated the bacteria as effectively as vancomycin, which is known to be effective in this model. The study showed that gatifloxacin decreases MRSA colony counts (Figure 3) and clinical signs, is more effective than levofloxacin and ciprofloxacin and, in this model, is comparable to standard therapy using cefazolin and vancomycin.¹² Frequent dosing of gatifloxacin can overcome in vitro laboratory resistance, according to results of the study on corneal infection caused by MRSA.¹² Therefore, ophthalmologists need better standards to describe susceptibility.

BAK improves efficacy

My colleagues and I also performed several time-kill studies evaluating the efficacy of benzalkonium chloride (BAK).¹³ The solutions tested include the vehicle (Mueller-Hinton broth), 0.005% BAK, moxifloxacin 0.5%, gatifloxacin 0.3%, gatifloxacin 0.3% with 0.005% BAK and moxifloxacin 0.5% with 0.005% BAK. No commercial products were used. Each solution was tested against gram-positive S. aureus endophthalmitis, gram-positive coagulase-negative S. epidermidis endophthalmitis and gram-negative Pseudomonas aeruginosa keratitis isolates.

Samples were procured at typical time-kill times at 0, 1, 2, 4, 6, 8 and 24 hours after instillation, and the results were surprising. We found that BAK alone and the BAK-added antibiotics killed S. aureus and S. epidermidis within 1 hour. Solutions without BAK took at least 4 hours to kill the gram-positive bacteria. BAK alone had no eliminating effect against Pseudomonas, which is also shown in the literature,¹⁴ but gatifloxacin and moxifloxacin with or without BAK killed Pseudomonas within an hour. BAK alone could not kill the Pseudomonas even after 8 hours (Figure 4). We concluded that BAK is not necessary to eradicate Pseudomonas, but BAK enhances eradication of the other gram-positive bacteria in conjunction with the antibiotics in this in vitro contamination model.

Demonstrating the clinical efficacy of BAK was our next step. Again, we used a rabbit model with MRSA and tested Zymar, which has BAK, and gatifloxacin 0.3%, which does not have BAK. Although we found that gatifloxacin without BAK and Zymar were effective in reducing the number of MRSA bacteria and signs of infection, Zymar was significantly more effective at killing the bacteria in the cornea.

Newer fluoroquinolones continue to demonstrate success. They are effective and safe, according to numerous studies. Additionally, fluoroquinolones with added BAK preservative demonstrate enhanced eradication of gram-positive bacteria in the rabbit model. The studies described above, however, illustrate the need for better methods to evaluate the clinical efficacy of topical antibiotics and the need to continue laboratory studies with clinical reports.

References

1. Stroman DW, Dajcs JJ, Cupp GA, Schlech BA. In vitro and in vivo potency of moxifloxacin and moxifloxacin ophthalmic solution 0.5%, a new topical fluoroquinolone. Surv Ophthalmol. 2005;50 (Suppl 1):S16-31.
2. Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: New weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133:463-466.
3. Kowalski RP, Romanowski EG, Mah FS, et al. Intracameral Vigamox (moxifloxacin 0.5%) is non-toxic and effective in preventing endophthalmitis in a rabbit model. Am J Ophthalmol. 2005;140:497-504.
4. Kowalski RP, Yates KA, Romanowski EG, et al. An ophthalmologist’s guide to understanding antibiotic susceptibility and minimum inhibitory concentration data. Ophthalmology. 2005;112:1987.
5. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol. 2003;136:500-505.
6. Morrissey I, Burnett R. Viljoen L, Robbins M. Surveillance of the susceptibility of ocular bacterial pathogens to the fluoroquinolone gatifloxacin and other microbials in Europe during 2001/2002. J Infect. 2004;49(2):109-114.
7. Kaliamurthy J, Nelso Jesudasan CA, Geraldine P, et al. Comparison of in vitro susceptibilities of ocular bacterial isolates to gatifloxacin and other topical antibiotics. Ophthalmic Res. 2005;37(3):117-122. Epub 2005 Mar 4.
8. Ulrich M, Berger J, Moller JG, Doring G. Moxifloxacin and ciprofloxacin protect human respiratory epithelial cells against Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae in vitro. Infection. 2005;33 (Suppl 2):50-54.
9. Schlech BA, Alfonso E. Overview of the potency of moxifloxacin ophthalmic solution 0.5% (Vigamox). Surv Ophthalmol. 2005;50 (Suppl 1):S7-15.
10. Yu-Speight AW, Kern TJ, Erb HN. Ciprofloxacin and ofloxacin aqueous humor concentrations after topical administration in dogs undergoing cataract surgery. Vet Ophthalmol. 2005;8(3):181-187.
11. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol. 2004;49 (Suppl 2):S79-83.
12. Romanowski EG, Mah FS, Yates KA, et al. The successful treatment of gatifloxacin-resistant Staphylococcus aureus keratitis with Zymar (gatifloxacin 0.3%) in a NZW rabbit model. Am J Ophthalmol. 2005;139:867-877.
13. Ocular Microbiology and Immunology Group. Paper presented at the annual meeting of the American Academy of Ophthalmology; October 15-18, 2005; Chicago, Ill.
14. Lambert RJ. Comparative analysis of antibiotic and antimicrobial biocide susceptibility data in clinical isolates of methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa between 1989 and 2000. J Appl Microbiol. 2004;97:699-711.