Topical Antimicrobial Agents

Topical Antimicrobial Agents

294

294 Topical Antimicrobial Agents Ishminder Kaur and Jane M. Gould

Topical antimicrobial therapy dates back 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, as well as 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 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 Chapters 293 and 295.

OPHTHALMIC THERAPY 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. 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 294.1.1–13 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 ocular surface, have been used for corneal protection after trauma, but lack of clinical trials limit their use in ocular infections.14,15

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 infectious, but infection can occur secondary to stasis and obstruction of the lacrimal duct. Treatment consists of relief of the obstruction by irrigation of the lacrimal outflow tract. The use of a topical antibiotic is controversial.6

Conjunctivitis Acute conjunctivitis in children is bacterial in >50% of cases16; 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.17–19 Treatment consists of a topical agent in solution form (sulfacetamide, erythromycin, azithromycin, gentamicin, gatifloxacin, ofloxacin, or besifloxacin) that has activity against major pathogens. Topical preparations of aminoglycosides and fluoroquinolones have been shown to be equally efficacious (84%–90%) in the treatment of acute conjunctivitis,20 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 compared with polymyxin B−trimethoprim in a randomized controlled trial for treatment of acute conjunctivitis in children.17c It is important 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 consist of the administration of 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 United States. The use of topical silver nitrate reduced

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PART IV  Laboratory Diagnosis and Therapy for Infectious Diseases SECTION B  Anti-Infective Therapy

TABLE 294.1  Commercially Available Topical Ophthalmic Antimicrobial Agents Spectrum of Activity Concentration

Mechanism of Action

Gram-Positive Organisms

Gram-Negative Organismsa

Chlamydia

Anaerobes

Adverse Effects

SINGLE AGENTS

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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

++

+++ (Pseudomonas spp. R)

++

++

Absorbed into blood; can cause aplastic anemia3

Ciprofloxacin (Ciloxan)

Ointment, solution, 0.3%

Inhibits DNA gyrase

++

+++

+++

−

Local burning and discomfort; reversible crystalline corneal deposits4

Erythromycin (generic)

Ointment, 0.5%

Inhibits protein synthesis

+++

+/− (Enterobacteriaceae and Pseudomonas spp. R)

++

+

Gatifloxacin (Zymar)

Solution, 0.3%

Inhibits DNA gyrase and topoisomerase IV

+++

++

+++

+

Gentamicin (generic)

Ointment, 0.3% solution, 0.3%

Inhibits protein synthesis

−

+++

ND

−

Levofloxacin (Quixen)

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 deposits4

Ofloxacin (Ocuflox)

Solution, 0.3%

Inhibits DNA gyrase

++

++

++

−

Local burning and discomfort

Povidone-iodine

Solution, 2.5%

Unknown

+++

+++

++

++

Discolors conjunctiva temporarily

Silver nitrate

Solution, 1%

Inhibits DNA replication; modifies cell membrane and disrupts superficial cells11

+

++

−

ND

Chemical conjunctivitis in 10%

(Staphylococcus aureus R)

Eyelid and facial dermatitis in 10%; keratitis with chronic use4

Topical Antimicrobial Agents

294

TABLE 294.2  Commonly Used Fortified Ophthalmic Drops—cont’d Spectrum of Activity Concentration

Mechanism of Action

Gram-Positive Organisms

Gram-Negative Organismsa

Chlamydia

Anaerobes

Adverse Effects

Sulfacetamide (generic)

Ointment, 10% Solution, 10%, 15%, 30%

Inhibits folic acid synthesis

++

++ (Pseudomonas spp. R)

++

−

Painful; absorption can cause Stevens-Johnson syndrome5

Sulfisoxazole diolamine (Gantrisin)

Ointment, 4% Solution, 4%

Inhibits folic acid synthesis

++

++ (Pseudomonas spp. R)

++

−

Same as sulfacetamide

Tetracycline (Achromycin)

