Chapter 61
Ocular Pharmacology of Antibacterial Agents
Main Menu   Table Of Contents



The empiric selection of an antibiotic to treat an ocular infection is based on several factors including the likely organisms, their historic susceptibilities, the host, and the properties of the drug. In all serious infections, attempts to identify the organism through culturing, polymerase chain reaction, or other methods should be completed before initiating treatment. Relevant features of the host include the immune status, site of the infection, history of drug allergies, drug interactions, special concerns such as age or pregnancy, and the host's ability to absorb and metabolize the drug. Features of the drug are its pharmacodynamics or interaction between the drug and the infecting organism, its pharmacokinetics or interaction between the host and the drug, its immunomodulatory and adverse effects, treatment costs, and concerns for antibiotic resistance.1

Immunomodulatory actions of antibiotics include direct effects on phagocytosis via opsonization or oxidative intermediates, on chemotaxis, on lymphocyte proliferation, on cytokine production, and on delayed hypersensitivity and natural killer cell activity. Antibiotics shown to be upregulating include the imipenems, cefodizime, and clindamycin. Downregulation is demonstrated by the tetracyclines, erythromycin, roxithromycin, cefodizime, rifampicin, gentamicin, teicoplanin, and ampicillin.2 The ideal antiinfective agent would combine an enhancement of the natural bacterial killing mechanism and downregulation of an exaggerated inflammatory response.3

Pharmacoeconomics compares the costs and consequences of antibiotic therapy in view of efficacy, safety, and health system expenditures.4 Cost factors are continually changing as drug patents expire and improved agents become available. Overall costs are related as much to the method of delivery as to the individual agents selected. The Endophthalmitis Vitrectomy Study not only showed the lack of effectiveness of intravenous therapy but also the characteristics of the infection indicating the need for more expensive vitrectomy in conjunction with intravitreal antibiotics.5

Bacterial resistance is due to a variety of mechanisms that aim at disrupting the antimicrobial mechanism of action (Fig. 1) Increasing resistance of ocular pathogens represents an important therapeutic challenge. Antibiotic resistance is caused, paradoxically, by both overuse and underuse. Especially in developing countries, resistance often develops when people stop taking their medication as soon as they feel better.6 In the United States, resistance more often stems from overuse. The Centers for Disease Control and Prevention estimates that as many as half of the antibiotics prescribed by office-based physicians each year to treat colds, coughs, and other viral infections are unnecessary.6,7 The result of the overuse of antibiotics for systemic use, ophthalmic use, and in poultry and livestock feed, is an increasing number of bacterial strains that are stronger than the antibiotics being used against them.

Fig. 1. Mechanisms of antibiotic resistance. (Modified with permission from Boothe DM: Small Animal Clinical Pharmacology and Therapeutics, p 141. Philadelphia, WB Saunders, 2001)

Back to Top
Pharmacodynamics is the quantitative relationship between observed plasma and/or tissue concentration of an active drug form and the pharmacologic effect. As opposed to pharmacokinetics, which studies how the body handles a drug, pharmacodynamics is the study of the effects of a drug on the microorganism and the pharmacologic effects of a drug in the body 8

The minimal inhibitory concentration (MIC) is the lowest concentration of an antimicrobial agent that prevents visible growth of bacteria after a period of incubation in vitro.9 The MIC90 is the concentration at which 90% of the isolates by genus and species are inhibited (not killed). The MIC90 is ideally based on at least 100 organisms.10 For antimicrobial therapy to be effective, it is believed that a drug should, at a minimum, reach a concentration that at least exceeds the MIC90 of the target organism.

The breakpoint MIC (MICBP) of a drug is a yardstick against which the MIC for an infecting organism can be compared. The MICBP is that MIC separating susceptibility from resistance and is typically the concentration of a drug that is achieved reasonably in the serum or tissue. An organism is considered susceptible (S) if its MIC is one sixteenth to one fourth the peak drug concentration that will be achieved using the recommended dose of a drug, but this should be correlated with clinical response to the selected antimicrobial.10,11 If the MIC of the organism equals or surpasses the MICBP, the organism is considered resistant (R).11 The breakpoints in defining bacterial resistance are based on what can be achieved with systemic therapy, and therefore they may not always reflect ocular levels.

The minimal bactericidal concentration (MBC) is the lowest concentration of antimicrobial that totally suppresses growth on antibiotic-free media or that results in a 99.9% (3 log) reduction or greater decline in colony counts after overnight incubation. The MIC may be the same as the MBC, but the MBC can be several multiples of the MIC, in which case the organism is said to be resistant.9

Bactericidal drugs are defined as drugs whose MIC is very close to the minimal bactericidal concentration. However, the bactericidal effects of a drug depend on achieving sufficient concentration of the drug at the antimicrobial target tissue.12 It is important to note that bactericidal drugs can be rendered bacteriostatic should insufficient concentrations be reached. A drugs whose MBC is more than 16-fold greater than the MIC is bacteriostatic.

The inhibitory quotient (IQ) is the ratio of the antibiotic concentration in the target tissue to the MIC90 of a particular organism.13 Generally, an IQ greater than 4 is preferred, because otherwise the antibiotic may inhibit the growth of the organism but not kill it. The concept of the “inhibitory quotient” links pharmacodynamics to pharmacokinetics but is susceptible to manipulation. For instance, the numerator is typically a mean tissue concentration, which does not reflect the high patient variability of 50% or more seen in drug penetration studies. The denominator can also be manipulated if strains are pre-selected or if several resistant strains are included. For this reason, development of an IQ expressed as a range of 25% to 75% might be a more accurate value than one number.

The relationship between bacterial killing and microbiological activity is described by the area under the curve (AUC) divided by the MIC of the organism (Fig. 2). This is known as the AUC/MIC ratio or area under the inhibition curve (AUIC). The AUC/MBC ratio is also used. Aminoglycosides and fluoroquinolones exhibit concentration-dependent killing; that is, bacteria succumb more rapidly when exposed to concentrations greatly in excess of MIC values than to concentrations just above their MIC. For β-lactams and glycopeptides (cellwall–active agents) this is not the case, and further increases to more than 4 to 8 times the MIC do not increase the rate of bactericidal kill.14 Not surprisingly, some studies note a plateau of fluoroquinolone induced killing rate at very high multiple of AUC/MIC.15

Fig. 2. Pharmacokinetic parameters related to the MIC (minimum inhibitory concentration). As one increases the AUC (area under the curve), the time above the MIC and the peak: MIC and AUC: MIC ratios all increase as well. (Reprinted by permission from Appleton & Lange, Stamford, CT: Principles of Therapeutic Drug Monitoring, third edition, by William E. Evans, Jerome J. Schentag, and William J. Jusko, published by Applied Therapeutics, Inc., Vancouver, Washington, 1992, Figure 97.11, p 1950.)

Microbial killing of aminoglycosides and fluoroquinolones is most likely linked to high AUC/MIC ratios, but high peak concentrations may be important to suppress resistant mutants. If the peak concentration (Cmax) to MIC ratio is not high enough, a mutant subpopulation may emerge (16). Thus, using a dose that is too low or too infrequent is particularly detrimental with fluoroquinolones and aminoglycosides.

Time-kill curves11 are derived from in vitro susceptibility tests that determine both the overall killing capability of the antibiotic and the time required to kill. The end point is the MBC, which means that 99.9% of bacteria are killed, compared to the MIC90, in which 90% are inhibited (Fig. 3). The potential advantage of time-kill curves is that they add a time component to the measurement of bacterial killing. However, all too often, the full potential of this approach is not realized because of inappropriate experimental design and/or suboptimal quantitation of bacterial killing and regrowth curves, or the antimicrobial effect itself.

Fig. 3. Time-Kill Curve. Broth cultures inoculated with 5 × 106 CFU/mL are incubated and then exposed to different antibiotics or to a control solution. The graph above illustrates different time-kill curves for antibiotics A, B, and C. These antibioticsC could also represent different concentrations of the same antibiotic. The end point is the time to a bactericidal effect, which is considered a 3-log reduction or 99.9% kill.

