Much of the impetus for developing the latest group of highly active fluoroquinolones—such as gatifloxacin 0.3% (Zymar; Allergan, Inc., Irvine, CA), moxifloxacin 0.5% (Vigamox; Alcon Laboratories, Inc., Fort Worth, TX), and levofloxacin 1.5% (Iquix; Santen, Inc., Napa, CA)—came from the observation that older ophthalmic fluoroquinolones such as ciprofloxacin (Ciloxan; Alcon Laboratories, Inc.) and ofloxacin (Ocuflox; Allergan, Inc.) had begun to show signs of declining therapeutic efficacy and increasing in vitro resistance.1 The reasons for this trend include, not just selection pressure caused by human systemic fluoroquinolone use and widespread fluoroquinolone use in US poultry farming, but also selection pressure potentially caused by indiscriminate and incorrect ophthalmic usage.1

Ophthalmologists must wisely use the newly available group of fluoroquinolones, which have improved activity relative to the older generations',2 or these agents will soon meet a fate similar to that of older fluoroquinolones. This article describes the most common errors and misconceptions associated with prescribing antibiotics and highlights new evidence that the proper use of these agents can maximize their efficacy, minimize potential side effects, and limit the development of bacterial resistance.

ERROR NO. 1: USING A SLEDGEHAMMER TO SWAT A FLY

Today's powerful, broad-spectrum antibiotics are appropriate for the treatment and prophylaxis of serious infections such as bacterial keratitis, post-LASIK keratitis, and postoperative endophthalmitis. Using these antibiotics as first-line treatment of relatively minor or chronic infections such as blepharitis or uncomplicated conjunctivitis, however, is overkill and can invite the development of resistance.

Not every infectious indication requires the newest antibiotic. Instead, the selection of an antibiotic should be tailored to the type and severity of the infection. In general, older antibiotics with a narrower spectrum can effectively treat less serious ocular infections such as blepharitis and uncomplicated bacterial conjunctivitis. Examples of excellent antimicrobials for these indications include bacitracin for blepharitis and polymyxin B-trimethoprim for uncomplicated bacterial conjunctivitis. Not only are these particular antimicrobials less likely to exert a strong degree of selection pressure that can promote resistance, but they also have the advantage of being considerably less expensive than newer fluoroquinolones.

For most routine, uncomplicated cases of bacterial conjunctivitis, older agents such as polymyxin B-trimethoprim, ciprofloxacin, and ofloxacin have been shown to be generally comparable to the newer fluoroquinolones in effecting a final clinical cure.3 The more recently introduced fluoroquinolones, however, may be more appropriate when laboratory resistance to first-line agents has been documented or when clinical nonresponsiveness or relapse has been encountered after treatment with a first-line antimicrobial. Furthermore, because fluoroquinolones with better antimicrobial activity may in some cases effect a more rapid microbiological cure than older fluoroquinolones,4 it may be preferable to use a newer fluoroquinolone as first-line therapy for cases of bacterial conjunctivitis in which rapid bacterial eradication is essential. Examples include patients at risk for secondary infectious complications from bacterial conjunctivitis (eg, those with bullous keratopathy or an avascular filtering bleb) or individuals for whom there is a need to limit horizontal transmission to their contacts at home, school, or workplace.

ERROR NO. 2: IF ONE ANTIBIOTIC IS GOOD, TWO MUST BE BETTER

Another common error is to add unneeded antibiotics to a regimen that already incorporates one of the newer, highly active fluoroquinolones. With few exceptions, as described later, this approach adds no more antibacterial activity or spectrum but instead increases costs and the likelihood of toxicity and noncompliance. Common examples of this prescribing error include using two different fluoroquinolones simultaneously or using a fluoroquinolone in combination with a nonfortified aminoglycoside.

In exceptional cases, the addition of a second agent to a newer fluoroquinolone may be justified for initial treatment or empiric prophylaxis. The prime example is infections for which the suspected pathogens are likely to display fluoroquinolone resistance, such as methicillin-resistant staphylococci or ciprofloxacin-resistant Pseudomonas. Although these pathogens can occur in community-acquired infections, they are more common in patients who have been exposed to a hospital environment (eg, healthcare workers5 or recently hospitalized patients) or who have recently been treated systemically or topically with fluoroquinolones or other broad-spectrum antimicrobials.

