key: cord-0037383-av5vvhws
authors: Tabbara, Khalid F.
title: Antimicrobial Agents in Ophthalmology
date: 2014-11-10
journal: Ocular Infections
DOI: 10.1007/978-3-662-43981-4_2
sha: 740988119748bf5a9dc82b511062576ba48fc636
doc_id: 37383
cord_uid: av5vvhws

Many types of antimicrobial agents have been introduced for the treatment of ocular infectious diseases. Some ocular infections have been eradicated such as smallpox, while others have been controlled by public health measures such as trachoma. The resilience of viruses and the tenacity of bacteria have led to the evolution of old diseases and the emergence of new infections. Continuous search for new antimicrobial agents for the treatment of infectious diseases is, therefore, highly desirable. New infectious agents are discovering the human race, and the ecological changes are exposing mankind to new viruses and bacteria. In addition, air travel and disruption of geographic barriers are leading to new forms of infectious diseases. In the twentieth century, there was a widespread false optimism that infectious diseases are eradicated by antimicrobial agents. It was soon discovered that many infections require new strategies for the treatment of ocular infections. The new antimicrobial agents that have been introduced over the past century can be classified into four major categories including (1) antibiotics that inhibit cell wall synthesis and integrity, (2) antibiotics that inhibit and suppress cell membrane functions, (3) antibiotics that interfere the protein synthesis, and (4) antibiotics that modulate nucleic acid synthesis. The selection of antimicrobial agents for the treatment of ocular infectious diseases is based on the most frequently encountered organisms, the pharmacokinetics of the antibiotics, the dosage required, the ocular penetration, and the cost of therapy. The stumbling blocks to safe and effective antimicrobial therapy in ocular infections include the resistance of the microorganisms, toxicity of the drug, and poor ocular penetration of antimicrobial agents.

The US Food and Drug Administration has approved more new antibiotics in the past 20 years than all antibiotics discovered in the twentieth century. The recent proliferation of new antibiotics has made the selection more diffi cult [ 1 -5 ] . The selection of an antibiotic depends on the clinical fi ndings, the most likely causative organism, the laboratory confi rmation, and the pharmacokinetics of the drug.

The purpose of this chapter is to put in the hands of the ophthalmologist a concise approach to the selection of topical or systemic antimicrobial agents in the management of infections of the eye. This would provide practical, concise, and objective information on antimicrobial agents used in the treatment of infections of the eye. The information is useful as a rapid reference for the eye care practitioner. The use of antibiotics in ocular infection can be preventive, preemptive, curative, or prophylaxis. The guidelines for the proper use of antimicrobial agents in ophthalmology are outlined (Table 2 .1 ).

The dramatic decrease in the incidence of classic infectious diseases is due largely to, fi rst, mass vaccination, which has eradicated certain infectious disease such as smallpox; second, the implementation of rigorous public health measures by many countries; and, third, the introduction of newly discovered antimicrobial agents. In the fi rst decade of the twenty-fi rst century, infectious diseases continue to be a serious cause of visual loss, mortality, and morbidity. We should not rest on the laurels we have won for overcoming the classic infections, but we should, rather, prepare ourselves to confront the microorganisms emerging from the degradation of our ecosystem as well as those bacteria that are becoming increasingly antibiotic resistant. Several new infectious agents have been recently identifi ed as a cause of disease in man (Table 2. 2 ).

Chemicals were used as early as the seventeenth century to treat infectious disease. Quinine was used for malaria, and emetine was used for amebiasis. Antibiotics, however, can cause harm as well as good. Erlich, in 1900 in Germany, introduced the concept of selective toxicity of chemicals, showing that it is possible to use an antibiotic that is toxic to the microorganism but does not harm the host. In 1929, Fleming recorded his observation that agar plates in his laboratory contaminated with Penicillium spp. were free of other bacteria such as staphylococci and went to discover penicillin. In 1935 in Germany, Domagk described sulfonamide, not only winning the Nobel Prize in 1939 but also launching a new era of antimicrobial agents. It was not until 1940, however, when Chain and Florey used penicillin in the treatment of Streptococcus pneumoniae infections, and that was the turning point in the management of infectious diseases.

Streptomycin was described in the late 1940s; tetracyclines were launched in the early 1950s, followed by chloramphenicol and later followed by lincomycin in the 1960s. Lincomycin was described from the systematic analysis of soil samples in Lincoln, Nebraska, in the United States and was named after the state's capital city, Lincoln. It was produced by a strain of Streptomyces lincolnensis. After this discovery, extensive soil sampling was conducted worldwide to isolate and identify antibiotic-producing organisms.

There are so many different types and generations of antibiotics. It is important, therefore, to identify those which are useful in ophthalmology and those that are not. It is of paramount importance to select the right antibiotic to treat ocular infection; fundamental to this is the identifi cation of the organism responsible for the infection.