Specifically, most of these studies have simulated human pharmacokinetics over a narrow dose range. This may not be appropriate for comparing different drugs, especially if the antimicrobial concentrations are close to the minimum or maximum values. Many time-kill curve studies are flawed because they compare different antibiotics at the same concentration, thereby ignoring pharmacokinetic factors such as the different penetration levels of drugs. Time-kill curves can vary greatly for a given antibiotic depending upon the concentration studied. The one-dose nature of such studies does not provide evaluation of the equiefficient dose of a new drug (the dose of the new drug that produces the same effect observed with a reference drug at its usual dose). Finally, most studies do not include a sufficient duration of observation to cover the entire regrowth phase in time-kill curve studies.17

Persistence of antimicrobial effects after brief exposure to, or the lack of detectable concentrations of, an antimicrobial is termed the post-antibiotic effect (PAE).18 For some drugs (e.g., fluorinated quinolones and aminoglycosides), the duration of the PAE, and thus antibiotic efficacy, is concentration dependent and is maximized by a large peak drug concentration (Cmax) to MIC ratio.10 The PAE may also give a patient's host defenses more time to recover, perhaps contributing to the absence of endophthalmitis in eyes with contaminated aqueous humor.

Very limited clinical data are available that could answer the question which of these pharmacodynamic variables are most important in the efficacy of ocular antibiotics under clinical conditions.16 Historically, the manner in which susceptibility is determined in vitro has been based on achievable serum levels of the drug that do not necessarily relate to ocular levels. The usual in vitro estimates of antimicrobial activity (MIC, MBC, and time-kill studies) are often determined at constant drug concentrations (static conditions) that do not consider pharmacokinetic parameters.17 Due to these limitations, in vitro data may not correlate with clinical outcomes.

The AUC/MIC ratio holds promise as a benchmark for comparing ophthalmic antimicrobial agents. In normal clinical practice, it is not possible to obtain a full concentration profile of a drug in the eye because of limited opportunity and the risks involved in the sampling of ocular fluids and tissues. A population pharmacokinetic approach (taking one sample per patient but at different times post-dose so that a curve can be plotted) may allow different agents to be compared and help us to better understand interpatient variability.19

Some clinicians are currently using AUC/MIC ratios as a measure for comparing different systemic antimicrobial agents. Since the interpretation of a value without correlation to outcome may be misleading, most clinicians rely primarily on evidence-based medical regimens obtained from clinical trials.20

Back to Top
Pharmacokinetics describes the quantitative relationship between the administered dose or dosing regimen and the observed plasma and/or tissue concentration of a drug. Pharmacokinetics can also be considered the study of what the body does to the drug.1

The eye is one of the few structures that can be considered pharmacokinetically separate from the body. This separation is possible because of two main factors: (1) absorption occurs directly into the eye before reaching the systemic circulation, and (2) elimination occurs directly into the body, which can be considered a large reservoir that can dilute drug concentration below a therapeutic threshold.21

There are five barriers to the entry of drugs into the eye (Fig. 4):

Fig. 4. Schematic diagram of the major pharmacokinetic features of the eye. There are three barriers to ocular penetration: the corneal epithelium, the blood-aqueous barrier (in the ciliary body), and the blood-retinal barriers. The outer blood-retinal barrier is in the retinal pigment epithelium; the inner one lies in the tight junctions of the retinal capillaries. Each contains an active transport pump for organic anions. Anterior-route drugs (aminoglycosides) leave the vitreous by way of the aqueous humor and canal of Schlemm. Posterior-route drugs (penicillins, cephalosporins) leave by active transport across the retina. (Barza M.: Pharmacokinetics of antibiotics. In Sabath LD (ed): Action of Antibiotics in Patients, p 29. Bern: Has Huber, 1982.)

  Corneal epithelium—Restricts the entry of water-soluble drugs into the cornea and aqueous humor. The barrier is breached by an epithelial defect or, if the epithelium is intact, is bypassed by subconjunctival injection.
  Conjunctiva/sclera—Compared to the cornea, the conjunctiva and the anterior sclera have a much larger area and are more permeable to water-soluble drugs. However, drug loss by uptake into the conjunctiva is as important as preocular clearance in reducing the fraction of drug available for corneal absorption.
  Aqueous-vitreous barrier—Bulk flow of aqueous humor from the eye and the presence of an intact lens and zonules retard the diffusion of drugs from the anterior chamber into the vitreous humor.
  Blood-aqueous barrier—tight junctions of the iridal vasculature endothelial cells limit entry into the aqueous from the blood. The epithelium of the iris and ciliary body pump anionic drugs from the aqueous into the blood stream.
  Blood-retinal barrier— tight junctions of the retinal vasculature limit the entry of drugs into the eye from the systemic circulation (internal). The pigment epithelial barrier also limits flow into the eye (external). There is an outward pumping of anions across the retina by the retinal pigment epithelium and the endothelial cells of the retinal vessels.22

In terms of drug delivery, the eye can be considered to have four target sites: (1) the pre-ocular structures of the front of the eye, such as the conjunctiva and eyelids; (2) the cornea; (3) the anterior and posterior chamber and associated tissues; and (4) the vitreous cavity. Topical administration to the front of the eye can be used to deliver pharmacologic agents to the preocular, corneal, and anterior/posterior sites, but this method is presently rarely used to deliver drugs to the vitreous cavity owing to difficulties in attaining an adequate drug concentration at the site following administration. More commonly, systemic administration or intraocular injection is used to deliver drugs to treat disorders associated with the vitreous cavity.23


A factor that influences drug availability to the three anterior ocular target sites following topical ocular administration is retention of the antibiotic in the preocular area. The volume of tears in the eye is approximately 7 μL, most of which resides in the conjunctival sacs, with approximately 1 μL covering the cornea. The volume delivered by most commercial ophthalmic eye drop dispensers is approximately 30 to 50 μL. About one half of a typical drop is spilled from the eye almost immediately because the conjunctival cul-de-sac can contain only 20 to 30 μL.24 Reflex tearing and blinking induced by instillation increases spillage onto the skin, and causes drainage through the puncta to the nasolacrimal duct and subsequent absorption. Five minutes should elapse before instillation of a second eye drop, because reflex stimulation persists for approximately 5 minutes following instillation of an eye drop.25

Average tear production of 1 μL/min will continue to dilute agents in the tear film. The antibiotic must be present in the tear film in amounts above the MIC values of the pathogen for a significant amount of time to produce microbiological and clinical improvement or cure. When the target site is intraocular, drug must be absorbed from the preocular region into the eye. However, absorption of drug across the cornea is inefficient owing to its impermeable nature and small surface area.

For drug delivery, the cornea can be considered to be composed of three layers: the epithelium, stroma, and endothelium. Bowman's layer and Descemet's membrane are important anatomically but not significant rate-determining barriers23 Drugs penetrate the outer epithelium either by partitioning through the cells (intracellular) or by passing between the cells (paracellular or intercellular). Most drugs penetrate the cornea via the intracellular route, although the paracellular route predominates for hydrophilic drugs.21 It has been demonstrated that for lipophilic compounds, the epithelium offers little resistance to absorption and the major barrier is passage across the hydrophilic stroma and the endothelium. For hydrophobic compounds, the major barrier is the outer lipophilic epithelium, whereas the hydrophilic stroma offers little resistance to drug absorption.26

Most data on antibacterial concentrations achieved in the cornea are based on assay of the contents of “full-thickness” corneal buttons. In reality, a gradient is established across the cornea, with different concentrations of drug in the different layers of the cornea.27,28 Antibacterial concentrations at the site of infection of the cornea may, therefore, be either considerably higher than published corneal concentrations (if organisms are superficially located) or significantly lower.24

The corneal route has always been assumed to be the major route of entry into the eye; however, recent evidence suggests that penetration across the conjunctiva and sclera may also contribute significantly to penetration into the anterior chamber. Several studies have shown that the outer layer of the sclera has less barrier resistance to hydrophilic drugs than the epithelium of the cornea. More research must be conducted to determine the precise conjunctival/scleral route, the critical factors, and the importance of this pathway to drug absorption into the eye.29–36 Overall, the intraocular bioavailability of topical antibiotics is typically less than 10% of the topical dose (Fig. 5).36

Fig. 5. Schematic diagram of ocular absorption. (Reprinted by permission from Worakul N, Robinson JR: Ocular pharmacokinetics/pharmacodynamics review. Eur J Pharmaceut Biopharmaceut 44:72, 1997.)

