Other Antibacterial Drugs
Tables 16-21 and 16-22 list ophthalmic antibacterial drugs and ophthalmic combination anti-inflammatory/antibiotic drugs, respectively.
Fluoroquinolones are synthetic fluorinated derivatives of nalidixic acid. These drugs are highly effective broad-spectrum antimicrobials with potent activity against common gram-positive and gram-negative ocular pathogens. Their mechanism of action targets bacterial DNA supercoiling through the inhibition of bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, 2 of the enzymes responsible for replication, genetic recombination, and DNA repair. Mutations in the bacterial genes for these enzymes allow the development of resistance to fluoroquinolone drugs, an incidence that is increasing, as well as evidence of cross-resistance among them. Fluoroquinolone resistance has been reported in Mycobacterium chelonae, S aureus, coagulase-negative Staphylococcus species, Pseudomonas aeruginosa, Clostridium difficile, Salmonella enterica, E coli, and Helicobacter pylori.
In vitro studies have demonstrated that the fluoroquinolones, especially ciprofloxacin and temafloxacin, inhibit 90% of common corneal bacterial pathogens and have a lower minimum inhibitory concentration than that of the aminoglycosides gentamicin and tobramycin and the cephalosporin cefazolin. They are also less toxic to the corneal epithelium than are the aminoglycosides. Methicillin-susceptible strains of S aureus are generally susceptible to fluoroquinolones, but methicillin-resistant strains of staphylococci are often resistant to them.
The older generations of fluoroquinolones have good potency against gram-negative bacteria, and the newer generations were designed to broaden the spectrum of coverage and increase potency against gram-positive bacteria. For example, the second-generation fluoroquinolone ciprofloxacin may be more effective against P aeruginosa than the newer drugs.
Table 16-21 Selected Ophthalmic Antibacterial Drugs
Table 16-22 Combination Ocular Anti-inflammatory and Antibiotic Drugs
Seven currently available topical fluoroquinolones are ofloxacin ophthalmic solution, 0.3%; ciprofloxacin, 0.3%; levofloxacin, 0.5%; gatifloxacin, 0.3% and 0.5%; moxifloxacin, 0.5%; norfloxacin, 0.3%; and besifloxacin, 0.6%. They are used to treat corneal ulcers caused by susceptible strains of S aureus, S epidermidis, Streptococcus pneumoniae, P aeruginosa, Serratia marcescens (efficacy studied in fewer than 10 infections), and Propionibacterium acnes. They are also indicated for bacterial conjunctivitis due to susceptible strains of S aureus, S epidermidis, S pneumoniae, Enterobacter cloacae, H influenzae, P mirabilis, and P aeruginosa. These fluoroquinolones have a high rate of penetration into ocular tissue. Their sustained tear concentration levels exceed the minimum inhibitory concentrations of key ocular pathogens for 12 hours or more after 1 dose. They also deliver excellent susceptibility kill rates; 1 in vitro study confirmed eradication of 87%–100% of indicated pathogenic bacteria, including P aeruginosa. Ofloxacin has a high intrinsic solubility that enables formulation at a near-neutral pH of 6.4. Ciprofloxacin is formulated at a pH of 4.5, gatifloxacin at a pH of 6.0, and moxifloxacin at a pH of 6.8.
The most frequently reported drug-related adverse reaction with fluoroquinolones is transient ocular burning or discomfort. Other reported reactions are stinging, redness, itching, chemical conjunctivitis/keratitis, periocular/facial edema, foreign-body sensation, photophobia, blurred vision, tearing, dry eye, and eye pain. Though rare, dizziness has also been reported. Both norfloxacin and ciprofloxacin have caused white, crystalline corneal deposits of medication, which have resolved after discontinuation of the drug.
Case reports of tendonitis and tendon rupture have been associated with systemic fluoroquinolone use. The possibility of damage to growth-plate cartilage poses a safety concern for the use of fluoroquinolones in children. However, larger cohorts and comparative studies did not show an increased risk of musculoskeletal disorders in children treated with systemic fluoroquinolones. There is no evidence that the ophthalmic administration of fluoroquinolones has any effect on weight-bearing joints in the pediatric population.