Solution, 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 use4

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

a

Gram-negative organisms include Haemophilus spp., Neisseria spp., Enterobacteriaceae, and Pseudomonas spp., unless otherwise indicated. +++, excellent activity and spectrum; ++, good activity and spectrum; +, fair activity and spectrum; −, no activity; ND, no or limited data; R, resistant. Data from references 1–14. 2006 Physician’s Desk Reference, 60th ed. Thomson PDR, Montvale, NJ.

the incidence of gonococcal ophthalmia neonatorum from 10% to 0.3%.21 Silver nitrate is no longer available in the United States, causes chemical conjunctivitis in 10% of patients,22 and has been replaced by ocular prophylaxis using 0.5% erythromycin ointment.22–24 Neither agent is effective prophylaxis against chlamydial infection. A 2.5% povidoneiodine solution was shown to be effective in preventing 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.12 In another comparison study conducted in Israel, 1% tetracycline was found to be marginally more effective than 2.5% povidone iodine25; 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.26

Keratitis Bacterial infections causing corneal ulceration are rare in children and most commonly follow corneal abrasion, a scratch, or a foreign-body injury. Usual bacterial etiologies include S. aureus, coagulase-negative staphylococci (CoNS), S. pneumoniae, M. catarrhalis, and gram-negative bacilli, especially P. aeruginosa.27 Adequate evaluation and treatment are essential to prevent permanent corneal injury. For existing infection,

TABLE 294.2  Commonly Used Fortified Ophthalmic Drops Antibiotic

Concentration

Amikacin

6.7 mg/mL

Bacitracin

9600 U/mL

Carbenicillin

6.2 mg/mL

Cefazolin

33 mg/mL

Gentamicin

14 mg/mL

Neomycin

33 mg/mL

Oxacillin

66 mg/mL

Penicillin G

333,000 U/mL

Pipercillin

12.5 mg/mL

Ticarcillin

6.3 mg/mL

Tobramycin

5 mg/mL

Vancomycin

31 mg/mL

Adapted from Baum JL. Antibiotic use in ophthalmology. In: Tasman W, Jaeger EA (eds). Duane’s Clinical Ophthalmology. Philadelphia, Lippincott-Raven, 1989, pp. 1–20.

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PART IV  Laboratory Diagnosis and Therapy for Infectious Diseases SECTION B  Anti-Infective Therapy

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 antibiotic 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 endophthalmitis6,13 (see Table 294.2). Monotherapy with moxifloxacin 0.5% was shown in a randomized trial to be equally effective compared with combination of fortified antibiotics (cefazolin and tobramycin for treatment of nonperforated bacterial corneal ulcers).28 The average drop volume far exceeds the capacity of the inferior culde-sac of the eye; spillage or drainage into the lacrimal sac is rapid.6 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 to 20 seconds after administration of an eyedrop.4 Systemic antibiotics have little role in the treatment of bacterial corneal ulcers because concentrations achieved in the cornea are inferior to those attained by topical or subconjunctival administration.

TABLE 294.3  Concentrations of Antimicrobial Agents Within Human Eyes After Systemic Administration

Antibiotic

Dosage

Vitreous Humor (Uninflamed Eye) (µg/mL)

Cefazolin

2 g IV

0.3–4.6

Cefotaxime

1 g IM

<0.2

Chloramphenicol

3 g PO

5–15

Ciprofloxacin102

1000 mg PO

0.3–1.2

Gentamicin

1.6 mg/kg IM

<0.2

Imipenem

1 g IV

1.4–3.6a

600 mg PO

1.5 ± 0.5

500 mg PO104

0–1.6

600 mg IV

1.8–2.4

600 mg PO × 2 (every 12 hr)

3.6–5.2

Ofloxacin

400 mg PO

1.8 ± 0.2

Oxacillin

2 g IV

<0.2–4.5

Levofloxacin

Linezolid105

106

103

a

A concentration of 13 µg/mL was achieved in one patient with an inflamed eye. IM, intramuscular; IV, intravenous; PO, oral. Partially Adapted from Barza M. Antibacterial agents in treatment of ocular infections. Infect Dis Clin North Am 1989;3:533.