Factors Affecting Absorption.

The solubility and pH of a topical antibiotic preparation are important factors affecting drug absorption. For example, when ciprofloxacin, more soluble at its commercial formulation of pH 4.5, comes into contact with tear film at neutral pH, its solubility equilibrium is shifted, and there is a tendency for the drug to precipitate.37 Increasing the concentration (but not the volume) of an antimicrobial eye drop will increase the level of drug in the precorneal tear film and, therefore, in ocular tissues. Hypertonic eyedrops dilute drug more rapidly than do less concentrated ones as a result of the osmotic effect through the conjunctiva38 Higher corneal concentrations of drug are achieved in abraded or inflamed corneas than in normal ones.39,40 Lipophilic antibiotics, such as chloramphenicol, penetrate the intact corneal epithelium more easily than do non-lipophilic antibiotics, such as gentamicin or cefazolin. However, with epithelium absent, as is the case with most infectious corneal ulcers, the epithelial barrier is eliminated, and hydrophilic antibiotics may enter the corneal stroma more easily.39,40 For instance, topical ciprofloxacin drops achieve anterior chamber levels 2 to 3 times greater if the epithelium is compromised than if it is intact.41,42


Although precorneal and corneal factors discourage absorption, tissues in the anterior and posterior chambers are bathed continuously by circulating aqueous humor. Therefore, peripheral tissues are readily available for distribution, provided that drug properties, such as partitioning and binding, are optimal. Factors interfering with distribution include binding to melanin in the iris and the ciliary body, binding to protein in the aqueous humor, and rapid elimination of drug to an inactive site that can act as a biological reservoir, releasing drug slowly over time but producing relatively low therapeutic concentrations.21

Metabolism and Elimination.

The time between drug instillation and its appearance in the aqueous humor is the lag time. Once drugs are absorbed into the anterior chamber, they are eliminated primarily by aqueous humor turnover, which is 1.5% per minute of the anterior chamber volume. When expressed as a half-life, aqueous turnover is 46.2 minutes, or 0.77 hours. Therefore, if drugs with a half-life of approximately 45 minutes (e.g., tobramycin) are eliminated from the eye, their elimination can be explained by aqueous turnover. For drugs with a half-life of less than 45 minutes, strong tissue binding is likely responsible for the longer half-life. If the half-life is less than 45 minutes, metabolism and uptake by blood vessels in the anterior uvea or iris are other likely pathways for elimination of drugs.21

Several antibacterials, including chloramphenicol and some fluoroquinolones, penetrate the cornea sufficiently rapidly to achieve potentially therapeutic concentrations in the aqueous humour if applied frequently. However, the constant flow of aqueous from the ciliary processes, where it is secreted, through the posterior and anterior chambers and out of the eye via Schlemm's canal, prevents the accumulation of high concentrations of antibacterials at this site. Some absorption of antibacterials from the aqueous by the anterior uvea and lens is inevitable but not well characterized. Concentrations achieved in the vitreous body following topical administration are generally subtherapeutic, necessitating the administration of antibacterials systemically or by local (preferably intravitreal) injection for patients with infectious endophthalmitis.21


In general, hydrophilic drugs are more effective when given by the subconjunctival route. Absorption occurs from the reservoir of drugs at the conjunctival depot, which is not subject to precorneal factors as in topical application. Also, a subconjunctival drug bypasses the conjunctival epithelium, a significant rate-determining barrier for water-soluble drugs. The conjunctival route of administration often provides therapeutically effective drug levels for 8 to 12 hours after a single injection.21

In studies of subconjunctival injections of third-generation cephalosporins, the corneal levels achieved were fourfold higher than levels in aqueous concentrations. Concentrations in the choroid were fivefold to 15-fold higher than for the retina; retinal concentrations were about tenfold higher than vitreous cavity. Thus, there is a significant concentration gradient from choroid to retina and from retina to vitreous. In these studies, when the eyes were inflamed, the barriers appeared to be preserved. This report suggested that subconjunctival injections cannot replace intravitreal injections in the treatment of endophthalmitis.9,43 Similarly, subconjunctival injections are not as efficient as frequent topical application in treating keratitis and should be limited to situations where topical therapy is limited (eg, when the eye is patched or in uncooperative or noncompliant patients.


Because most antimicrobial agents penetrate the vitreous humor relatively poorly after systemic or periocular administration, the most effective route of administration for the treatment of endophthalmitis is by intravitreal injection.43 Once antibiotics are injected into the eye, they diffuse through the vitreous cavity without significant barriers and are eliminated from the eye by either an anterior route or a posterior route. Drugs exiting from the anterior route are removed by the flow of the aqueous humor or by diffusion across the iris surface. Drug must move through the vitreous cavity, around the lens when it is present, into the anterior chamber, and exit through the trabecular meshwork into the canal of Schlemm9 (see Fig. 2). These anatomic barriers slow egress and are the reason why drugs eliminated anteriorly have longer half-lives than those that exit by the posterior route.

Aminoglycosides, streptomycin, vancomycin, and sulfacetamide are thought to be eliminated anteriorly. The posterior route, or retinal route, is the alternative pathway for drug elimination from the vitreous cavity. The first- and second-generation cephalosporins, clindamycin, and dexamethasone are believed to be eliminated posteriorly. Posteriorly, the barrier between the vitreous humor and the retina is normally impermeable to materials of high molecular weight, but there is active transport of numerous substances out of the vitreous by the retinal structures.9 Ocular inflammation generally causes a prolongation of the half-life of drugs eliminated by the retinal route, presumably by damaging the transport pump.43 Both anterior and posterior routes of egress may come into play for some substances; ceftriaxone, a third generation cephalosporins, has been suggested as one example.9

In parallel with drug metabolism, the anterior chamber and the aqueous humor more effectively clear themselves of microorganisms than does the vitreous humor. Experimental studies have found that more organisms must be injected into the anterior chamber than into the vitreous cavity to produce endophthalmitis.44,45 One study showed positive anterior chamber contamination in 5.7% of cases during sutureless, one-handed, small incision phacoemulsification.46 Another study employing extracapsular cataract extraction (ECCE) with and without phacoemulsification showed a similar level (7.6%) of anterior chamber bacterial contamination.47 Despite the presence of bacteria in the anterior chamber, none of the patients in either of these studies developed endophthalmitis. Antimicrobial properties, immunoglobulins, and complement have been detected in the aqueous humor. These substances may help clear bacteria and explain why endophthalmitis does not develop in cases with positive cultures upon anterior chamber aspiration.46

Tissue toxicity defines the upper end of the therapeutic range for intravitreal injections. Because intravitreal injections often result in intraocular concentrations much higher than routinely achieved elsewhere in the body by intravenous dosing, toxicity considerations are particularly important in this mode of administration.9 Safe levels are typically one tenth that required to produce toxicity in rabbit models.

The selection of a periocular or intraocular route of administration depends on the ability of the drug to penetrate the cornea and on the location of the target site. In general, lids and lid margins are best treated with ointments, whereas the conjunctiva, limbus, cornea, and anterior chamber are treated most effectively by instillation of solutions or suspensions or, if unresponsive, by subconjunctival injection (21).