The initial selection of antibiotics for the treatment of ocular infections is based on the most frequently encountered organism, pharmacokinetics of the antibiotic, dosage, and cost.

The great stumbling blocks to safe and effective antibiotic therapy are resistance and toxicity, two factors which must always be taken into account when choosing an antibiotic. Cost is another factor and one that is often overlooked. It is important to be aware of the fact that some antibiotics are expensive. There have been 1. The use of antibiotics for treatment of ocular infections should be initiated whenever a patient has an infection which is microbial in nature and the organism is susceptible to the antibiotic prescribed 2. The patient's history and eye examination should be consistent with the diagnosis of microbial infection 3. Ocular specimens for stain, cultures, or molecular diagnosis (e.g., PCR) should be obtained before the initiation of therapy and sent immediately to the laboratory. The etiologic organism causing the infection should be identifi ed 4. In serious infections, treatment may be started empirically before laboratory results are obtained 5. The selection of the antibiotic should be based on the susceptibility of the organisms, adverse effects, penetration into the affected tissue, and cost 6. Discrepancies between the results of the laboratory sensitivity tests and the patient clinical response should be carefully evaluated 7. Adverse effects from the use of the antibiotic (allergic or toxic) should be taken into account in the selection and administration of antibiotic agents' autotoxicity, nephrotoxicity, or hepatotoxicity. The antibiotic should be discontinued if an allergic or serious adverse reaction occurs after its use 8. Blood level monitoring of systemic antibiotics should be assessed whenever indicated 9. Duration of therapy is dependent on the nature of the infection and site of the infection but should not be less than 1 week 10. The route of antibiotics should be given at a dosage level that will allow penetration of the antibiotic into the desirable infected site within the safe margin and for the shortest period of time to eradicate the offending agent 11. The possibility of a superinfection should always be kept in mind when antibiotics are used for a prolonged period of time 12. The use of antibiotic combinations should be avoided unless the organism has not been cultured and the fi ndings are highly suggestive of infectious etiology 13. Antibiotic prophylaxis in surgery should be used very carefully; the antibiotic used should cover both Gram-negative and Gram-positive organisms and be started just before surgery and discontinued immediately following surgery 14. Long-term use of antibiotics should be avoided instances of patients receiving very expensive therapy when in fact the organism responsible for their infection was sensitive to much cheaper antibiotics. The combination of antibiotic agents may be used simultaneously in the following conditions: (a) In a severe devastating vision-threatening ocular infection of unknown etiology and after lab tests have been initiated to determine a specifi c etiologic agent (b) If an infection is caused by more than one organism (c) The emergence of resistant strains of bacteria during the treatment (d) In case of infections caused by organisms that are known to respond better to simultaneous use of more than one antibiotic such as Toxoplasma and Acanthamoeba (e) Organisms not cultured and the clinical fi ndings are highly suggestive of infectious etiology

Although antibiotics can be described as being either bacteriostatic or bactericidal, this is a less useful classifi cation than the one which is based on the drug mechanism of action, namely, how and where they affect the target organism. Under this system of classifi cation, the fi rst group of antibiotics inhibits synthesis of the cell wall, the second group inhibits the cell membrane, the third group affects ribosomal function and protein synthesis, and the fourth group affects nucleic acid synthesis. Topical antimicrobial agents used in ocular infections are listed in Table 2 

Several antibiotics affect the cell wall of organisms including penicillins, cephalosporins, gramicidin, and bacitracin [ 6 -17 ] . Bacterial survival can be compromised without a cell wall. The cell wall protects bacteria from the environmental noxious agents and maintains the intracellular milieu. The thickness of bacterial cell walls varies: Gram-positive bacteria have thick cell walls, and Gram-negative bacteria have thin cell walls.

The internal osmotic pressure of Gram-positive organisms is higher than that in Gram-negative organisms. A Gram-positive organism, in particular, is under considerable risk of death when the cell wall is compromised. Bacterial cell wall contains peptidoglycans and ligands of alternating pyranoside residues of two amino sugars, N -acetylglucosamine and N -acetylmuramic acid (the latter is not found in mammalian cells), and is cross-linked by pentapeptide chains. Pentapeptide cross-linking gives the cell wall its rigidity; consequently, the introduction of antimicrobial agents or antibiotics that interfere with cross-linking causes the cell wall to weaken and the organism to die.

Unlike bacteria, mammalian cells do not have cell walls a selective target and an example of selective toxicity.

Penicillins are beta-lactam antibiotics. There are four generations of penicillins. The fi rst three are important in the treatment of ocular infections. The fi rst-generation penicillins are penicillin G and penicillinase-resistant penicillins, of which there are two types, methicillin and nafcillin. Methicillin was used to treat beta-lactamaseproducing organisms. Methicillin can cause interstitial nephritis and is no longer used in most centers. The penicillins are used specifi cally to treat ocular infections caused by Streptococcus , Neisseria , Clostridium spp., syphilis, and Actinomyces .