Endophthalmitis Infectious endophthalmitis is a virulent, sight-threatening infection of intraocular tissue. Prompt diagnosis and therapy are essential. Risk factors for endophthalmitis include ocular trauma or surgery, periocular infection, and systemic infection. Common bacterial pathogens include S. aureus, CoNS, streptococci, and gram-negative bacilli, especially Enterobacteriaceae and P. aeruginosa.29 When endophthalmitis is suspected, aspiration of vitreous humor for culture is essential to determine the pathogen or pathogens and to guide antimicrobial therapy. The corneal epithelium, retinal capillaries, and pigmented retinal epithelium provide mechanical barriers to antimicrobial penetration into the vitreous humor. In addition, the flow of aqueous humor anteriorly impairs the movement of drugs to the vitreous humor. Thus administration of antibiotics by the topical, subconjunctival, or systemic route may not achieve an adequate intravitreal concentration (Table 294.3). The optimal route of administration is intravitreal instillation (see Chapter 84). Many parenterally administered antibiotics have been used for intravitreal injection (Table 294.4). Current recommendation for empiric therapy include intravitreal instillation of vancomycin plus ceftazidime.30 Disadvantages of intravitreal administration are possible damage to the retina and intraocular structures, as well as the need for anesthesia for injection. Adjuvant therapy consists of subconjunctivally and parenterally administered antibiotics, vitrectomy, and corticosteroids (systemically, intraocularly, or by both routes).13 For treatment of endogenous fungal endophthalmitis, systemically administered antifungal agents have variable penetration into the posterior segment of the eye. Therapeutic concentrations of fluconazole and voriconazole usually can be achieved, but not amphotericin B, posaconazole, or the echinocandins.31 Intravitreal injection of amphotericin B (5–10 µg) or voriconazole (100 µg) usually is used for sight-threatening involvement to achieve high local antifungal activity as rapidly as possible.

OTIC THERAPY Topical antibiotic therapy is used in the treatment of otitis externa and chronic suppurative otitis media (CSOM) and as prophylaxis for surgery. Controlled studies documenting efficacy or assessing safety are generally lacking.

Otitis Externa Otitis externa describes an inflammatory condition of the auricle, ear canal, or outer surface of the tympanic membrane. Infectious etiologies

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TABLE 294.4  Typical Dosage of Antibiotics for Subconjunctival and Intravitreal Administrationa Dose Antibiotic

Subconjunctival (mg)

Intravitreal (µg)b

Interval (hr)

Amikacinc

40

400

24–48

Amphotericin

NR

5–10

NR

Ampicillin

100

5000

48

Cefazolin

100

2250

24

Ceftazidime

100

2250

48–72

Ceftriaxone

125107

NR

NR

Cefuroxime

NR

1000

48–72

Ciprofloxacin

NR

100

12

Clindamycin

30

1000

72

Fluconazole

1 mL of 0.2% solution

NR

NR

Gentamicin

20d

200

72–96

Methicillin

100

2000

NR

Penicillin G

NR

2–4000U

48

Tobramycin

20

200–400

NR

Vancomycine

25

1000

72

Voriconazole

NR

50–200

NR

NR, not reported in studies referenced. a Partially adapted from Radhika M, Mithal K, Bawdekar A, et al. Pharmacokinetics of intravitreal antibiotics in endophthalmitis. J Ophthalmic Inflamm Infect 2014;4:22; and Lemley CA, Han DP. Endophthalmitis: a review of current evaluation and management. Retina. 2007;27:662–680. Intervals are those reported in studies referenced. Doses are based primarily from studies in adults. b Each drug is diluted to provide the indicated dose (µg) in a volume of 0.1 mL (sterile water or normal saline. 1 µg = 0.001 mg. c Less toxic to the retina than gentamicin or tobramycin when given intravitreally. d In children who weight <40 kg, the dose should not exceed half of a single intravenous dose. e May cause tissue necrosis/sloughing when administered subconjunctivally.