Drugs administered systemically penetrate the aqueous and vitreous humors with difficulty because of anatomic barriers .48 Penetration into the aqueous humor is restricted by the blood-aqueous barrier, which exists because the epithelium overlying the capillaries of the ciliary body has tight intracellular junctions. Penetration into the vitreous humor is limited because the endothelial cells of the retinal capillaries and the retinal pigment epithelium (RPE) cells overlying the choroidal capillaries have tight junctions; together, these constitute the blood-retinal barriers.49

By removing the lens and vitreous, systemically administered drugs can readily enter the vitreous cavity through both the anterior and posterior chambers. Inflammation can also increase the antimicrobial penetration into the vitreous cavity. For example, in a study of patients undergoing penetrating keratoplasty with vitrectomy, topically applied ofloxacin achieved therapeutic levels in the cornea and aqueous. Mean levels were well above the MIC90 for the bacteria responsible for the majority of endophthalmitis and corneal ulceration. The addition of oral ofloxacin to topical therapy increased vitreous penetration sevenfold.50 In another study of patients undergoing vitrectomy, inhibitory aqueous and vitreous levels above the MIC90 for many ocular pathogens were achieved with oral 500 mg of levofloxacin in two doses 4 and 16 hours before sampling at surgery.51

Back to Top
There are presently over 20 classes of antibiotics available for ocular infections, including penicillins, cephalosporins, macrolides, glycopeptides, aminoglycosides, lincosamides, flouroquinolones, carbapenems, monobactams, oxazolidinones, streptogramins, peptides, ketolides, chloramphenicol, sulfonamides, sulfones, metronidazole, azoles, triazoles, polyenes, and polymyxins. othO anti-infectives for ocular infections include amebicides, anthelmintics, abd antituberculous and antiviral agents.52 Important and widely used ocular antibiotics include the following classes.


The basic mechanism by which beta-lactam antibiotics achieve their bactericidal effect is through inhibition of bacterial cell wall synthesis. Penicillin-binding proteins, enzymes needed for bacterial cell wall synthesis, are bound and inactivated by these antibiotics, resulting in reduced integrity of the cell wall. The affinity of an individual beta-lactam antibiotic for a microbial penicillin-binding protein may in part determine the bactericidal efficacy of that particular antibiotic. Within each class of beta-lactam antibiotics, additional mechanisms of action may be present.53

Microbial resistance to beta-lactam antibiotics occurs mainly by alteration of bacterial penicillin-binding proteins, production of beta-lactamases, and/or reduced penetration of the antibiotic into the bacterium.53

Penicillins, Synthetic Penicillins, and Penicillin/Beta-Lactamase Inhibitor Combinations

The natural penicillins, such as benzathine penicillin, still have clinical use against susceptible gram-positive organisms. Unfortunately, emergence of bacterial resistance through aforementioned mechanisms has limited their efficacy. More commonly used in practice presently are penicillinase-resistant antibiotics such as oxacillin, nafcillin, and dicloxacillin.

Aminopenicillins, exemplified by amoxicillin and ampicillin, have improved penetration through the outer membranes of gram-negative organisms and thus increase the spectrum of activity while retaining good gram-positive efficacy. These agents are readily inactivated by beta-lactamases. Through side chain modifications, broader spectrum and greater stability against beta-lactamases are achieved. Carboxypenicillins such as carbenicillin and ticarcillin, have improved efficacy against Pseudomonas and Enterobacter species.

Further modifications of the basic aminopenicillin molecule led to development of the ureidopenicillins (acylaminopenicillins), such as mezlocillin and piperacillin. These agents are referred to as extended spectrum penicillins because they demonstrate improved gram-negative coverage, especially against pseudomonas and Klebsiella species. This class of antimicrobials is alsosusceptible to hydrolysis by beta-lactamases.

To further improve the efficacy of the aminopenicillins, carboxypenicillins, and ureidopenicillins, they have been combined with beta-lactamase inhibitors. Clavulinic acid, sulbactam, and tazobactam bind to and inactive beta-lactamases by irreversible competitive inhibition. These inhibitors possess only weak inherent antimicrobial activity and are always paired with another agent. There is, however, some synergistic action when the molecules are combined. Examples in this class include ampicillin-sulbactam, amoxicillin-clavulinic acid, ticarcillin-clavulinic acid, and piperacillin-tazobactam.53


Although loosely grouped into “generations” according to their spectrum of activity, individual agents within each group may have broader activity than its generation may indicate. First-generation cephalosporins, such as cephalexin and cefazolin, have in vitro activity against most gram-positive methicillin-sensitive staphylococci and streptococci. Second-generation cephalosporins, such as cefuroxime and cefotetan, have increased activity against gram-negative and enteric organisms. Resistance to beta-lactamase enzymes adds to the usefulness of these antibiotics. The third-generation cephalosporins, such as ceftazidime and ceftriaxone, further expand gram-negative activity but lose efficacy against gram-positive organisms. There is wider variation in spectrum of activity among the various agents in this class. The recent introduction of fourth-generation cephalosporins, such as cefepime, promise even better gram-negative activity, especially against Enterobacter and Pseudomonas species, with increased gram-positive activity compared to third-generation drugs. These agents appear to induce less production of beta-lactamases, and hopefully lower rates of resistant organisms. Similar to all other cephalosporin family antibiotics, these agents have no activity against enterococci or methicillin-resistant staphylococci.54


The only currently available monobactam antibiotic, aztreonam, has activity limited to gram-negative aerobic organisms. It can be used synergistically with aminoglycosides against gram-negative bacilli.54


This class of beta-lactam antibiotics, including imipenem and meropenem, has broad activity against both gram-positive and gram-negative aerobic and anaerobic species, including most enterococci. A notable exception to its range of activity are methicillin-resistant staphylococci (MRSA). Although MRSA possess resistance to most beta-lactams, these organisms can quickly induce cephalosporinases. Although the induction of these enzymes do not have a significant impact upon the carbapenems themselves, the activity of concomitantly given antibiotics, especially third-generation cephalosporins, is greatly reduced.54


The aminoglycosides include neomycin, streptomycin, gentamicin, tobramycin, and amikacin. These bactericidal drugs act in part by irreversible binding of the 30S subunit of the bacterial ribosome, inhibiting protein synthesis. Often used in conjunction with beta-lactam antibiotics, an interval of at least 5 minutes should be allowed when dosing with aminoglycosides avoid inactivation.24 Clinicians take advantage of the concentration-dependent killing of these antibiotics by fortifying commercially available preparations. Unfortunately, topical toxicity reduces the overall effectiveness of these agents.

Microbial resistance to aminoglycosides can be a result of several different factors. Most simply, the aminoglycosides may fail to penetrate the cytoplasm of the organism. Penetration of the bacterial cytoplasmic membrane is an oxygen-dependent active process. Strictly anaerobic bacteria and facultative bacteria under anaerobic conditions are therefore highly resistant. Bacteria can produce enzymes that inactivate or destroy aminoglycosides. These enzymes are usually plasmid mediated and are termed aminoglycoside-modifying enzymes.55 There are reports of gentamicin resistance among Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococci, and Pseudomonas aeruginosa.56 In a recent report, only 64% of organisms isolated from ocular infections were sensitive to tobramycin.57 Cross-resistance between gentamicin and tobramycin has been reported.58


Although available as topical preparations such as sulfacetamide 10%, these bacteriostatic agents are not widely used because of ocular irritation.24 Bacterial resistance to trimethoprim and sulfamethoxazole is a rapidly increasing problem, often occurring due to acquisition of a plasmid (extrachromosomal DNA) that codes for an altered dihydrofolate reductase.59


Fluoroquinolones are bactericidal agents that penetrate the corneal stroma and produce their bactericidal effects by working on two enzymes, DNA gyrase (topoisomerase II) and topoisomerase IV.60 DNA gyrase is an enzyme active in the process of DNA supercoiling. It allows the DNA strands within the bacterial cell to be compacted in an orderly fashion; inhibition of DNA gyrase permits the DNA strands to become entangled, thus preventing DNA replication, transcription, recombination, and repair, resulting in bacterial death.61

Table 1 includes some of the currently available topical fluoroquinolones (levofloxacin 0.5%, ofloxacin 0.3%, and ciprofloxacin 0.3%). Also listed are three new fluoroquinolones: levofloxacin 1.5%, gatifloxacin 0.5%, and moxifloxacin 0.3%. Reported achievable levels in the aqueous of humans are listed and compared with typical inhibitory concentrations of various ocular isolates. The newer compounds have increasing activity against gram positive isolates, particularly S. pneumoniae, but ciprofloxacin has the best anti-pseudomonal effect. The inhibitory quotient can be calculated from the table to guide antibiotic selection.