The second-generation penicillins include ampicillin and amoxicillin. These antibiotics have a slightly broader spectrum than those of the fi rst generation. The second-generation penicillins are used to treat ocular infections caused by Haemophilus species and enterococci.

The third-generation penicillins are carbenicillin and ticarcillin. Ticarcillin has been combined with clavulanic acid as a suicide inhibitor of beta-lactamase. These antibiotics occupy receptor sites on Gram-negative bacteria making them more active against Gram-negative bacteria. Until recently, carbenicillin was used to treat Pseudomonas infections. Ticarcillin has replaced carbenicillin and may be used in combination Sterile intravitreal insert designed to release the drug over a 5-8-month period with aminoglycosides. The fourth group of penicillins comprises of mezlocillin, piperacillin and azlocillin which are derivatives of ampicillin and are similar to carbenicillin and ticarcillin. These antibiotics are also effective against Gramnegative organisms because they have a greater affi nity to cell wall receptor sites in Gramnegative organisms than in Gram-positive organisms. The fourth-generation penicillins have limited role in ophthalmology. New generations of antibiotics are not necessarily better or more effective than earlier generations. Each generation of antibiotics plays a specifi c role and has specifi c indication and advantages in the treatment of infections caused by susceptible organisms.

Organisms become resistant by producing beta-lactamase. The enzyme disrupts the betalactam ring, rendering it ineffective. In order to counteract this, an antibiotic called clavulanic acid, produced by Streptomyces spp., has been introduced. Clavulanic acid has a very weak antibiotic effect and binds to beta-lactamase and inhibits its effects, "suicide inhibition." Clavulanic acid has unique affi nity to beta-lactamase and leads to its deactivation. The combination of clavulanic acid to existing antibiotics does not constitute a new generation of antibiotics but is a new therapeutic strategy to improve the effectiveness of existing antibiotics.

A combination of 500 mg amoxicillin and 250 mg clavulanic acid (Augmentin ® ) is effective against beta-lactamase-producing organisms such as Haemophilus and streptococci. The drug is used for the treatment of preseptal cellulitis in young children where Haemophilus is a common cause. Similarly, a combination of ticarcillin and clavulanic acid (Timentin ® ).

Cloxacillin is similar to clavulanic acid (Timentin ® ) in that it has strong affi nity for betalactamase and neutralizes its effects.

Several examples of monobactam antibiotics are available which are Impenem meropenen, ectapenem which have wide antimicrobial activity. Impenen is effective against anaerobes, Gram-positive and Gram-negative organisms, Streptococcus pneumoniae , Streptococcus Group A, Staphylococcus aureus , Streptococcus faecalis , and Haemophilus infl uenzae . The minimum inhibitory concentration of imipenem to Haemophilus infl uenzae and Neisseria spp. is less than 0.6 μg/ml. Imipenem is also effective against Enterobacteriaceae , Pseudomonas , and Acinetobacter calcoaceticus. Imipenem has been marketed in combination with silastin. Silastin inhibits hydropeptidase, an enzyme released by the brush border of the kidney which destroys imipenem. Consequently, cilastatin prolongs the half-life of imipenem and increases the concentration of imipenem in the urine. Imipenem should not be used in conjunction with cephalosporin because of potential antagonism.

Cephalosporins are an important group accounting for some 50 % of all antibiotics prescribed in hospitals (Tables 2.8a and 2.8b ). Over 25 cephalosporins are available, and many more are under investigation. The advantages of cephalosporins include a broad-spectrum bactericidal with selective toxicity. Cephalosporins (fi rst generation) are effective against penicillinase-producing Staphylococcus aureus . The disadvantages of cephalosporins include low CSF level, and therefore the agents are not recommended to treat meningitis. They have limited effects against enterococci, and they may potentiate nephrotoxicity if they are used intravenously in combination with aminoglycosides.

The fi rst generation of cephalosporins was introduced in the 1970s. One of the antibiotics in this generation is cefazolin. As with other groups of antibiotics, each generation of cephalosporins has its own spectrum: the fi rst-generation cephalosporins are more effective against Grampositive cocci than the third-or fourth-generation cephalosporins.

The second-generation cephalosporins include cefuroxime and cefonicid. Cefuroxime is the treatment of choice for sinus infections. It has been used intracamerally in phacoemulsifi cation for the prevention of postoperative endophthalmitis. Unfortunately, it has no effects against Pseudomonas or other enteric Gram-negative organisms. It is a good single drug for the treatment of patients with sinusitis or orbital cellulitis as it covers most of the Gram-positive cocci (staphylococci, streptococci) as well as non-enteric Gramnegative organisms; it is also effective against Haemophilus . In addition, cefuroxime has a long half-life and can be administered intravenously twice daily. Unlike cefamandole, cefuroxime does not cause bleeding tendencies and is well tolerated. The disadvantages of cefuroxime are as follows: (1) it is not active against Pseudomonas spp . , enterococci, or B. fragilis , and (2) the drug is relatively expensive. Cefaclor is for oral administration.

