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Topical Antimicrobial Agents
Topical antimicrobial therapy dates to ancient times when a wide variety of substances such as grease, lint oil, wine, and metallic salts were applied to wounds. Since then, topical antibiotics have been developed. They are most frequently used to treat infections affecting the skin and mucous membranes. Agents include topical preparations of parenterally administered antibiotics and antibiotics and antiseptics not given by any other route because of their toxicity. As a general principle, agents used topically should not be those relied on for systemic use because resistance develops rapidly. Precise recommendations for the use of topical agents are limited by the difficulty of in vitro assays, establishment of breakpoints for susceptibility, effect of the vehicle on delivery, and lack of clinical efficacy trials. Antifungal and antiviral agents are described in Chapter 293, Chapter 295 .
Agents for Ophthalmic Infections
Antibiotics administered topically are used for the prophylaxis and treatment of many ophthalmologic pathogens. Topical agents are used for the prophylaxis of neonatal conjunctivitis, perioperative infections, and ophthalmologic trauma such as corneal abrasions, foreign bodies, and ruptured globes. They are used for the treatment of blepharitis, chronic dacryocystitis, conjunctivitis, corneal ulcers, and endophthalmitis. The selection of an antimicrobial agent should be based on its activity against the most likely pathogenic organisms and lack of adverse effects. Ophthalmic topical antimicrobial agents, their spectrum of activity, and adverse events are shown in Table 294.1 . Different routes of administration (topical, subconjunctival, retrobulbar, and intravitreal) can be used, depending on the site of infection. Formulations are available as suspensions, ointments, solutions, and extemporaneously prepared “fortified drops” ( Table 294.2 ). To optimize antibiotic delivery, devices impregnated with antibiotics, such as collagen shields that prolong antibiotic contact with the ocular surface, have been used for corneal protection after trauma, but lack of clinical trials limit their use in ocular infections. ,
TABLE 294.1
Commercially Available Topical Ophthalmic Antimicrobial Agents
Data from references Mechanisms of action of clinically used antimicrobial drugs. In: Meyer FH, Jawetz E, Goldfien A, eds. Review of Medical Pharmacology . Los Altos, CA: Lange; 1978; Drugs with specialized indications. In: Meyer FH, Jawetz E, Goldfien A, eds. Review of Medical Pharmacology . Los Altos, CA: Lange; 1976; Carpenter G. Chloramphenicol eye-drops and marrow aplasia. Lancet 1975;2:326–327; Trube JD. Ophthalmic medications. In: The Physician’s Guide to Eye Care . San Francisco: American Academy of Ophthalmology; 1993:101–107; Trimethoprim-polymyxin B for bacterial conjunctivitis. Med Lett Drugs Ther . 1990;32:71; Baum JL. Antibiotic use in ophthalmology. In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology . Philadelphia: Lippincott-Raven; 1989:1–20; Topical anti-infective agents: drugs used topically in eye and ear infections. In: Drug Evaluations, Annual . Chicago: American Medical Association; 1995:1617–1635; Kucers A, Bennett NM. Bacitracin and gramicidin. In: Kucers A, Bennett NM, eds. The Use of Antibiotics. A Comprehensive Review with Clinical Emphasis . Philadelphia: Lippincott-Raven; 1987; Baker CJ, Webb BJ, Barrett FF. Antimicrobial susceptibility of group B streptococci isolated from a variety of clinical sources. Antimicrob Agents Chemother . 1976;10:128–131; Finland M, Garner C, Wilcox C, et al. Susceptibility of beta-hemolytic streptococci to 65 antibacterial agents. Antimicrob Agents Chemother . 1976;9:11–19; Fisher MC. Conjunctivitis in children. Pediatr Clin North Am . 1987;34:1447; Isenberg SJ, Apt L, Wood M. A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med . 1995;332:562; Barza M. Antibacterial agents in treatment of ocular infections. Infect Dis Clin North Am . 1989;3:533; Peymen GA, Daum M. Prophylaxis of endophthalmitis. Ophthalm Surg . 1994;25:671–674, 15; 2006 Physician’s Desk Reference . 60th ed. Montvale, NJ: Thomson PDR.