TABLE 1. Upper portion of table gives the attainable aqueous concentrations for selected ocular fluoroquinolones commercially available or in development. The lower portion gives the mean and range MIC90 for sample ocular isolates. Levofloxacin HC is highly concentrated.78–101

 LevofloxacinLevofloxacin 1.5%CiprofloxacinOfloxacinMoxifloxacinGatifloxacin
Aqueous Concentration0.5%1.5%0.3%0.3%0.5%0.3%
Solubility of raw drug78 pH pH 7)High (35.8mg/mL)Low-moderate (0.09mg/mL)Moderate (3.23mg/mL)Low-moderate (NA)Moderate (NA)
Aqueous humor level in humans79,80 q10 min × 51.135μg/mLNA0.208μg/mL0.707μg/mLNANA
Aqueous humor level in Humans79,80 qid × 20.284μg/mLNA0.067μg/μL0.2463μg/mLNANA
MIC90 Data81–101*
Staphylococcus aureus MSSA0.2510.50.060.12
Staphylococcus aureus MRSA 1 22
Staphylococcus epidermidis MSSE(0.5–12.5)(1–50)(0.5)(0.12–0.13)(0.25–1.56)
Staphylococcus epidermidis MRSE(1–>100)(1–50)(16)(2–0.13)(0.25–50)
Streptococcus pneumoniae1 20.120.25
Enterocococcus faecalis(2–32)(2–32)(1.56–>64)(0.5–16)(0.78–25)
Haemophilus influenzae(0.025–0.03)(0.015–0.03)(0.05)(0.03–0.03)(0.013–0.03)
Molaxella catarrhalis(0.03–0.125)(0.016–0.125)(0.025–0.25)(0.03–0.125)(0.03–0.05)
Pseudomonas aeruginosa(3.13–>100)(0.78–100)(12.5–32)(8–32)(3.13–100)
Escherichia coli(0.2–0.39)(0.025–0.5)(0.1–0.12)(0.06–1)(0.06–0.2)

*The figure in the top line of each entry is the MIC90 value obtained in comparative studies, if available; the figure in parentheses in the bottom line shows the range of MIC90 values published in the literature.
MIC90, the [minimum inhibitory] concentration at which 90% of the isolates by genus and species are inhibited; MSSA; MRSA; MSSE; MRSE; NA.


There have been reports of inherent and emerging acquired resistance to fluoroquinolones among gram-positive bacteria.54,62 Reports in the United States document the increasing resistance of S. aureus isolated from patients with bacterial keratitis to both ciprofloxacin—from 6% of isolates in 1993 to 35% in 1997—and ofloxacin—from 5% to 35%.63Streptococcus species and coagulase-negative Staphylococcus species also showed significant resistance to both agents.

The initial mutation, conferring low-level resistance, is thought to be found on topoisomerase IV. Other researchers have suggested that an efflux mechanism or another unknown mechanism is the cause of low-level resistance. Mutations to DNA gyrase are responsible for high-level resistance when it occurs in gram-negative or gram-positive organisms. The gram-negative organisms can alter their outer membrane proteins to decrease penetration by the hydrophilic fluoroquinolones that rely on transport by porins (outer membrane proteins) to enter the bacteria. Gram-negative and gram-positive organisms may alter other factors such as lipopolysaccharides to decrease the activity of the hydrophobic transport mechanism for fluoroquinolones into the cell.

Data have correlated the development of bacterial resistance with low AUC, high MIC, and trough below the MIC.64 The rate of mutation increases exponentially as the concentration of fluoroquinolones decline near the MIC.65 Therefore, when a large ratio between the concentration of antibiotic and the MIC exists, there is an exponentially less chance that resistance will develop.

To combat the growing problem of antibiotic resistance, it is recommended that antibiotics be prescribed for as short a period of time as possible. Whenever a true active infection exists, this is probably in most cases no more than 5 to 7 days.66 Also, the highest dose consistent with acceptable safety should be employed. Dosing regimens with currently available topical antimicrobials in the United States should not be less than four times daily. Antibiotic regimens should be stopped, never tapered.

These recommendations are based on the fact that bacterial mutations emerge more commonly in tissues with low or borderline (sub-MIC) drug levels than in tissues with high drug levels.67 Such an approach is further supported by research, demonstrating that a somewhat longer time period will elapse from the beginning of administration to development of resistance if the antibiotic is heavily used in the early treatment phase.68

The propensity to increase resistance if bacteria are exposed to low AUC/MIC or troughs below MIC may become the single greatest reason to counter marketing-driven attempts to lower quinolone dosages or to prolong dosing intervals. If a pharmacodynamic perspective can be used to extend the useful and microbiologically active life of fluoroquinolones, then its purpose will have been well served indeed.64


This bacteriostatic compound enjoys wide use in Europe because of its broad spectrum of activity (except for P. aeruginosa and C. trachomatis) and low topical toxicity. Despite a very low incidence of documented bone marrow toxicity associated with prolonged topical use, ophthalmologists in the United States limit its use to documented cases of resistance to other antibiotics (particularly with Haemophilus influenzae), absence of a family history of drug-related hematopoietic toxicity, and for short periods (less than 5 days).24


Tetracycline and chlortetracycline are available as topical ointments. Resistance of these agents to gram-negative organisms and some staphylococci is widespread and due to the bacteria increasing efflux of the tetracyclines reducing intracellular levels. Tetracycline is used primarily for C. trachomatis infections because of its high intracellular penetration; it is also used widely for its anti-inflammatory and anti-collagenolytic properties in ocular surface disorders and bacterial keratitis.


Both of these bactericidal compounds have high molecular weight, which limits effectiveness in infections of the ocular surface. Polymyxin B binds to gram-negative cellular membranes, and bacitracin to gram-positive bacteria. They are generally used in combination with a complementary agent for conjunctivitis or blepharitis only.69 Colistin (polymyxin E) has been used in a fortified topical preparation for multiply-resistant gram-negative keratitis.


Macrolides and lincosamides inhibit bacterial protein synthesis chiefly by binding to the 50S bacterial ribosome subunit. Resistance occurs mainly by alteration of the antibiotic binding site of the bacterial ribosome or macrolide-inactivating enzymes.


Erythromycin was the first antibiotic in this class and is especially useful in the treatment of gram-positive organisms. Its efficacy against intracellular organisms such as legionella, mycoplasma, and chlamydia is important. High tissue concentrations and prolonged half-life allow azithromycin to be used in a single dose for treating Chlamydiatrachomatis infections. Gram-negative coverage of erythromycin is limited by its inability to penetrate the outer cell wall membrane; clarithromycin and, to a greater extent, azithromycin have better penetration and thus a broader spectrum of activity against gram-negative organisms. The latter two agents are also increasingly important in the treatment of atypical mycobacterial keratitis. These agents are generally considered bacteriostatic when given systemically, but these latter two agents are bactericidal for S. pneumoniae, S. pyogenes and H. influenzae. (70)


Clindamycin is representative of this class and has fairly broad action against gram-positive cocci, as well as against anaerobes, mycoplasma, and protozoa. Its use has been tempered by the incidence of Clostridium difficile colitis.