The third-generation cephalosporins include ceftazidime, cefotaxime, and ceftriaxone. Ceftriaxone is the drug of choice for treating Neisseria gonorrhoeae . Most current strains of N. gonorrhoeae are resistant to penicillins, and many of them are resistant to other antimicrobial agents as well. Ceftriaxone is effective against infections caused by Neisseria meningitidis. Ceftriaxone is used for the treatment of ocular infections caused by Borrelia , Leptospira , and Treponema and infections caused by Haemophilus and betalactamase-producing organisms. Other advantages of ceftriaxone include its long half-life and, therefore, can be used once or twice daily (unlike other cephalosporins which have to be administered three or four times daily) which makes it cost-effective. Ceftriaxone has certain disadvantages including its limited value in the treatment of infections caused by Pseudomonas spp. except when combined with aminoglycosides and has little or no effect against Staphylococcus aureus and may prolong the bleeding time.

The fourth and fi fth generations of cephalosporins have so far limited use in ocular infections.

Teicoplanin (Targocid ® , Sanofi Aventis Ltd.) is a glycopeptide antibiotic similar to vancomycin and is effective against Gram-positive cocci including methicillin-resistant staphylococci (MRSA) [ 18 , 19 ] . The drug affects the cell wall synthesis of Gram-positive bacteria. Experience in ophthalmic infections is limited. Oral teicoplanin has been shown to be effective in the treatment of Clostridium diffi cile -associated pseudomembranous colitis [ 20 ] .

Fumagillin is used for the treatment of corneal microsporidiosis [ 21 ] . It is compounded as eyedrops at a concentration level of 0.113 mg/ml (Leiter's Pharmacy Inc., 1700 Park Ave #30, San Jose CA, USA, Telephone No.: 800-292-6773). It has also been shown to inhibit angiogenesis.

Antibiotics that inhibit cell membrane function include polymyxin B, amphotericin B, colistin, imidazoles, and polyenes. Some of these antibiotics, such as amphotericin B and the polyenes, act against fungi and do not affect bacterial cell membranes. Polyenes bind to ergosterol, a sterol moiety in the cell membrane of fungi. Ergosterol is not present in mammalian or bacterial cell membranes.

The imidazoles act against fungi but have different modes of action from the polyenes. Imidazoles act by inhibiting ergosterol synthesis leading to disruption of cell membrane function. In addition, imidazoles inhibit cytochrome C and peroxidase and allow the intracellular accumulation of hydrogen peroxidase leading to death of the fungus. Since ergosterol is the binding site for amphotericin B, the use of imidazoles may render amphotericin B less effective by competing ergosterol in the fungal cell membrane. Polymyxins bind to phosphatidylethanolaminerich membranes, particularly in Gram-negative organisms. They have a detergent-like effect which disrupts the cell membrane, eventually causing death of the organism.

Polymyxins are effective in treating infections caused by species of Pseudomonas as well as certain other Gram-negative organisms. Polymyxins cannot be given systemically because of nephrotoxicity [ 22 -26 ] .

Daptomycin is a new lipopeptide antibiotic used for the treatment of resistant Gram-positive organisms. It is produced by the fungus Streptomyces roseosporus. The trade name is Cubicin ® .

It binds to the bacterial cell membrane leading to depolarization and loss of membrane function. Daptomycin may also act by inhibiting protein synthesis.

Daptomycin is effective against Gram-positive cocci and shows signifi cant corneal penetration following 1 % topical eyedrops in rabbits [ 27 ] . Daptomycin appears to be safe and effective when given intravitreally [ 28 ] .

The third group of antibiotics consists of compounds which inhibit protein synthesis and include chloramphenicol, tetracycline, lincomycin, clindamycin, aminoglycosides, and macrolides. They are used extensively in ocular infections [ 22 ] . Binding to bacterial ribosomes by erythromycin leads to inhibition of protein synthesis. Inhibition of protein synthesis is also achieved when tetracyclines and aminoglycosides bind to 30S portion of the bacterial ribosome, while the chloramphenicols, lincomycins, and erythromycin bind to the 50S portion of the bacterial ribosome. The selectivity is partial and these antibiotics may have some toxic effect on human cells. Topical chloramphenicol, is widely used to treat ocular surface infections. There have been several reports of fatal aplastic anemia following topical administration of chloramphenicol. The incidence of idiosyncracy to chloramphenicol is not high; nonetheless, if large numbers of patients are given topical chloramphenicol, cases of fatal aplastic anemia will occur. In other situations, the use of certain antibiotics is neither ideal nor appropriate. Approximately 30 % of staphylococci isolated from ocular infections are resistant to erythromycin. Erythromycin cannot be considered the drug of choice for the treatment of infections caused by these organisms. Fusidic acid is another antibiotic in this group and is helpful in the treatment of staphylococcal blepharitis [ 29 , 30 ] .