Sulfonamides are derivatives of para-aminobenzenesulfonamide. They are structural analogues of para-aminobenzoic acid (PABA) and competitive antagonists of dihydropteroate synthase for the bacterial synthesis of folic acid. Unlike mammals, bacteria cannot use exogenous folic acid but must synthesize it from PABA. Sulfonamides are bacteriostatic only and are more effective when administered with trimethoprim or pyrimethamine, each of which is a potent inhibitor of bacterial dihydrofolate reductase; together, they block successive steps in the synthesis of folic acid. For example, sulfadiazine, systemic pyrimethamine, and folinic acid are used in the treatment of toxoplasmosis, with the folinic acid coadministered to minimize bone marrow suppression. A 3-week course of systemic sulfonamide therapy is also useful for chlamydial infection.
Sulfacetamide ophthalmic solution (10%–30%) and ointment (10%) penetrate the cornea well but may sensitize the patient to sulfonamide medication. Susceptible organisms include S pneumoniae, Corynebacterium diphtheriae, H influenzae, Actinomyces species, and Chlamydia trachomatis. Local irritation, itching, periorbital edema, and transient stinging are common adverse effects from topical administration. As for all sulfonamide preparations, severe sensitivity reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported. The incidence of adverse reactions to all sulfonamides is approximately 5%.
The cross-allergenicity between sulfonamide antibiotics and nonantibiotic sulfonamide-containing drugs complicates drug therapy. The immunologic determinant of type I immediate hypersensitivity reaction to sulfonamide antibiotics is the N1 heterocyclic ring. Nonantibiotic sulfonamides do not contain this structural feature. Non–type I hypersensitivity responses to sulfonamide antibiotics are largely attributable to reactive metabolites formed at the N4 amino nitrogen of the sulfonamide antibiotics, a structure that is also absent from nonantibiotic sulfonamide drugs. Therefore, cross-reactivity between sulfonamide antibiotics and nonantibiotic sulfonamide-containing drugs is unlikely. However, a T-cell–mediated immune response to the parent sulfonamide structure appears to be responsible for hypersensitivity that occurs in a small subset of patients. Thus, cross-reactivity remains possible, at least theoretically. There is no crossallergenicity between sulfonamide and the sulfate group (sulfate refers to the bivalent SO4 group of a compound).
Brackett CC, Singh H, Block JH. Likelihood and mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group. Pharmacotherapy. 2004;24(7):856–870.
Lehmann DF. The metabolic rationale for a lack of cross-reactivity between sulfonamide antimicrobials and other sulfonamide-containing drugs. Drug Metab Lett. 2012;6(2):129–133.
Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med. 2003;349(17):1628–1635.
The tetracycline family includes agents produced by Streptomyces species (chlortetracycline, oxytetracycline, demeclocycline), as well as the semisynthetically produced medications tetracycline, doxycycline, and minocycline. Tetracyclines enter bacteria by active transport across the cytoplasmic membrane. They inhibit protein synthesis by binding to the ribosomal subunit 30S, thereby preventing access of aminoacyl transfer RNA to the acceptor site on the mRNA–ribosome complex. Host cells are less affected because they lack an active transport system. Doxycycline and minocycline are more lipophilic and thus more active by weight.
Tetracyclines are broad-spectrum bacteriostatic antibiotics that are active against many gram-positive and gram-negative bacteria and against Rickettsia species, Mycoplasma pneumoniae, and Chlamydia species. However, many strains of Klebsiella and H influenzae and nearly all strains of Proteus vulgaris and P aeruginosa are resistant. These medications demonstrate cross-resistance. Tetracycline is poorly water soluble but is soluble in eyedrops containing mineral oil; it readily penetrates the corneal epithelium. Chlortetracycline was previously used in ophthalmic preparations, but neither chlortetracycline nor tetracycline is currently available for ophthalmic use in the United States. Oxytetracycline is available in combination with polymyxin as an ophthalmic ointment.