Topical Antimicrobial Agents

294

TABLE 294.5  Topical Otic Antimicrobial Agents Spectrum of Activity Agent

Concentration

Mechanism

Gram-Positive Organisms

Acetic acid

36% solution

Unknown

ND

Pseudomonas aeruginosa36,37

Boric acid

2.75%–5% solution

Unknown

ND; yeasts > bacteria38

ND

Marked systemic absorption can lead to shock and death

Ciprofloxacin (Cipro HC Otic)

Ciprofloxacin, 2 mg/mL Hydrocortisone, 10 mg/mL

Interferes with DNA gyrase

++

+++ Pseudomonas aeruginosa

Pruritus rarely

Colistin (polymyxin E)

3 mg/mL

Same as polymyxin

−

++ (Pseudomonas spp. R)

Renal toxicity; neurotoxicity if absorbed

Unknown

ND

ND

Modified Burow solution (water, aluminum, and sodium acetate)

Gram-Negative Organismsa

Adverse Effects

Finafloxacin (Xtoro)

0.3% suspension

Inhibits DNA gyrase and DNA topoisomerase IV

+ Staphylococcus aureus

+ P. aeruginosa

Nausea and pruritus in 1% of studied patients

Neomycin

3.3–3.5 mg/mL

Inhibits protein synthesis

+

++ (Pseudomonas spp. R)

Contact hypersensitivity34

Ofloxacin (Floxin)

0.3% solution

Interferes with DNA gyrase

++

+++

Taste perversion, pruritus, site irritation; dizziness, earache, and vertigo in ~1% of patients studied

Polymyxin B

10,000 U/mL

Attaches to cell membrane, with disruption of osmotic properties leading to cell death

−

+++

Renal toxicity if absorbed

a Gram-negative organisms include Haemophilus spp., Neisseria spp., Enterobacteriaceae, and Pseudomonas spp., or as otherwise indicated. +++, excellent activity and spectrum; ++, good activity and spectrum; +, fair activity and spectrum; −, no activity; ND, no or limited data; R, resistant. Data from references 7, 10, 33–35,43.

include primarily bacteria (most commonly S. aureus, P. aeruginosa, and anaerobic bacteria), followed by fungi and mycobacteria.32,33 Therapy for otitis externa consists of cleansing of the canal, elimination of pathogens, reduction of the accompanying inflammation and edema, symptomatic relief, restoration of the oil and water content of the skin, and elimination or control of predisposing factors. Topical antimicrobial agents are noninferior to systemic antibiotics and are effective as sole agents for uncomplicated acute otitis externa.34,35 The spectrum of activity and adverse events of the most commonly used topical antibiotics are shown in Table 294.5.7,10,36–38 Commercial preparations for the treatment of external otitis are combinations of broad-spectrum antibiotics, often with anti-inflammatory agents (Table 294.6). Topical ciprofloxacin (with hydrocortisone), ofloxacin, and finafloxacin have been shown to be effective treatment of otitis externa and are approved by the United States Food and Drug Administration (FDA) for patients older than 1 year.39–43 Topical antibacterial therapy for otitis externa should be used in conjunction with aural toilet to hasten cure and because prolonged use of topical agents alone can induce fungal overgrowth.

Chronic Suppurative Otitis Media CSOM is defined as otorrhea through a nonintact tympanic membrane that lasts >6 weeks and is unresponsive to medical management. This condition usually is a complication of acute otitis media with chronic mastoiditis. The pathogens, however, are different in this condition, with