We recovered 163 staphylococcal isolates from ocular infection sites and assessed their sensitivity to different antibiotics [ 29 ] . Vancomycin was found to be the most effective antibiotic against all types of staphylococci, including Staphylococcus epidermidis and Staphylococcus aureus. The results showed that while 95 % of strains of S. epidermidis were sensitive to fusidic acid and 84 % were sensitive to bacitracin, only 45 % were sensitive to methicillin, 53 % to gentamicin, 56 % to erythromycin, and 33 % to chloramphenicol [ 29 ] . Unfortunately, resistant strains of staphylococci to fusidic acid started to appear. Currently, close to 52 % of ocular isolates of staphylococci are sensitive to fusidic acid. The topical use of antibiotics such as chloramphenicol is less effective and carries risks of systemic adverse effects. Chloramphenicol is an antibiotic which is considered to have a very narrow spectrum, with many organisms resistant to it, and carries the risk of aplastic anemia. It is vital that chloramphenicol be prescribed only when absolutely necessary, for example, treating strains of Haemophilus that are resistant to other antibiotics.

Vancomycin is a valuable antibiotic that should be used carefully. Wide or inappropriate use may lead to emergence of resistant strains. In addition, nephrotoxicity is likely to increase when systemic vancomycin is combined with gentamicin.

There is antagonism when tetracycline is used in combination with quinolone, erythromycin, and all the beta-lactam antibiotics. A beta-lactam antibiotic should not be used in combination with tetracyclines, erythromycin, or chloramphenicol; since the latter inhibit ribosomal function, they will interfere with the effects of beta-lactam antibiotics.

Azithromycin is a macrolide antibiotics belonging to the azalide group. It has been shown to be highly effective against chlamydial infections as well as against Gram-positive bacteria [ 31 -33 ] . Azithromycin has a long elimination life reaching 68 h. Azithromycin has been found to be effective in the treatment of genital Chlamydia . A single, 1-g dose is suffi cient to eradicate it. Azithromycin is also effective in the treatment of trachoma [ 34 ] . A 1-week course or repeated 3-day courses of azithromycin are required in chronic active cases of trachoma. The drug has high intracellular concentration in the macrophages and polymorphonuclear cells. Following a single oral dose of azithromycin, the drug remains in the conjunctiva above the minimum inhibitory concentration (MIC) of Chlamydia for up to 2 weeks [ 31 ] . The drug is currently available as eyedrops at a concentration of 1.5 % as Azyter ® (Laboratoires Theá, Clermont-Ferrand, France) and 1.0 % concentration as Azasite (Inspire Pharmaceuticals Inc, NC, USA). The tear concentration of topical azithromycin was studied following topical administration of a single dose of azithromycin 1.0 and 1.5 % in healthy volunteers [ 32 ] . This study was a prospective, randomized double-masked study. A total of 91 healthy volunteers with normal tear functions were included. Twenty-three subjects received azithromycin 0.5 % eyedrops, 58 subjects received azithromycin 1.0 % eyedrops, and 38 subjects received azithromycin 1.5 % eyedrops. Tears were collected from each subject at seven time points over a 24-h period using the Schirmer strips that were weighed before and after tear sampling. The tear samples were analyzed for azithromycin by high-performance liquid chromatography mass spectrometry (HPLC-MS). The peak of azithromycin was noted 10 min after instillation and the mean concentration remained above 7 mg/l for 24 h. A late-onset increase in the tear concentration of azithromycin was noted at 8-12 h and may be explained by the known azithromycin release from the tissues after storage in the cells [ 31 , 35 , 36 ] .

In another study, Kuehne and coworkers [ 33 ] measured the concentration of azithromycin and clarithromycin in rabbit corneal tissue following topical application of 2 mg/ml (0.2 %) of azithromycin and 10 mg/ml (0.1 %) of clarithromycin. It was shown that topical azithromycin concentrations were higher in the corneal tissue than clarithromycin. Azithromycin is used for the treatment of chlamydial conjunctivitis, trachoma, keratitis due to Mycobacterium chelonae , and chronic blepharitis [ 31 , 36 -38 ] .Topical azithromycin is used for the treatment of blepharitis [ 36 -38 ] . Corneas exposed to desiccation showed signifi cant increase in the azithromycin tissue level compared to normal eyes following topical application of azithromycin 1.5 % eyedrops [ 39 ] . It appears that dryness may increase the tissue absorption of the cornea [ 39 ] .