| Concentration | Mechanism of Action | Spectrum of Activity | Chlamydia | Anaerobes | Adverse Effects | ||
|---|---|---|---|---|---|---|---|
| Gram-Positive Organisms | Gram-Negative Organisms a | ||||||
| Single Agents | |||||||
| Azithromycin (Azasite) | Solution, 1% | Inhibits protein synthesis | +++ | ++ | + | + | Skin and eye irritation, altered taste |
| Bacitracin (generic) | Ointment, 500 U/g | Inhibits early steps in peptidoglycan biosynthesis, thus inhibiting cell wall synthesis; also changes membrane permeability | +++ (Group B Streptococcus, usually R) | +(Enterobacteriaceae and Pseudomonas spp. R) | ND | ++ | Hypersensitivity skin reactions |
| Besifloxacin (Besivance) | Solution, 0.6% | Inhibits DNA gyrase and topoisomerase IV | +++ | +++ | +++ | + | Hypersensitivity reaction |
| Chloramphenicol (generic) | Ointment, 1% Solution, 0.5% |
Inhibits protein synthesis | ++( Staphylococcus aureus R) | +++( Pseudomonas spp. R) | ++ | ++ | Absorbed into blood; can cause aplastic anemia |
| Ciprofloxacin (Ciloxan) | Ointment, solution, 0.3% | Inhibits DNA gyrase | ++ | +++ | +++ | − | Local burning and discomfort; reversible crystalline corneal deposits |
| Erythromycin (generic) | Ointment, 0.5% | Inhibits protein synthesis | +++ | +/−(Enterobacteriaceae and Pseudomonas spp. R) | ++ | + | |
| Gatifloxacin (Zymar) | Solution, 0.3% or 5% | Inhibits DNA gyrase and topoisomerase IV | +++ | ++ | +++ | + | |
| Gentamicin (generic) | Ointment, 0.3%Solution, 0.3% | Inhibits protein synthesis | − | +++ | ND | − | Eyelid and facial dermatitis in 10%; keratitis with chronic use |
| Levofloxacin (Quixin) | Solution, 0.5% | Inhibits DNA gyrase and topoisomerase IV | +++ | ++ | +++ | − | |
| Moxifloxacin (Vigamox) | Solution, 0.5% | Inhibits DNA gyrase and topoisomerase IV | +++ | ++ | +++ | − | |
| Norfloxacin (Chibroxin) | Solution, 0.3% | Inhibits DNA gyrase | ++ | +++ | ++ | − | Local burning and discomfort; reversible crystalline corneal deposits |
| Ofloxacin (Ocuflox) | Solution, 0.3% | Inhibits DNA gyrase | ++ | ++ | ++ | − | Local burning and discomfort |
| Povidone-iodine | Solution, 5% | Unknown | +++ | +++ | ++ | ++ | Discolors conjunctiva temporarily |
| Silver nitrate | Solution, 1% | Inhibits DNA replication; modifies cell membrane and disrupts superficial cells | + | ++ | − | ND | Chemical conjunctivitis in 10% |
| Sulfacetamide (generic) | Ointment, 10%Solution, 10% | Inhibits folic acid synthesis | ++ | ++( Pseudomonas spp. R) | ++ | − | Painful; absorption can cause Stevens-Johnson syndrome |
| Sulfisoxazole diolamine (Gantrisin) | Ointment, 4%Solution, 4% | Inhibits folic acid synthesis | ++ | ++( Pseudomonas spp. R) | ++ | − | Same as sulfacetamide |
| Tetracycline (Achromycin) | Ointment, 1% | Inhibits protein synthesis | + | ++( Pseudomonas spp. R) | ++ | + | Photosensitivity |