Methicillin resistance in staphylococci is frequently associated with the concomitant expression of fluoroquinolone resistance.6 Although newer fluoroquinolones may show somewhat better activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis (MRSA and MRSE, respectively) than the older fluoroquinolones, such activity can be variable. Therefore, infections due to MRSA and MRSE are best treated with vancomycin.

The recommendations for surgical prophylaxis in patients at increased risk for acquiring MRSA and MRSE infections are somewhat different. For intraoperative use in intraocular surgery, vancomycin may be administered via various routes, including intracamerally, subconjunctivally, and in collagen shields. The use of vancomycin delivered intracamerally by injection or via irrigating solutions, however, has been associated with an increased risk of developing clinically significant cystoid macular edema.7 Using topical vancomycin for perioperative surgical prophylaxis is also problematic because of the lack of a commercially available formulation and the strong association of topical vancomycin use with ocular surface irritation and epithelial toxicity. For these reasons, a reasonable alternative in the subgroup of patients at risk for MRSA and MRSE is to use a topical, commercially available,

8-methoxyfluoroquinolone such as gatifloxacin or moxifloxacin. Although the activity of the 8-methoxyfluoroquinolones against MRSA and MRSE can be variable2 and is less consistent than that of vancomycin, it is generally superior to the activity of fluoroquinolones such as ciprofloxacin, ofloxacin, and levofloxacin.8,9

When treating Pseudomonas aeruginosa ocular infections, all of the fluoroquinolones available for ophthalmic use (except for norfloxacin 0.3% [Chibroxin; Merck & Co., Inc., West Point, PA]) provide reasonable coverage for empiric use, but ciprofloxacin may be preferable in more severe, culture-positive cases due to its superior in vitro antipseudomonal activity compared with the other ophthalmic fluoroquinolones. Although data are lacking concerning the potential clinical benefit of combining a fluoroquinolone with a second antipseudomonal drug (such as tobramycin or amikacin), there are some strains for which in vitro testing can show an additional benefit from combination therapy. It therefore may be reasonable to consider adding an aminoglycoside in severe cases of Pseudomonas infection. Also, in cases of P. aeruginosa infection that occur in the setting of prior topical or systemic treatment with a fluoroquinolone, the possibility of encountering a fluoroquinolone-resistant P. aeruginosa strain is greater. For the empiric treatment or prophylaxis of these cases, the inclusion of fortified tobramycin or amikacin in the antibiotic regimen would be prudent.

ERROR NO. 3: IN VITRO = IN VIVO

How would one predict if a particular bacterial pathogen is likely to be resistant or susceptible to a given antibiotic? At first glance, the answer seems simple: one should perform culture and susceptibility testing (eg, Kirby-Bauer disk diffusion assay) and, on that basis, determine whether the pathogen is “susceptible,” “intermediate,” or “resistant.” Yet, relying on such in vitro testing alone in an attempt to predict the clinical response to an antimicrobial is a vast oversimplification and can lead to an erroneous therapeutic strategy.

It is important to remember that the susceptibility breakpoints are based on systemic dosing, not ophthalmic dosing. A pathogen that is deemed resistant to the typical levels of an antibiotic that can be achieved with systemic dosing might be susceptible to the higher levels achievable with topical dosing. Until ocular susceptibility breakpoint criteria are established, clinicians must interpret susceptibility reports with caution. For example, aminoglycoside resistance in P. aeruginosa is typically relative and can be overcome by increasing the aminoglycoside concentration. Thus, bacterial keratitis caused by so-called gentamicin-resistant P. aeruginosa may in fact respond well to topical gentamicin administration, which can achieve relatively higher concentrations in ocular tissues.10 Conversely, in vitro susceptibility may not necessarily predict a good clinical response. For example, streptococcal keratitis isolates that are susceptible to ciprofloxacin on in vitro testing frequently respond poorly to ciprofloxacin in vivo.11