Linezolid (Zyvox ® ) is a synthetic antibiotic, is a member of the oxazolidinones used for the treatment of serious infections caused by Grampositive bacteria [ 40 ] . Linezolid inhibits protein synthesis and appears to work by disrupting the translation of messenger RNA into proteins in the ribosomes. Linezolid binds to 50S subunit of the ribosome. It has been shown that linezolid is most active against Gram-positive bacteria including streptococci, vancomycinresistant-enterococci, and methicillin-resistant-Staphylococcus aureus (MRSA). The main indications of linezolid are infections of the skin and soft tissues and pneumonia. The drug is available in the United States and the United Kingdom under the name of Zyvox ® and in European countries under the name of Zyvoxid ® . On the other hand, in Canada and Mexico, the drug is known as Zyvixam ® . Generics of these drugs are available in India under the name of Linospan by Cipla.

Linezolid is an oxazolidinone antibiotic which is a protein synthesis inhibitor. Resistance to linezolid by bacteria has remained low. Linezolid has proven to be safe and effective in infections due to susceptible organisms. The US Food and Drug Association approved linezolid in April 2000. It is considered a bacteriostatic agent, and the main indication of linezolid is the treatment of severe infections caused by Gram-positive bacteria that are resistant to other antibiotics. It has a narrow spectrum and, therefore, remains a reserved antibiotic for cases with severe infections due to resistant bacteria. Linezolid has been associated with Clostridium diffi cile -associated diarrhea and pseudomembranous colitis. The long-term use of linezolid may lead to bone marrow suppression and thrombocytopenia.

The fourth group of antibiotics, the quinolones, comprises antibiotics which inhibit nucleic acid synthesis [ 5 , 41 -66 ] .

Pyrimethamine interferes with the synthesis of the hydrofolate which is an important building block of bacterial DNA. The drug is used for the treatment of Toxoplasma . Rifamycin interferes with nucleic acid synthesis by the inhibition of RNA-dependent DNA polymerase. Sulfonamides are synergistic with trimethoprim and, have been combined for systemic use.

Fluoroquinolones have a fl uorine substitution at position 6 of the quinolone molecule. Additional substitutions at position 1 and position 7 markedly affect antimicrobial effi cacy as well as penetration. These alterations have substantially improved the antimicrobial effects against Gram-positive as well as Gram-negative organisms in addition to improving solubility in ophthalmic solutions. Norfl oxacin was the fi rst fl uoroquinolone to be used topically for ocular infections. It has primarily Gram-negative activity, including antipseudomonal activity as well as limited Gram-positive activity.

The regulation of DNA supercoiling is essential to DNA transcription and replication. In supercoiling, the DNA molecule coils up and shortens the molecule. The DNA helix must unwind to permit the proper function of the enzymatic machinery involved in these processes. Topoisomerases serve to maintain both the transcription and replication of DNA. Type I and type II topoisomerases cut one strand or two strands of DNA, respectively.

The underlying mechanism of action is reversible trapping of DNA gyrase (topoisomerase II) and topoisomerase IV-DNA complexes. Complex formation is followed by reversible inhibition of DNA synthesis. As fl uoroquinolone concentrations increase, cell death occurs as doublestranded DNA breaks releasing trapped gyrase and/or topoisomerase IV complexes. In many Gram-negative bacteria, resistance arises primarily from mutation of the gyrase A protein, while in some Gram-positive bacteria, primary resistance occurs via mutation in topoisomerase IV. In addition, effl ux pumps that actively pump antibiotics out of the bacteria confer multidrug resistance via these membrane-associated effl ux pumps. Gatifl oxacin and moxifl oxacin are more resistant to these effl ux pumps. This change additionally confers added anaerobic activity. Gram-negative organisms may also exhibit decreased levels of outer membrane proteins that facilitate diffusion into the bacterial cell of drug, thereby conferring additional resistance, which can work in concert with the effl ux pumps. These last two mechanisms confer a form of resistance and can be overwhelmed by higher concentrations of drug [ 65 ] .

Fluoroquinolones include moxifl oxacin, gatifl oxacin, besifl oxacin, ciprofl oxacin, fl eroxacin, lomefl oxacin, norfl oxacin, ofl oxacin, perfl oxacin, and temfl oxacin, all of which are C-7 1-piperazinyl and C-7 fl uoro-substituted quinolones. The drugs are more potent than the original nalidixic acid structure. Several quinolones are available in topical eyedrop form. These drugs have good in vitro actions against many Gram-negative and Gram-positive bacteria, while action against anaerobic bacteria remains poor. The mechanism of action of the quinolones is through inhibition of DNA gyrase. Lomefl oxacin is effective against most Gram-negative and Gram-positive organisms. Studies on Chlamydia trachomatis show that this organism is moderately susceptible to lomefl oxacin.

These susceptibilities are in contrast to the aminoglycosides and β-lactam antibiotics which have activity against bacterial cells in the growth phase, whereas fl uoroquinolones are rapidly bactericidal in vitro and in vivo in both growth phase and secondary phase of cell growth.

Studies carried out on the rabbit model have revealed that lomefl oxacin readily penetrates the cornea, iris, and ciliary body of the eye and reaches an appreciable concentration in the aqueous. Penetration occurs after both local and systemic administration and penetration have been shown to be increased in the presence of melanin.

