Penetration and potency of current generation fluoroquinolones

ByTerry Kim, MD

Infections following cataract and refractive surgery can have devastating consequences. Although significant progress has been made with regard to antibiotic prophylaxis and treatment, it is still important to be aware of the capabilities and limitations of the available agents. This article discusses the penetration and potency of the newest members of the antibiotic family, the current generation 8-methoxy fluoroquinolones.

Etiology of infections

An understanding of the treatments for infection should be precluded by an understanding of the infections. Keratitis following LASIK is caused by a number of pathogens including non-tuberculous Mycobacteria and gram-positive bacteria such as Staphylococcus aureus, and less commonly by gram-negative bacteria and fungi.¹ Treatment for this complication can include flap amputation, as well as a prolonged antibiotic regimen.²

Another important type of infection, post-cataract surgery endophthalmitis, is caused mainly by the gram-positive, coagulase-negative bacteria Staphylococcus epidermidis; it can also be caused by other gram-positive bacteria and gram-negative organisms.³ Most of the time, these bacteria are present on the patient’s eyelids or lashes and surrounding areas, suggesting that preoperative reduction of ocular flora is important in preventing endophthalmitis.⁴

Current generation fluoroquinolones

The category of 8-methoxy current generation fluoroquinolones includes moxifloxacin 0.5% and gatifloxacin 0.3%. Surveys performed by the American Society of Cataract and Refractive Surgery in 2001 and 2004, before and after the introduction of these antibiotics, illustrate the organisms covered by the current generation fluoroquinolones.

In the first survey, 48% of infections following LASIK were caused by Mycobacteria strains, whereas 33% were caused by Staphylococcus species. Fungal infections accounted for 10%, followed by 3% each for Streptococcus, Nocardia and gram-negative bacterial infections.

In the second survey, non-tuberculous mycobacteria accounted for 5% of infections and Staphylococcus accounted for 61%. Gram-negative and Streptococcus bacteria also increased in share of total infections, with 12% each, followed by fungal infections and Nocardia at 5% each. The increased rate of Staphylococcus infections is most likely due to more resistant strains such as methicillin-resistant S. aureus.

Potency vs. various bacteria

Clearly, these new antibiotics are more effective against non-tuberculous Mycobacteria than earlier generation fluoroquinolones. In vitro research studies have shown them both to be more effective in fighting these organisms than previous generations of antibiotics. Minimum inhibitory concentrations (MIC) against a variety of mycobacterial strains were found to be significantly lower for moxifloxacin; notably, against Mycobacteria chelonae, the MIC for moxifloxacin was 1.6 µg/mL vs. 3.2 µg/mL for gatifloxacin.⁵ This was a statistically significant difference, showing moxifloxacin’s strength in fighting the most common Mycobacteria species seen following LASIK surgery.

Potency of Fluoroquinolones:
MICs of Selected Bacterial Isolates

Figure 1. Gatifloxacin and moxifloxacin had lower MICs than earlier generation fluoroquinolones for bacterial isolates of Staphylococcus and Streptococcus pneumoniae.⁶

Source: Kim T

In a comparison of the two current generation fluoroquinolones and some older fluoroquinolones including ciprofloxacin, ofloxacin and levofloxacin, both gatifloxacin and moxifloxacin had lower MICs for bacterial isolates of two common strains of Staphylococcus and Streptococcus pneumoniae (Figure 1).⁶ They also had similar MICs against gram-negative bacteria.

Another study of the same antibiotics’ MICs for bacterial endophthalmitis isolates further illustrated the superiority of gatifloxacin and moxifloxacin vs. even the third-generation fluoroquinolone levofloxacin. The study found that organisms resistant to the second-generation fluoroquinolones (ciprofloxacin and ofloxacin) were also resistant to levofloxacin; they were not, however, resistant to gatifloxacin or moxifloxacin.

Penetration

Aside from potency, the other important aspect in determining an antibiotic’s efficacy is its ability to penetrate the ocular tissues. Several recent studies have analyzed this, generally finding that topical moxifloxacin penetrates better than gatifloxacin and earlier generation fluoroquinolones and achieves higher concentrations in ocular tissue.

One of these studies measured the concentrations of the various antibiotics in human conjunctival tissue 20 minutes after topical administration. The mean concentration of moxifloxacin was 18.0 µg/g; none of the other four fluoroquinolones tested in the study had a concentration exceeding 2.65 µg/g (P<.0001).⁷

A prospective, randomized, multicenter trial studied human corneal concentrations of both moxifloxacin and gatifloxacin in 48 patients undergoing penetrating keratoplasty.⁸ Before the surgery, patients were treated with the commercial preparations of either of the two agents; two drops were given 5 minutes apart. High pressure liquid chromatography methods were then used to test the antibiotic concentrations in the corneal endothelium, stroma and epithelium.

In all three areas, moxifloxacin concentrations were significantly higher than gatifloxacin. Notably, the moxifloxacin concentration was approximately three times the gatifloxacin concentration in the stroma (48.5 µg/g vs. 15.7 µg/g). This is particularly important during LASIK, as high antibiotic concentrations in the corneal stroma during flap creation can help prevent contamination.

An analogous study looked at the penetration of these agents into the aqueous humor. In 50 patients undergoing cataract surgery, four drops of either of the two current generation fluoroquinolones were given 10 minutes apart up to 1 hour before surgery. The mean maximum concentration of moxifloxacin in the aqueous humor was found to be 1.80 µg/mL vs. 0.48 µg/mL for gatifloxacin (P=.00003).⁹

The reason for the differences in penetration between these two agents is most likely related to differences in molecular structure and intrinsic solubility.

Overall efficacy

Combining potency and penetration can give a better picture of the overall efficacy of the antibiotics available for cataract and refractive surgery. An agent that has the lowest MIC, the lowest minimal bactericidal concentration (MBC) and the lowest mutant prevention concentration (MPC) will be the most potent, ¹⁰ and higher concentrations found in the ocular tissues (ie, better penetration) will give the antibiotic a higher chance of eradicating these organisms and preventing the emergence of resistant strains.

The efficacy of agents can be determined by comparing the MICs for the common organisms encountered in keratitis and endophthalmitis cases with the mean tissue concentrations previously discussed. With moxifloxacin, the stroma concentration of 48.5 µg/g is many times greater than the highest MIC (6.25 for Mycobacterium intracellulare). In contrast, gatifloxacin’s concentration of 15.7 µg/g only barely exceeds the two highest MICs (12.5 for M. intracellulare and Mycobacterium avium) (Figure 2).^5,8

Moxifloxacin vs. Gatifloxacin: Atypical Mycobacteria
MICs in Relation to Human Stroma Concentrations

Figure 2. The efficacy of agents can be determined by comparing the MICs for the common various organisms encountered in keratitis and endophthalmitis cases with the mean tissue concentrations of gatifloxacin and moxifloxacin.^5,8

Source: Kim T

With regard to gram-positive bacteria, moxifloxacin’s mean concentration in the aqueous humor (1.80 µg/mL) exceeds all MICs for these organisms. Gatifloxacin’s mean concentration (0.48 µg/mL), however, barely exceeds some MICs and does not come close to exceeding others.^5,8

What do these studies tell us about infection prevention and treatment? Current generation fluoroquinolones are effective in fighting infection caused by non-tuberculous Mycobacteria as well as gram-positive bacteria such as S. aureus. Furthermore, as a result of lower MICs and higher mean concentrations in a number of tissues, moxifloxacin should provide additional assurance of efficacy in preventing and treating infections such as keratitis and endophthalmitis.

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