What can explain the discrepancies between in vitro susceptibility results and clinical response? Certainly, the ocular pharmacokinetic characteristics of the antibiotic in question play an important part. One must take into account a drug's ability to achieve and sustain a desired therapeutic concentration in the tissue or fluid compartment of interest. A drug that is highly active against a particular organism but penetrates poorly into the aqueous might be adequate for treating superficial ocular surface infections, but it would be a poor choice for postoperative endophthalmitis prophylaxis. Nonfortified aminoglycosides, for example, are generally not effective for topical prophylaxis after intraocular surgery, because the anterior-chamber levels of drug achievable after topical dosing are exceedingly low.12

Pharmacodynamics is a discipline that attempts to describe how pharmacology, pharmacokinetics, pharmacogenetics, and other factors work together to govern the biological activity of a given drug over time in a living organism. Although the application of pharmacodynamics to ophthalmology (and ocular infectious disease in particular) is still in its infancy, this discipline promises to help clinicians predict whether a treatment regimen is likely to be effective or not and, in the case of antimicrobial therapy, whether such a regimen is likely to promote the development of resistance.

As an example, for fluoroquinolones, there is a dose-response relationship between the tissue concentration of the antibiotic and biological response. In general, the higher the concentration, the better. A higher tissue concentration (relative to the minimum inhibitory concentration [MIC]) translates into better bacterial killing, improved clinical response to infection, and a lower propensity for the development of resistance.1 In contrast, for cephalosporin antibiotics, bacterial killing is concentration-dependent. Thus, raising the concentration of cephalosporin would have little benefit, but extending the duration of treatment with cephalosporin would be advantageous.

ERROR NO. 4: INCORRECT DOSING

The consequences of inadequate dosing include not only a suboptimal therapeutic effect but also an increased propensity for the development of antibiotic resistance. Examples of dosing regimens that are incorrect include a dosing frequency of less than four times daily, a length of treatment or prophylaxis that extends well beyond the susceptible period for infection, and tapering rather than simply abruptly discontinuing the antibiotic. Table 1 lists some guidelines for proper dosing.

Although researchers have suggested that the ophthalmic use of fluoroquinolones should rarely lead to the development of antibiotic resistance—due to the relatively small amount of fluoroquinolones used as compared with the amounts needed for systemic and veterinary use—there is evidence that incorrect ophthalmic dosing can lead to the rapid development of high-level fluoroquinolone resistance.1 Insufficiently frequent daily dosing leads to the prolonged exposure of the lid flora to subinhibitory concentrations of fluoroquinolone, a situation that rapidly promotes the development of drug-resistant strains. Indeed, among individuals in whom either ciprofloxacin or ofloxacin was tapered over 4 weeks, the percentage of patients harboring fluoroquinolone-resistant lid flora increased from fewer than 10% before treatment to nearly 40% after 4 weeks of treatment.1 Furthermore, the majority of these isolates were found to be highly resistant, implying that the bacteria had acquired multiple mutations that were conferring resistance. The fact that the newer fluoroquinolones generally show better activity than their older counterparts does not mean they need not be adequately dosed.

Recent evidence suggests that the optimal target concentration of an antibiotic is not the MIC but a concentration significantly higher than that value. For empiric treatment and prophylaxis, the minimum target value should be the MIC90, not the more commonly reported MIC50. The MIC90 designates the concentration of antibiotic at which 90% of tested bacterial strains of a given species are inhibited, and it is generally several times higher than the more commonly reported MIC50, which represents the antibiotic concentration at which 50% of tested bacterial strains of a given species are inhibited. The minimum bacteriocidal concentration is slightly higher yet and designates the antibiotic concentration needed to kill 90% of tested bacterial strains of a given species. Finally, the mutant prevention concentration (MPC) designates the concentration at which the mutational resistance occurs at a frequency of less than 1 in 109 or, alternatively, the concentration that is sufficient to prevent the growth of a first-step resistant mutant.13 According to the MPC hypothesis, keeping the antibiotic concentration at or above the MIC can prevent the development of mutational resistance. The MPC must be determined experimentally for each strain, species, and antibiotic, but, in general for ophthalmic fluoroquinolones, it is three- to fourfold higher than the corresponding MIC. Because a much larger population of bacteria is exposed during treatment than during prophylaxis, the MPC is a more important goal for treatment than for prophylaxis.