The fl uoroquinolones have two pKa values on each side of physiological pH with an isoelectric point at pH 7.4. Unionized fl uoroquinolones are considered to be very lipophilic, a factor that is thought to infl uence considerably the mechanism by which these compounds penetrate bacterial cell membranes. Fluoroquinolones are approximately 20-30 % protein bound. This value has been found to be independent of the drug concentration. Following oral administration of lomefl oxacin, 10 % of the drug is protein bound in the serum. Evidence from animal studies suggests that lomefl oxacin is excreted unchanged by the kidney, although small concentrations of 5 metabolites have been described. The most notable drug interaction occurring is the effect of fl uoroquinolones on the clearance of theophylline. Plasma concentrations of theophylline are raised by approximately 19 % during coadministration with perfl oxacin as compared to 111 % for enoxacin and 23 % for ciprofl oxacin. Ofl oxacin and nalidixic acid do not increase the apparent plasma level of theophylline. The interaction is supposed to rise, not through the parent fl uoroquinolone but through their 4-oxo metabolites. This interaction is produced through the effect on hepatic p450-related isoenzymes resulting in reduced capacity of N -demethylation of theophylline. No oxo-metabolite is produced in the metabolic elimination of lomefl oxacin, and the drug is extensively excreted. Theophylline adjustment does not seem to be necessary in patients receiving concomitant lomefl oxacin.

Quinolones are interesting in ophthalmology because several of them are available in topical forms. Levofl oxacin, lomefl oxacin, ciprofl oxacin, ofl oxacin, norfl oxacin, moxifl oxacin, gatifl oxacin, besifl oxacin, and temefl oxacin are available for topical use. They are effective against Gram-negative organisms, and in topical form ciprofl oxacin has a useful role in the treatment of bacterial keratitis caused by Pseudomonas. Certain fourth-generation quinolones, however, have limited effi cacy against Gram-positive cocci.

Quinolones are highly effective against Gramnegative organisms and have intermediate activity against staphylococci. They are effective against group B streptococci but not useful against group A streptococci, Streptococcus pneumonia , and anaerobes. Clearly, these antibiotics have selective effects against microorganisms, making them unsuitable for "blind shot blanket" therapy. In addition, systemic fl uoroqui-nolones may cause cartilage erosion in children. They should not be used in children or pregnant women. As the case with tetracyclines, antacids may decrease absorption of oral quinolones.

The antibiotics of choice for common ocular pathogens are shown in Table 2 .9 . The compounding dosages for intravitreal injections of antimicrobial agents are shown in Table 2 .10 . The antimicrobial therapy for tuberculosis ( Table 2 .11 ) and for ocular toxoplasmosis is also listed ( Table 2 .12 ).

Confl ict of Interest The author declares that he has no confl ict of interest.

No human studies were carried out by the authors for this article.

No animal studies were carried out by the authors for this article. Azithromycin, 500 mg orally twice daily for 4 weeks, or clindamycin 300-450 mg orally q 6 h for 4 weeks Trimethoprim, 160 mg/sulfameth o xazole 800 mg twice daily for 4 weeks Vision-threatening lesions Corticosteroids to be used only when vision is threatened: prednisone, 1 mg to 1.5 mg/kg/day, gradually tapered over a period of 4 weeks, or periocular injection of triamcinolone acetonide 40 mg once Give corticosteroids 3 days after initiation of antimicrobial agents Congenital toxoplasmosis Pyrimethamine, 1 mg/kg/day orally once every 3 days, and sulfadiazine, 50 mg to 100 mg/kg/day orally in two divided doses for 3 weeks Corticosteroids for vision-threatening lesions: 1 mg/kg/day orally in two divided doses. The dosage should be tapered progressively and later discontinued Folinic acid, 3 mg twice weekly during treatment with pyrimethamine Adapted and modifi ed from [ 1 , 68 ] 

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Pediatric bacterial keratitis cases in Shanghai: microbiological profi le, antibiotic susceptibility and visual outcome

Intracameral cefuroxime injection at the end of cataract surgery to reduce the incidence of endophthalmitis: French study

Review of endophthalmitis following Boston Keratoprosthesis type 1

Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections

Atypical presentations of orbital cellulitis caused by methicillin-resistant Staphylococcus aureus

Povidone-iodine and ophthalmia neonatorum

Subperiosteal abscess of the orbit: duration of intravenous antibiotic therapy in nonsurgical cases

Vancomycin resistance in ocular infections

Prophylaxis against postoperative endophthalmitis in cataract surgery

Perioperative antibiotic prophylaxis during cataract surgery in Greece

Extended-spectrum beta-lactamase resistance among bacterial isolates recovered from ocular infections

Microbial keratitis in East Africa: why are the outcomes so poor?