Systemic therapy with the tetracyclines is used to treat chlamydial infections; because these drugs are excreted into oil glands, they are also used to treat staphylococcal infections of the meibomian glands. Tetracyclines have anti-inflammatory properties that include suppression of leukocyte migration, reduced production of NO and reactive oxygen species, inhibition of matrix metalloproteinases, and inhibition of phospholipase A2. In the management of meibomian gland dysfunction and rosacea, they are used mainly for their anti-inflammatory and lipid-regulating properties, rather than for their antimicrobial effects (see BCSC Section 8, External Disease and Cornea).
As bacteriostatic drugs, tetracyclines may inhibit bactericidal medications such as the penicillins; therefore, these drugs should not be used concurrently. Tetracyclines also depress plasma prothrombin activity and thereby potentiate warfarin. In addition, the use of tetracyclines may decrease the efficacy of oral contraceptives. Patients should be instructed to use an additional form of birth control during administration of tetracyclines and for 1 month after discontinuation of their use.
Tetracyclines chelate to calcium in milk and antacids and are best taken on an empty stomach. Because tetracyclines may cause gastric irritation, they may be taken with nondairy foods to improve patient compliance. Tetracyclines should not be given to children or pregnant women because they may be deposited in growing teeth, causing permanent discoloration of the enamel, and they may deposit in bone and inhibit bone growth. They can also cause photosensitivity; consequently, patients taking tetracycline should avoid extended exposure to sunlight. Degraded or expired tetracyclines may cause renal toxicity, also called Fanconi syndrome. Tetracyclines have been implicated as a cause of idiopathic intracranial hypertension, a condition discussed in BCSC Section 5, Neuro-Ophthalmology.
Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction. Invest Ophthalmol Vis Sci. 2011;52(4):2050–2064.
Chloramphenicol, a broad-spectrum bacteriostatic drug, inhibits bacterial protein synthesis by binding reversibly to the ribosomal subunit 50S, preventing aminoacyl transfer RNA from binding to the ribosome. Chloramphenicol is effective against H influenzae, Neisseria meningitidis, and N gonorrhoeae, as well as all anaerobic bacteria. It has some activity against S pneumoniae, S aureus, Klebsiella pneumoniae, Enterobacter and Serratia species, and P mirabilis. P aeruginosa is resistant.
Chloramphenicol penetrates the corneal epithelium well during topical therapy and penetrates the blood–ocular barrier readily when given systemically. However, the use of this medication is limited because it has been implicated in an idiosyncratic and potentially lethal aplastic anemia. Although most cases of this type of anemia have occurred after oral administration, some have been associated with parenteral and even topical ocular therapy. Chloramphenicol is available as a powder for compounding, but it should not be used if an alternative drug with less potential toxicity is available.
The aminoglycosides consist of amino sugars in glycosidic linkage. They are bactericidal agents that are transported across the cell membrane into bacteria, where they bind to ribosomal subunits 30S and 50S, interfering with initiation of protein synthesis. The antibacterial spectrum of these drugs is determined primarily by the efficiency of their transport into bacterial cells. Such transport is energy dependent and may be reduced in the anaerobic environment of an abscess. Resistance to aminoglycosides may be caused by failure of transport, low affinity for the ribosome, or a plasmid-transmitted ability to enzymatically inactivate the drug. The co-administration of drugs such as penicillin that alter bacterial cell-wall structure can markedly increase aminoglycoside penetration, resulting in a synergism of antibiotic activity against gram-positive cocci, especially enterococci. One such aminoglycoside, amikacin, is remarkably resistant to enzymatic inactivation.
Gentamicin, tobramycin, kanamycin, and amikacin have antibacterial activity against aerobic, gram-negative bacilli such as P mirabilis; P aeruginosa; and Klebsiella, Enterobacter, and Serratia species. Gentamicin and tobramycin are also active against gram-positive S aureus and S epidermidis. Kanamycin is generally less effective than the others against gram-negative bacilli. Resistance to gentamicin and tobramycin has gradually increased as a result of the plasmid-transmitted ability to synthesize inactivating enzymes, as described earlier. Amikacin, which is generally impervious to these enzymes, is particularly valuable in treating these resistant organisms. It is effective against tuberculosis, as well as atypical mycobacteria, and can be compounded for topical use against mycobacterial infection.