The bactericidal glycopeptide vancomycin is the mainstay of treatment for infections by methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci and for other multiply resistant gram-positive infections. Glycopepides inhibit bacterial cell wall synthesis by inhibiting peptidoglycan polymerase during the second stage of cell wall synthesis. There is no cross-resistance with beta-lactamase organisms that act in the third stage. Vancomycin-resistant enterococci (VRE) are increasing in prevalence, with the VanA protype retaining teicoplanin sensitivity; however, VanB is teicoplanin-resistant. The mechanism may be through synthesis of an inducible precursor that has less affinity for vancomycin,72 and transfer has occurred with staphylococcal DNA in the laboratory. Glycopeptide-intermediate–resistant Staphylococcus aureus (GISA) was first reported in Japan in 1996. GISA may be a phenomenon of prolonged exposure to vancomycin. The Centers for Disease Control has posted guidelines recommending restricting the use of vancomycin.72,73 Topical vancomycin (1% to 5%) has been used in ocular infections, but the higher concentration is very viscous with more surface toxicity. Systemic vancomycin has resulted in “red man” syndrome due to nonimmunologically mediated histamine release. Ototoxicity and neutropenia are dose related and may be reversible if recognized early. Teicoplanin is a glycopeptide with activity similar to that of vancomycin; however, there is no reported ocular experience with this agent.74


The rifamycins are bactericidal for both intracellular and extracellular organisms. They inhibit RNA synthesis by directly interacting with DNA-dependent RNA polymerase of bacteria, but not of mammals. Rifampin is used in ophthalmology for atypical mycobacteria, especially Mycobacterium kansasii and M. marinum. Resistance occurs rapidly with monotherapy. Systemically, rifampin is a potent inducer of hepatic microsomal enzymes with significant drug-drug interactions. Anaphylaxis has been reported with topical use.75,76


Quinupristin/dalfopristin, a combination streptogramin drug, has been approved for systemic use in the ratio 70/30. This water-soluble compound works by inhibiting bacterial protein synthesis on different sites of the 50S ribosome. The susceptibility patterns are very similar to to those of vancomycin, and its clinical indications are for Enterococcusfaecium resistant to vancomycin and potentially to GISA. Resistance occurs by decreased ribosomal binding to either component through efflux mechanisms or inactivating enzymes.74


Linezolid is the first representative of the oxalidazones, a new synthetic class of antimicrobial agents that act early in protein synthesis by inhibiting the initiation complex of the 30S ribosome. This unique action means there is no cross-resistance with other available agents. Linezolid is bacteristatic for enterococci and most staphylococci but bactericidal for S. aureus and Bacterioides fragilis. Clinically it is used in treatment of gram-positive pneumonia, bacteremia, and skin and skin-structure infections, principally VRE and GISA. Resistance has not been reported during treatment, and no ocular experience has been reported.74


Not all new antibiotics will come from existing antibiotic classes. Novel approaches include targeting bacterial resistance factors, blocking bacterial virulence factors such as cell adhesion, attacking bacterial membranes, and microbial genomics.71,77 One approach is to use segments of DNA from nonculturable bacteria placed into streptomycetes by cloning and then screening against target bacteria for natural antibiotics. Others are using target-directed screens of genomes and rational drug design by identifying genes associated with virulence or host invasion. These studies may lead to development of oligonucleotides that have antisense properties even to highly resistant strains.77

Blocking bacterial adherence mimics breast milk's antibacterial properties. Oligosaccharides may achieve this in Helicobacter infections and ear infections. Bacterial resistance is less likely because altered adhesion molecules may not recognize the host.71,77

Cationic peptides are ubiquitous in nature, evolving as first-line defense agents. Low molecular weight polypeptides such as magainins and defensins are thought to attach to bacterial lipopolysaccharides, migrate through the cell wall, and create pores that disrupt the transmembrane proton gradient. Most are broad spectrum, but a few, including bacterial permeability-increasing protein (BPI, Nuprex), are active only against gram-negative bacteria. Clinical trials are underway, but approval is still pending.77

Back to Top
The authors wish to acknowledge the Research to Prevent Blindness, Inc. and Ayed A. Fanjo, M.D.
Back to Top

1. Hessen MT, Kaye D: Principles of selection and use of antibacterial agents in vitro activity and pharmacology. Infect Dis Clin N Am 14:265–79, 2000.

2. Van Vlem B, Vanholder R, De Paepe P et al: Immunomodulating effects of antibiotics: literature review. Infection 24:275–291, 1996.

3. Labro MT: The prohost effect of antimicrobial agents as a predictor of clinical outcome. J Chemother 9:100–108, 1997.

4. Paladino JA: Pharmacoeconomics of antimicrobial therapy. Ame J Health Syst Pharm 56:S25–S28, 1999.

5. Wisniewski SR, Hammer ME, Grizzard WS et al: An investigation of the hospital charges related to the treatment of endophthalmitis in the Endophthalmitis Vitrectomy Study. Ophthalmology 104:757–758, 1997.

6. World Health Organization (WHO): Antibiotic resistance a growing threat, WHO reports. Improper drug use to blame [press release]. June 12, 2000. Available at:

7. Centers for Disease Control and Prevention (CDC): Antibiotic resistance. Available at:

8. Worakul N, Robinson J: Ocular pharmacokinetics-pharmacodynamics, Eur J Pharmaceut Biopharmaceut 44:71–83, 1997.

9. Meredith TA: Antibiotics and Antifungals. In Zimmerman TJ (ed): Textbook of Ocular Pharmacology, pp 363–385. Philadelphia: Lippincott-Raven1997.

10. Boothe DM: Small Animal Clinical Pharmacology and Therapeutics, pp 131–136. Philadelphia, WB Saunders, 2001.

11. Amsterdam D: Susceptibility testing of antimicrobials in liquid media. In Lorian V (ed): Antibiotics in Laboratory Medicine, pp 52–111. 4th ed. Baltimore, Williams & Wilkins, 1996.

12. Levison ME, Bush LM: Pharmacodynamics of antimicrobial agents. Bactericidal and postantibiotic effects. Infect Dis Clin North Am 3:415–421, 1989.

13. Ellner PD, Neu HC.: The Inhibitory Quotient A method for interpreting minimum inhibitory concentration data:JAMA 246:1575–1578, 1981.

14. Estes L: Review of pharmacokinetics and pharmacodynamics of antimicrobial agents. Mayo Clinl Proc 73:1114–1122, 1998.

15. Forrest A, Nix DE, Ballow CH et al: Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 37:1073–1081, 1993.

16. Kays MB, Conklin M: Comparative in vitro activity and pharmacodynamics of five fluoroquinolones against clinical isolates of Streptococcus pneumoniae. Pharmacotherapy 20:1310–1317, 2000.

17. Firsov AA, Vostrov SN, Shevchenko AA et al: A new approach to in vitro comparisons of antibiotics in dynamic models: Equivalent area under the curve/MIC breakpoints and equiefficient doses of trovafloxacin and ciprofloxacin against bacteria of similar susceptibilities,Antimicrob Agents Chemother; 42:2841–2847, 1998.

18. Craig WA, Gudmundsson S: Postantibiotic Effect. In Lorian V (ed): Antibiotics in Laboratory Medicine, pp 296–329. 4th ed. Baltimore, Williams & Wilkins, 1996.

19. Morlet N, Graham GG, Gatus B: Pharmacokinetics of ciprofloxacin in the human eye: A clinical study and population pharmacokinetic analysis. Antimicrob Agents Chemother 44:1674–1679, 2000.

20. Bertino J, Drusano G, Kashuba ADM et al: Inability of a commercially available antibiotic utilization information consultation program (AUIC) to predict outcome (OUT) or time to event (TTE) in gram negative nosocomial pneumonia (GNNP). Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy of the American Society for Microbiology, San Francisco, CA, September 1999: Abstract # 1007, p A247.

21. Schoenwald RD: Ocular pharmacokinetics. In Zimmerman TJ et al (eds): Textbook of Ocular Pharmacology, pp 119–138. Philadelphia, Lippincott-Raven, 1997.