| Tobramycin (generic) | Ointment, 0.3%Solution, 0.3% | Inhibits protein | − | +++ | + | − | Eyelid/facial dermatitis in 10%; keratitis with chronic use |
| Combination Preparations | |||||||
| Neomycin + Polymyxin B/bacitracin + Polymyxin B + Polymyxin B/gramicidin |
Various concentrations | Inhibits protein synthesis | + | ++( Pseudomonas spp. R) | ND | − | Allergic reaction manifested as follicular conjunctivitis |
| Polymyxin B + Bacitracin + Neomycin + Neomycin/bacitracin + Neomycin/gramicidin + Oxytetracycline + Trimethoprim |
Various concentrations | Attaches to cell membrane, with disruption of osmotic properties leading to cell death | − | +++( Neisseria gonorrhoeae R, Proteus spp. R) | ND | +( Bacillus fragilis R) | Adverse effects of components |
| Trimethoprim + Polymyxin B |
Various concentrations | Inhibits dihydrofolic acid reductase | ++ | ++( Pseudomonas spp. and Neisseria gonorrhoeae R) | ND | − | Adverse effects of components |
| Gramicidin + Polymyxin B/neomycin | Various concentrations | Uncouples oxidative phosphorylation | ++ | − | ND | − | Adverse effects of components |
+++, excellent activity and spectrum; ++, good activity and spectrum; +, fair activity and spectrum; −, no activity; ND, no or limited data; R, resistant.
a Gram-negative organisms include Haemophilus spp., Neisseria spp., Enterobacteriaceae, and Pseudomonas spp., unless otherwise indicated.
TABLE 294.2
Commonly Used Fortified Ophthalmic Drops
Adapted from Baum JL. Antibiotic use in ophthalmology. In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology . Philadelphia: Lippincott-Raven; 1989:1–20; Flynn HW. Antimicrobial treatment: routes/dosages/preparation/adverse effects, antimicrobial resistance, and alternatives. In: Flynn HW, Batra NR, Schwartz SS, Grzybowski A, eds. Endophthalmitis in Clinical Practice . Cham, Switzerland: Springer International; 2018:123–140.
| Antibiotic | Concentration |
|---|---|
| Amikacin | 8 mg/mL |
| Cefazolin | 50 mg/mL |
| Gentamicin | 14 mg/mL |
| Linezolid | 2 mg/mL |
| Imipenem-cilastin | 10 mg/mL |
| Oxacillin | 66 mg/mL |
| Penicillin G | 333,000 U/mL |
| Ticarcillin | 5 mg/mL |
| Tobramycin | 14 mg/mL |
| Vancomycin | 25 or 50 mg/mL |
Blepharitis
Blepharitis is commonly caused by Staphylococcus aureus, and treatment consists of the topical application of an antistaphylococcal agent in ointment form to the eyelids.
Dacryocystitis
Acute dacryocystitis and dacryoadenitis are commonly caused by S. aureus and should be treated systemically. Chronic dacryocystitis is not usually due to infection, but infection can occur secondary to stasis and lacrimal duct obstruction. Treatment consists of relief of the obstruction by irrigation of the lacrimal outflow tract. The use of a topical antibiotic is controversial.