Aminoglycosides are not absorbed well orally but are given systemically, either intramuscularly or intravenously. They do not readily penetrate the blood–ocular barrier but may be administered as eyedrops, ointments, or periocular injections. Gentamicin and carbenicillin should not be mixed for intravenous administration because carbenicillin inactivates gentamicin over several hours. Similar incompatibilities exist in vitro between gentamicin and other penicillins and cephalosporins.
The use of streptomycin is now limited to Streptococcus viridans bacterial endocarditis, tularemia, plague, and brucellosis. Neomycin is a broad-spectrum antibiotic that is effective against Enterobacter species, K pneumoniae, H influenzae, N meningitidis, C diphtheriae, and S aureus. It is given topically in ophthalmology and orally as a bowel preparation for surgery. Topical allergy to ocular use of neomycin occurs in approximately 8% of cases. Neomycin can cause punctate epitheliopathy and retard re-epithelialization of abrasions.
All aminoglycosides can cause dose-related vestibular and auditory dysfunction and nephrotoxicity when they are given systemically. Dosage adjustments must be made to prevent accumulation of drugs and toxicity in patients with renal insufficiency.
Vancomycin is a tricyclic glycopeptide produced by Streptococcus orientalis. It is bactericidal for most gram-positive organisms through the inhibition of glycopeptide polymerization in the cell wall. Vancomycin is useful in the treatment of staphylococcal infections in patients who are allergic to or have not responded to the penicillins and cephalosporins. It can also be used in combination with aminoglycosides to treat S viridans or Streptococcus bovis endocarditis. Oral vancomycin is poorly absorbed but is effective in the treatment of pseudomembranous colitis caused by C difficile. Vancomycin resistance has increased in isolates of Enterococcus and Staphylococcus, and antibiotic resistance is transmitted between pathogens by a conjugative plasmid.
Vancomycin may be used topically or intraocularly to treat sight-threatening infections of the eye, including infectious keratitis and endophthalmitis caused by MRSA or multidrug-resistant streptococci. It has been used within the irrigating fluid of balanced salt solution during intraocular surgery. The contribution of this prophylactic use of vancomycin to the emergence of resistant bacteria, as well as to an increased risk of postoperative CME, is controversial. Vancomycin is a preferred substitute for a cephalosporin used in combination with an aminoglycoside in the empirical treatment of endophthalmitis. See BCSC Section 8, External Disease and Cornea, and Section 9, Uveitis and Ocular Inflammation, for further discussion.
Topical vancomycin may be compounded and given in a concentration of 50 mg/mL in the treatment of infectious keratitis. Intravitreal vancomycin combined with amikacin has been used for initial empirical therapy for exogenous bacterial endophthalmitis. Ceftazidime has largely replaced amikacin in clinical practice, primarily because of concerns about potential aminoglycoside retinal toxicity. A vancomycin dose of 1 mg/0.1 mL establishes intraocular levels that are significantly higher than the minimum inhibitory concentration for most gram-positive organisms. The intravenous dosage of vancomycin in adults with normal renal function is 500 mg every 6 hours or 1 g every 12 hours. Dosing must be adjusted in patients with renal impairment.
Unlike systemic treatment with vancomycin, topical and intraocular vancomycin has not been associated with ototoxicity or nephrotoxicity. Hourly use of 50 mg of vancomycin per milliliter delivers a dose of 36 mg per day, which is well below the recommended systemic dose. In addition to the ototoxicity and nephrotoxicity associated with systemic therapy, possible complications include chills, rash, fever, and anaphylaxis. Furthermore, rapid intravenous infusion may cause “red man syndrome” due to flushing.