22. Seal DV, Bron AJ, Hay J: Antimicrobial pharmacology for the eye. In Ocular Infection, Investigation and Treatment in Practice, pp 12–13. London, Martin Dunitz, Ltd, 1998.

23. Davies N: Biopharmaceutical considerations in topical ocular drug delivery. Clin Expl Pharmacol Physiol 27:558–562, 2000.

24. Leeming JP: Treatment of ocular infections with topical antibacterials. Clin Pharmacokinet 37:351–360, 1999.

25. Mishima S, Gassett A, Klyce SD Jr et al: Determination of the tear volume and tear flow. Invest Ophthal Vis Sci 5:264, 1966.

26. Schoenwald RD: Chemical delivery systems with enhanced pharmacokinetic properties. In Mitra AK (ed): Ophthalmic Drug Delivery Systems, pp 307–330. New York, Marcel Dekker, 1993.

27. Sieg JW, Robinson JR: Mechanistic studies on transcorneal penetration permeation of pilocarpine. J Pharm Sci 65:1816–1822, 1976.

28. Mindel JS, Smith H, Jacobs M et al: Drug reservoirs in topical therapy. Invest Ophthal Vis Sci 25:346–350, 1984.

29. Doan MG, Jensen AD, Dohlman CH: Penetration routes of topically applied eye medications. Am J Ophthalmol 85:383–386, 1978.

30. Ahmed I, Patton TF: Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest Ophthalmol Vis Sci 26:584–587, 1985.

31. Edelhauser HF, Maren TH: Permeability of human cornea and sclera to sulfonamide carbonic anhydrase inhibitors. Arch Ophthalmol 106:1110–1111, 1988.

32. Chien DS, Honsy JJ, Gluchowski C et al: Corneal and conjunctival/scleral penetration of p-aminoclonidine, AGN 190342, and clonidine in rabbit eyes. Curr Eye Res 9:1051–1059, 1990.

33. Weng W, Sasaki H, Chien DS et al: Lipophilicity influence on conjunctival drug penetration in the pigmented rabbit: A comparison with corneal penetration. Curr Eye Res 10:571–579, 1991.

34. Lee DY, Schoenwald RD, Barfknecht CF: Biopharmaceutical explanation for the topical activity of 6-hydroxyethoxy-2-benzothiazole-sulfonamide in the rabbit eye. J Ocul Pharmacol 8:247–265, 1992.

35. Pech B, Chetoni P, Saettone MF et al: Preliminary evaluation of a series of amphiphilic timolol prodrugs: Possible evidence for transscleral absorption. J Ocul Pharmacol 9:141–150, 1993.

36. Worakul N, Robinson J: Ocular pharmacokinetics-pharmacodynamics. Eur J Pharmaceut Biopharmaceut 44:71–83, 1997.

37. Patel G, Chuang A, Kiang E, et al: Epithelial healing rates with topical ciprofloxacin, ofloxacin, and ofloxacin with artificial tears after photorefractive keratectomy. J Cataract Refract Surg 26:690–694, 2000.

38. Maurice DM: The tonicity of an eyedrop and its dilution by tears. Exp Eye Res 11:30, 1971.

39. Swan KD, White NG: Corneal permeability: I. Factors affecting penetration of drugs into the cornea. Am J Ophthalmol 25: 1043, 1942.

40. Benson H: Permeability of the cornea to topically applied drugs. Arch Ophthalmol 91:313, 1974.

41. McDermott ML, Tran TD, Cowden JW et al: Corneal stromal penetration of topical ciprofloxacin in humans. Ophthalmology 100:197–200, 1993.

42. O'Brien TP, Sawuch MR, Dick JD et al: Topical ciprofloxacin treatment of Pseudomonas keratitis in rabbits. Ophthalmology 106:1444–1446, 1988.

43. Barza M, Lynch E, Baum JL: Pharmacokinetics of newer cephalosporins after subconjunctival and intravitreal injection. Arch Ophthalmol 111:121–125, 1993.

44. Shockley RK, Jay WM, Fishman PH, et al: Effect of inoculum size on the induction of endophthalmitis in aphakic rabbit eyes. Acta Ophthalmol (Copenhag) 63:35–38, 1985.

45. Maylath FR, Leopold PH: Study of experimental intraocular infection. I. The recoverability of organisms inoculated into ocular tissue and fluids. II. The influence of antibiotics and cortisone, alone and combined, on intraocular growth of these organisms. Am J Ophthalmol 40:86–101, 1955.

46. John T, Sims M, Hoffmann C: Intraocular bacterial contamination during sutureless, small incision single-port phacoemulsification. J Cataract Refract Surg 26:1786–1791, 2000.

47. Egger SF, Huber-Spiezy V, Scholda C et al: Bacterial contamination during extracapsular cataract extraction; prospective study on 200 consecutive patients. Ophthalmologica 208:77–81, 1994.

48. Barza M: Antimicrobial barriers for antimicrobial agents. Eur J Clin Microbiol Infect Dis 12:S31–S35, 1993.

49. Barza M: Treatment of eye infections. In Hooper DC, Wolfson JS (eds): Quinolone Antimicrobial Agents, pp 423–424. 2nd ed. Washington, DC, American Society for Microbiology, 1993.

50. Donnenfeld ED, Perry HD, Snyder RW et al: Intracorneal, Aqueous humor, and vitreous humor penetration of topical and oral ofloxacin. Arch Ophthalmol 115:173–176, 1997.

51. Fiscella RG, Nguyen TKP, Cwik MJ et al: Aqueous and vitreous penetration of levofloxacin after oral administration. Ophthalmology 106:2286–2290, 1999.

52. American Society of Health-System Pharmacists: Anti-infective agents. In: McEvoy GK, Litvak K, Welsh OH Jr et al (eds): American Hospital Formulary Service (AHFS) Drug Information. Bethesda, MD,1: American Society of Health-System Pharmacists, 2000.

53. Bush LM, Johnson CC: Ureidopenicillins and beta-lactam/beta-lactamase inhibitor combinations. Infect Dis Clin N Am 14:409–433, 2000.

54. Asbel LE, Levison ME: Cephalosporins, carbapenems, and monobactams. Infect Dis Clin N Am 14:435–447, 2000.

55. Patalano SM, Hyndiuk RA: Aminoglycosides in ophthalmology. In ZimmermanTJ et al: Textbook of Ocular Pharmacology, pp 531–535. Philadelphia, Lippincott-Raven, 1997.

56. Chan-Tack KM: Changing antibiotic sensitivity patterns at a university hospital, 1992 through 1999. South Med J 94:619–620, 2001.

57. Milazzo G, Papa V, Carstocea B et al: Topical netilmicin compared with tobramycin in the treatment of external ocular infection. Int J Clin Pharmacol Ther 37:243–248, 1999.

58. Daikos GL, Jackson GG, Lolans VT et al: Adaptive resistance to aminoglycoside antibiotics from first-exposure down-regulation. J Infect Dis 162:414–420, 1990.

59. Widdowson CA, Klugman KP: Molecular mechanisms of resistance to commonly used non-beta lactam drugs in Streptococcus pneumoniae. Semin Respir Infect 14:255–268, 1999.

60. Crumplin GC: The Mechanism of Action of Quinolones: Quinolones—Their Future in Clinical Practice, pp 1–14. London, Royal Society of Medicine Services; 1986.

61. Gwon A: Ofloxacin vs tobramycin for the treatment of external ocular infection. Arch Ophthalmol 110:1234–1237, 1992.

62. Drugeon HB, Juvin ME, Bryskier A: Relative potential for selection of fluoroquinolone-resistant Streptococcus pneumoniae strains by levofloxacin: Comparison with ciprofloxacin, sparfloxacin, and ofloxacin. J Antimicrobiol Chemother 43(SupplC):55–59, 1999.

63. Goldstein MH, Kowalski RP, Gordon YJ: Emerging fluoroquinolone resistance bacterial keratitis: a 5-year review. Opththalmology 106:1313–1318, 1999.