Conjunctivitis
Acute conjunctivitis in children is bacterial in >50% of cases; nontypable Haemophilus influenzae , Streptococcus pneumoniae, and Moraxella catarrhalis are the most common causative agents. Although conjunctivitis usually is self-limited, treatment with topical antibiotics has been shown to hasten the rate of clinical and microbiologic resolution. , Treatment consists of a topical agent in solution form (sulfacetamide, erythromycin, azithromycin, gentamicin, gatifloxacin, ofloxacin, or besifloxacin) that has activity against significant pathogens. Topical preparations of aminoglycosides and fluoroquinolones have been shown to be equally efficacious (84%–90%) in the treatment of acute conjunctivitis, but these topical preparations should be reserved for serious infections when gram-negative bacilli are causative, especially Pseudomonas aeruginosa. Further, topical fluoroquinolones (moxifloxacin) were not shown to be superior to polymyxin B−trimethoprim in a randomized controlled trial for treatment of acute conjunctivitis in children. It is essential to keep in mind that drops are washed out rapidly in a crying child. In infants, ointments may be preferable for ease of application, but the resultant visual blurring can be discomforting to older children. When otitis media accompanies conjunctivitis, as is frequently the case with nontypable H. influenzae, treatment should include administering an appropriate antibiotic orally; concomitant topical therapy is not necessary. Such is also the case for chlamydial conjunctivitis, which is treated systemically to eradicate nasopharyngeal colonization; topical therapy is not necessary.
Neonatal Conjunctivitis
Antibiotic prophylaxis has greatly reduced the incidence of ophthalmia neonatorum in the US. The use of topical silver nitrate reduced the incidence of gonococcal ophthalmia neonatorum from 10% to 0.3%. Silver nitrate is no longer available in the US, causes chemical conjunctivitis in 10% of patients, and has been replaced by ocular prophylaxis using 0.5% erythromycin ointment. Neither agent is effective prophylaxis against chlamydial infection. A 2.5% povidone-iodine solution was shown to effectively prevent ophthalmia neonatorum in a study in Kenya, demonstrating efficacy against Neisseria gonorrhoeae similar to that of erythromycin or silver nitrate and superiority against Chlamydia trachomatis . In another comparison study conducted in Israel, 1% tetracycline was found to be marginally more effective than 2.5% povidone iodine ; however, testing for C. trachomatis was limited to serology. In 2015, the Canadian Pediatric Society advocated against universal topical prophylaxis, favoring screening of mothers for C. trachomatis and N. gonorrhoeae .
Keratitis
Bacterial infections causing corneal ulceration are rare in children and commonly follow corneal abrasion, a scratch, or a foreign-body injury, including contact lens wear. Usual bacterial etiologies include S. aureus, coagulase-negative staphylococci (CoNS), S. pneumoniae, M. catarrhalis, and gram-negative bacilli, especially P. aeruginosa. Adequate evaluation and treatment are essential to prevent permanent corneal injury. For existing infection, Gram stain and culture of the ulcer surface are essential to determine the causative organism, direct antimicrobial therapy, and distinguish bacterial keratitis from herpetic and fungal keratitis. Treatment consists of frequent topical administration of antimicrobial agents.
The achievable concentration of antibiotics in corneal stroma after topical application is limited because the corneal epithelium is a barrier to drug transport. The damaged cornea allows greater penetration of antibiotics into the cornea, and lipophilic antibiotics such as chloramphenicol achieve higher concentrations. “Fortified drops” are solutions prepared extemporaneously to contain higher concentrations of antibiotics than available commercially or antibiotics not commercially available for ophthalmic application; they are used frequently for the treatment of bacterial corneal ulcers and endophthalmitis ( Table 294.2 ). , Monotherapy with moxifloxacin 0.5% was shown in a randomized trial to be equally effective compared with the combination of fortified antibiotics (cefazolin and tobramycin for the treatment of nonperforated bacterial corneal ulcers).
The average drop volume far exceeds the capacity of the inferior cul-de-sac of the eye; spillage or drainage into the lacrimal sac is rapid. Drug draining through the lacrimal system is absorbed systemically and may be of sufficient amount in patients with hepatic or renal insufficiency to cause toxicity. To avoid lacrimal sac drainage and systemic absorption, the puncta in the medial canthal area can be occluded by digital pressure for 15–20 seconds after administration of an eyedrop. Systemic antibiotics have a minor role in the treatment of bacterial corneal ulcers because concentrations achieved in the cornea are inferior to those attained by topical or subconjunctival administration.
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