The biosynthesis of teicoplanin-type glycopeptide antibiotics: assignment of p450 mono-oxygenases to side chain cyclizations of glycopeptide a47934

Glycopeptide biosynthesis: Dbv21/Orf2 from dbv/tcp gene clusters are N-Ac-Glm teicoplanin pseudoaglycone deacetylases and Orf15 from cep gene cluster is a Glc-1-P thymidyltransferase

Prospective study of oral Teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium diffi cile associated diarrhea

Agence Nationale de Recherches sur le SIDA 090 Study Group . Fumagillin treatment of intestinal microsporidiosis

Infections of the eye

Hospital constructionassociated outbreak of ocular aspergillosis after cataract surgery

Voriconazole for fungal corneal ulcers

Microbiological fi ndings and predisposing risk factors in corneal ulcers

Practice patterns and opinions in the treatment of acanthamoeba keratitis

Ocular penetration of topically applied 1% daptomycin in a rabbit model

Intravitreal daptomycin: a safety and effi cacy study

Effects of fusidic acid on staphylococcal keratitis

Corneal and intraocular penetration of topical and subconjunctival fusidic acid

Ocular levels of azithromycin

Tear concentrations of azithromycin following topical administration of a single dose of azithromycin 0.5%, 1.0%, and 1.5% eyedrops (T1225) in healthy volunteers

Corneal pharmacokinetics of topically applied azithromycin and clarithromycin

Single-dose Azithromycin in the treatment of trachoma: a randomized, controlled study

Topical antibacterial therapy for mycobacterial keratitis: potential for surgical prophylaxis and treatment

Effi cacy of tropical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis

Oral azithromycin for treatment of posterior blepharitis

Current evidence for topical azithromycin 1% ophthalmic solution in the treatment of blepharitis and blepharitis-associated ocular dryness

Effects of dehydration on corneal tissue absorption of topical azithromycin in rabbits

Linezolid treatment for gram positive infections: a retrospective comparison with teicoplanin

Fluoroquinolones: mechanism of action, classifi cation, and development of resistance

Treatment of acute bacterial conjunctivitis with topical Lomefl oxacin 0.3% compared to topical Ofl oxacin 0.3%

Shifting trends in bacterial keratitis in South Florida and emerging resistance to fl uoroquinolones

Emerging ciprofl oxacinresistant Pseudomonas aeruginosa

Emerging fl uoroquinolone resistance in bacterial keratitis: a 5-year review

Comparative effi cacy of topical moxifl oxacin versus ciprofl oxacin and vancomycin in the treatment of P. aeruginosa and ciprofl oxacin-resistant MRSA keratitis in rabbits

Effectiveness of fl uoroquinolones against Mycobacterium abscessus in vivo

Antibacterial activity of the fourthgeneration fl uoroquinolones gatifl oxacin and moxifl oxacin against ocular pathogens

Effectiveness of ciprofl oxacin, levofl oxacin or moxifl oxacin for treatment of experimental Staphylococcus aureus keratitis

Susceptibility of clinically signifi cant ocular isolates to Lomefl oxacin 0.3%

Comparison of corneal surface effects of gatifl oxacin and moxifl oxacin using intensive and prolonged dosing protocols

In vitro activity of fl uoroquinolones against Mycobacterium abscessus and Mycobacterium chelonae causing infectious keratitis after LASIK in Brazil

Fourth-generation fl uoroquinolones in the treatment of mycobacterial infectious keratitis after laserassisted in situ keratomileusis surgery

Comparative penetration of moxifloxacin and gatifloxacin in rabbit aqueous humor after topical dosing

Fourthgeneration fl uoroquinolone-resistant bacterial keratitis after refractive surgery

Nocardia keratitis after laser in situ keratomileusis: clinicopathologic correlation

Effect of gatifl oxacin 0.3% and moxifl oxacin 0.5% ophthalmic solutions on human corneal epithelium following 2 dosing regimens

A laboratory evaluation of antibiotic therapy for ciprofl oxacin-resistant Pseudomonas aeruginosa

Ocular pharmacokinetics of moxifl oxacin after topical treatment of animals and humans

Decrease in tear bioavailability of ciprofl oxacin in eyes with carbon containing eyeliners

Quantitative comparison of fl uoroquinolone therapies of experimental gram-negative bacterial keratitis

Safety of besifl oxacin ophthalmic suspension 0.6% as a prophylactic antibiotic following routine cataract surgery: results of a prospective, parallel-group, investigatormasked study

Comparison of corneal and aqueous humor penetration of moxifl oxacin, gatifl oxacin and levofl oxacin during keratoplasty

Comparison of moxifl oxacin and levofl oxacin in an epithelial disorder model using cultured rabbit corneal epithelial cell sheets

Antibiotic resistance in microbial keratitis: ten-year experience of corneal scrapes in the United Kingdom

Clinical use of gatifl oxacin ophthalmic solution for treatment of bacterial conjunctivitis

Uvea section