Erythromycin is a macrolide (many-membered lactone ring attached to deoxy sugars) antibiotic that binds to subunit 50S of bacterial ribosomes and interferes with protein synthesis. The drug is bacteriostatic against gram-positive cocci such as Streptococcus pyogenes and S pneumoniae, gram-positive bacilli such as C diphtheriae and Listeria monocytogenes, and a few gram-negative organisms such as N gonorrhoeae and C trachomatis. In sufficient dosing, it may be bactericidal against susceptible organisms.
Drug resistance to erythromycin is rising and is as high as 40% among Streptococcus isolates. There are 4 mechanisms of resistance:
esterases from Enterobacteriaceae
mutations that alter the ribosomal subunit 50S
enzyme modification of the ribosomal binding site
active pumping to extrude the drug
Macrolide antibiotics such as erythromycin are the treatment of choice for Legionella pneumophila, the agent of legionnaires’ disease, as well as for M pneumoniae. Erythromycin is administered orally as enteric-coated tablets or in esterified forms to avoid inactivation by stomach acid. It can also be administered parenterally or topically as an ophthalmic ointment. The drug penetrates the blood–ocular and blood–brain barriers poorly.
Clarithromycin and azithromycin are semisynthetic macrolides with a spectrum of activity similar to that of erythromycin. Clarithromycin is more effective against staphylococci, streptococci, and Mycobacterium leprae, whereas azithromycin is more active against H influenzae, N gonorrhoeae, and Chlamydia species. Both drugs have enhanced activity against Mycobacterium avium-intracellulare, atypical mycobacteria, and Toxoplasma gondii. Azithromycin, 1%, has been approved by the FDA for bacterial conjunctivitis caused by coryneform group G, H influenzae, S aureus, the Streptococcus mitis group, and S pneumoniae.
Polymyxin B sulfate is a mixture of basic peptides that function as cationic detergents to dissolve phospholipids of bacterial cell membranes, thereby disrupting cells. It is used topically or by local injection to treat corneal ulcers. Gram-negative bacteria including Enterobacter and Klebsiella species and P aeruginosa are susceptible; bacterial sensitivity is related to the phospholipid content of the cell membrane, and resistance may occur if a cell wall prevents access to the pathogen cell membrane. Systemic use of this medication has been abandoned because of severe nephrotoxicity. Topical hypersensitivity is uncommon. One commercially available topical antibiotic contains polymyxin B sulfate and trimethoprim sulfate. Sulfonamide allergy does not preclude the use of products with trimethoprim or with a sulfate group.
Bacitracin is a mixture of polypeptides that inhibits bacterial cell-wall synthesis. It is active against Neisseria and Actinomyces species, H influenzae, most gram-positive bacilli and cocci, and most but not all strains of MRSA. It is available as an ophthalmic ointment either alone or in various combinations with polymyxin, neomycin, and hydrocortisone. The primary adverse effect is local hypersensitivity, although it is not common.
Topical povidone-iodine solution, 5%, exhibits broad-spectrum antimicrobial activity when used to prepare the surgical field and to rinse the ocular surface; it is approved by the FDA for this purpose. It is the only drug that has had a significant effect on the development of postsurgical endophthalmitis. Povidone-iodine scrub may be used periocularly, but it is contraindicated in the eye because it is damaging to the corneal epithelium.
Topical povidone-iodine solution has been incorrectly considered contraindicated in patients with hypersensitivity to iodine or to intravenous contrast dye. Reported allergies to seafood or contrast media are not a contraindication to the use of topical povidone-iodine solution. Iodine is not thought to be the eliciting factor in iodinated contrast media reactions or in those related to shellfish, for which tropomyosin has been implicated. Iodine, a ubiquitous element (eg, iodized salt), is a simple molecule that is widely believed to lack the complexity required for antigenicity. Instead, patients probably develop hypersensitivity reactions to specific proteins of the food itself (eg, seafood) or to the contrast medium, rather than to the iodine in the compound. Cases of hypersensitivity to povidone, another common substance, have been reported. It is important to carefully discuss the ramifications of not using povidone-iodine with patients before intraocular procedures. One can also ask, “Have you ever had a reaction to Betadine?” or refer patients for allergy testing. This is especially important in patients who may need repeated procedures, such as intravitreal injections.
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Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.