64. Schentag JJ, Nix DE, Forrest A: Pharmacodynamics of Fluoroquinolones. In Hooper DC, Wolfson JS (eds): Quinolone Antimicrobial Agents, pp 259–271. 2nd ed. Washington, DC, American Society for Microbiology, 1993.

65. Antibiotic Update—Current Treatment Modalities. In: Ocular Surgery News, January 1, 2000 supplement, p. 12.

66. Prober GC: Bacterial resistance and the dilemma of antibiotic usage. West J Med. 1997; 166:337–338.

67. Ogawa GSH, Hyndiuk RA: The fluoroquinolones: New antibiotics in ophthalmology. Int Ophthalmol Clin 33:59–68.

68. Martínez-Martínez L, Pascual A, Jacoby GA: Quinolone resistance from a transferable plasmid. Lancet 351:797–799, 1998.

69. Robert PA, Adenis JP: Comparative review of topical ophthalmic antibacterial preparations. Drugs 61:175–185, 2001.

70. Zuckerman JM: The newer macrolides: azithromycin and clarithromycin. Infect Disease ClinN Am 14:449–462.

71. Setti EL, Micetich RG: New trends in antimicrobial development. Curr Med Chem 5:101–113, 1998.

72. Centers for Disease Control and Prevention: Update: Staphylococcus aureus with reduced susceptibility to vancomycin—United States, 1997. MMWR. Morb Mortal Wkly Rep 46:813–815, 1997.

73. Centers for Disease Control and Prevention: Update: Staphylococcus aureus with reduced susceptibility to vancomycin—Japan, 1997. MMWR. Morb Mortal Wkly Rep 46:765, 1997.

74. Lundstrom TS, Sobel JD: Antibiotics for gram-positive bacterial infections: Vancomycin, teicoplanin, quinupritin/dalfopristin, and linezolid. Infect Dis Clin N Am 14:463–474, 2000.

75. Epstein ME, Amodio-Groton M, Sadick NS: Antimicrobial agents for the dermatologist. II. Macrolides, trimethoprim-sulfamethoxazole and clindamycin. JAm Acad Dermatol 37:365–381, 1997.

76. Garcia F, Blanco J, Carretero P et al: Anaphylactic reactions to topical rifamycin. Allergy 54:527–528, 1999.

77. Breithaupt H: The new antibiotics. Nat Biotechnol 17:1165–1169, 1999.

78. Mitsui Y, Ooishi M, Sasaki K et al: AQCmax as a pharmacokinetic parameter of ophthalmic solution. Jpn J Eye 12:783–786, 1995.

79. Bucci FA: An in vivo comparison of the ocular absorption of levofloxacin versus ciprofloxacin prior to phacoemulsification. The Association for Research in Vision and Ophthalmology Annual Meeting. Poster B589, Presentation 1579, May, 2002.

80. Bucci FA, O'Brien TP, Evans RE et al: A prospective comparison of four methods of pre-phacoemulsification antibiotic treatment with ofloxacin and ciprofloxacin [abstract]. Invest Ophthalmol Vis Sci 41:5768, 2000.

81. Hoogkamp-Korsranje JAA, Roelofs-Willemse J: Comparative in vitro activity of moxifloxacin against Gram-positive clinical isolates. J Antimicrob Chemother 45:31–39, 2000.

82. Fung-Tomc J, Gradelski E, Huczko E et al: Activity of gatifloxacin against strains resistant to ofloxacin and ciprofloxacin and its ability to select for less susceptible bacterial variants. Int J Antimicrob Agents 18:77–80, 2001.

83. Tsurumaki Y, Manda H, Takei M et al: In vitro antimicrobial activity of gatifloxacin against 873 clinical isolates from respiratory tract, urinary tract and surgical infections during 1997–1998 in Japan. Journal of American Chemotherapy 45:685–689, 2000.

84. Jones ME, Staples AM, Critchley I et al: Benchmarking the in vitro activity of moxifloxacin against recent isolates of Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae. A European multi-center study. Diagn Microbiol Infect Di 37:203–211, 2000.

85. Huczko E, Conetta B, Bonner D et al: Susceptibility of bacterial isolates to gatifloxacin and ciprofloxacin from clinical trials 1997–1998. Int J Antimicrob Agents 16:401–405, 2000.

86. Jones ME, Angel M, Staples AM et al: Benchmarking the in vitro activity of moxifloxacin and comparator agents against recent respiratory isolates from 377 medical centers throughout the United States. Antimicrob Agents Chemother 44:2645–2652, 2000.

87. Hoban DJ, Bouchilon SK, Karlowsky JA et al: A comparative in vitro surveillance study of gemifloxacin activities against 2632 recent Streptococcus pneumoniae isolates from across Europe, North America, and South America. The Gemifloxacin Surveillance Study Research Group. Antimicrob Agents and Chemother 44:3008–11, 2000.

88. Ieven M, Goossens W, De Wit S et al: In vitro activity of gemifloxacin compared with other antimicrobial agents against recent clinical isolates of streptococci. J Antimicrob Chemother 45(Suppl1):51–53, 2000.

89. Lemmen S, AlpLahham A, Utticken R et al: In vitro activity of gemifloxacin against Streptococcus pneumoniae isolates in Germany. Chemotherapy 45:104–109, 2000.

90. Biedenbach DJ, Jones RN, Pfaller MA et al: Activity of BMS284756 against 2681 recent clinical isolates of Haemophilus influenzae and Moraxella catarrhalis: report from the SENTRY Antimicrobial Surveillance Program (2002) in Europe, Canada, and the United States. Diagn Microbiol Infect Dis 39:245–250, 2000.

91. Lewis MT, Jones RN: Activity of macrolides, lincosamines, streptgramins and fluoroquinolones against Streptococcus pneumoniae and Enterococci isolated from the Western Hemisphere: Example of international surveillance (SENTRY Antimicrobial Surveillance Program) in the development of new drugs. Braz J Infect Dis 4:15–21, 2000.

92. Dubois J, St.-Pierre C: In vitro activity of ABT-773 versus macrolides and quinolones against resistant respiratory tract pathogens. Diagn Microbiol Infect Dis 40:35–40, 2001.

93. Betriu C, Redondo M, Palau ML et al: Comparative in vitro activities of linezolid, quinupristin-dalfopristin, moxifloxacin, and trovafloxacin against erythromycin-susceptible and -resistant streptococci. Antimicrob Agents Chemother 44:1838–1841, 2000.

94. Doern GV, Heilmann KP, Huynh HK et al: Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999–2000, including a comparison of resistance rates since 1994–1995. Antimicrob Agents Chemother 45:1721–1729, 2001.

95. Cercenado E, Garcia-Garrot F, Bouza E: In vitro activity of linezolid against multiple resistant Gram-positive clinical isolates. J Antimicrob Chemother 47:77–81, 2001.

96. Hoban DJ, Bouchillon SK, Johnson JL et al: Comparative in vitro activity of gemifloxacin, ciprofloxacin, levofloxacin and ofloxacin in a North American surveillance study. Diagn Microbiol Infect Dis 40:51–57, 2001.

97. Bauernfeind A: Comparison of the antibacterial activities of the quinolones BAY 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. J Antimicrob Chemother 40:639–651, 1997.

98. Souli M, Wennersten CB, Eliopoulos GM: In vitro activity of BAY 12-8039, a new fluoroquinolone, against species representative of respiratory tract pathogens. Int J Antimicrob Agents 10:23–30, 1998.

99. Fass RJ: In vitro activity of BAY 12-8039, a new 8-methoxyquinolone. Antimicrob Agents Chemother 41:1818–1824, 1997.

100. Woodcock JM, Andrews JM, Boswell FJ et al: In vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrob Agents Chemother 41:101–106, 1997.

101. Wakabayashi E, Mitsuhashi S: In vitro antibacterial activity of AM-1155, a novel 6-fluoro-8-methoxy quinolone. Antimicrob Agents Chemother 38:594–601, 1994.

Back to Top