Thus, it can be argued that the optimal target concentration for a fluoroquinolone for prophylaxis is the MIC90 and the optimal target for treatment is the MPC90. These values may be two- to tenfold higher than the MIC50. Older fluoroquinolones such as ofloxacin and ciprofloxacin typically can maximally achieve only the MIC50 in the aqueous humor, even with very frequent dosing (eg, five times in 1 hour). With the newer fluoroquinolones and their enhanced ability to achieve high levels of concentration in target tissues (eg, in the case of levofloxacin 1.5%) and/or significantly lower MICs, reaching the optimal target concentration is easier. Newer fluoroquinolones, if properly dosed, can more readily achieve the tissue concentrations that are necessary to exert the desired antibacterial effect while minimizing the likelihood of the development of resistance.

CONCLUSION

Ophthalmologists are fortunate to have a new group of fluoroquinolones that provide better options for the prophylaxis and treatment of serious ophthalmic infections than older generations. Incorrectly using these agents, however, could lead to increased risks of suboptimal therapeutic effect, side effects, and antimicrobial resistance. The guidelines presented in this article describe how judicious use, a rational application of susceptibility and pharmacokinetic data, and proper dosing can maximize the therapeutic effect of the newer fluoroquinolones and extend their useful lifetime.

David G. Hwang, MD, FACS, is Professor of Ophthalmology and Director of the Cornea Service at the University of California, San Francisco. Dr. Hwang has received speaking honoraria from Allergan Pharmaceuticals and Santen, Inc., as well as unrestricted research funds from Alcon Laboratories, Inc. He states that he holds no financial interest in any of the products mentioned herein. Dr. Hwang may be reached at (415) 476-7977; dghwang@itsa.ucsf.edu.

1. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol. 2004;49(suppl 2):S79-83.
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. Hwang DG. Bacterial conjunctivitis. In: Pepose J, Holland GN, Wilhelmus K, eds. Infections and Immunity. St. Louis: CV Mosby; 1996: 799-817.
4. Schwab IR, Friedlaender M, McCulley J, et al, 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;110:457-465.
5. Donnenfeld ED, O'Brien TP, Solomon R, et al. Infectious keratitis after photorefractive keratectomy. Ophthalmology. 2003;110:743-747.
6. Venezia RA, Domaracki BE, Evans AM, et al. Selection of high-level oxacillin resistance in heteroresistant Staphylococcus aureus by fluoroquinolone exposure. Antimicrob Chemother. 2001;48:375-381.
7. Axer-Siegel R, Stiebel-Kalish H, Rosenblatt I, et al. Cystoid macular edema after cataract surgery with intraocular vancomycin. Ophthalmology. 1999;106:1660-1664.
8. Marangon FB, Miller D, Muallem MS, et al. Ciprofloxacin and levofloxacin resistance among methicillin-sensitive Staphylococcus aureus isolates from keratitis and conjunctivitis. Am J Ophthalmol. 2004;137:453-458.
9. Dajcs JJ, Thibodeaux BA, Marquart ME, et al. Effectiveness of ciprofloxacin, levofloxacin, or moxifloxacin for treatment of experimental Staphylococcus aureus keratitis. Antimicrob Agents Chemother. 2004;48:1948-1952.
10. Ormerod LD, Heseltine PN, Alfonso E, et al. Gentamicin-resistant pseudomonal infection. Rationale for a redefinition of ophthalmic antimicrobial sensitivities. Cornea. 1989;8:195-199. 11. Hwang DG, Biswell R, Holsclaw DS, et al. Clinical failures associated with ciprofloxacin monotherapy of streptococcal keratitis. Ophthalmology. 1995;102(9A):101.
12. Durmaz B, Marol S, Durmaz R, et al. Aqueous humor penetration of topically applied ciprofloxacin, ofloxacin and tobramycin. Arzneimittelforschung. 1997;47:413-415.
13. 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.