P. aeruginosa, S. aureus, and anaerobic bacteria most commonly implicated. Therapy usually is systemic antimicrobial therapy in conjunction with aural toilet. A Cochrane Review of 9 trials of patients with CSOM concluded that a topical fluoroquinolone compared with systemic antibiotics was associated with shorter duration of otorrhea.44 A study in 44 children with tympanostomy tubes who received topical otic therapy for CSOM did not demonstrate excessive hearing loss, as measured by a change in bone conduction thresholds.45 Despite the lack of extensive safety data, topical otic agents (see Table 294.5) have been used extensively, alone or in combination with systemic therapy, with apparent success and without adverse effects attributed solely to their use. Cortisporin is used most commonly. Topical ofloxacin is approved by the FDA for the treatment of CSOM in individuals 12 years and older and for acute otitis media in children 1 year and older with tympanostomy tubes because of its microbiologic profile and favorable performance in clinical trials.46,47 Availability of effective, approved otic antibiotics has supplanted off-label use of ophthalmic aminoglycoside otically. Combined medical therapy and surgical debridement frequently are necessary. Failure of management or the presence of cholesteatoma is an indication for surgical intervention.

Prophylaxis After Tympanostomy Tube Placement Topical otic therapy has been used as prophylaxis for otorrhea after tympanostomy tube placement. Studies performed to determine whether

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PART IV  Laboratory Diagnosis and Therapy for Infectious Diseases SECTION B  Anti-Infective Therapy

TABLE 294.6  Commercially Available Topical Otic Preparations Trade Name

Composition

Cipro HC Otic

Ciprofloxacin, 2 mg/mL Hydrocortisone, 10 mg/mL

Ciprodex

Ciprofloxacin, 3 mg/mL Dexamethasone, 1 mg/mL

Coly-Mycin S Otic

Colistin sulfate, 3 mg/mL Neomycin sulfate, 3.3 mg/mL Thonzonium bromide, 0.5 mg/mL Hydrocortisone acetate, 10 mg/mL

Cortisporin (solution, suspension)

Neomycin, 3.5 mg/mL Polymyxin B, 10,000 U/mL Hydrocortisone, 10 mg/mL

Floxin

Ofloxacin, 0.3%

LazerSporin-C solution

Neomycin sulfate, 3.5 mg/mL Polymyxin B, 10,000 U/mL Hydrocortisone, 10 mg/mL

Otic Domeboro solution

Acetic acid, 2% Modified Burow solution (water, aluminum acetate, and sodium acetate) Acetic acid, 2% Desonide, 0.5% (nonfluorinated corticosteroid)

Otic Tridesilon solution

Pedotic suspension

Neomycin sulfate, 3.5 mg/mL Polymyxin B sulfate, 10,000 U/mL Hydrocortisone, 10 mg/mL

Star-Otic ear solution

Acetic acid, 2% Burow solution (aluminum acetate) Boric acid

Tobra Dex

Tobramycin, 0.3% Dexamethasone, 0.1%

VōSol HC Otic

Acetic acid, 2%

VōSol Otic

Acetic acid, 2%

Xtoro

Finafloxacin, 0.3%

Hydrocortisone, 10 mg/mL

this strategy is efficacious have had conflicting results. A Cochrane Review of 15 randomized controlled trials concluded that various interventions, including multiple saline washouts, single application of topical antibiotics, and prolonged application of topical antibiotics were effective in reducing otorrhea after tympanostomy tube placement.48

Acute Tympanostomy Tube Otorrhea Acute otorrhea that occurs while the tympanostomy tube is in place is considered to be an episode of acute otitis media. In a recent randomized controlled trial in children with tympanostomy tubes and acute otorrhea, therapy with antibiotic-glucocorticoid drops was shown to be more effective than compared with oral antibiotic therapy or initial observation alone.49

THERAPY FOR SKIN INFECTIONS Topical antibiotics are used for the prophylaxis and treatment of a wide variety of skin infections (Table 294.7).50–57 The most common conditions for which the use of topical therapy has been found to be efficacious are acne, impetigo, and burns. Topical antimicrobial agents also often are used at intravascular catheter sites to prevent infection.

Acne Minor acne can be treated with topical antibiotics, keratolytics, and drying agents. Antibiotics active against Propionibacterium acnes are

1546

frequently used as adjunctive therapy. Topical erythromycin and clindamycin have been shown to decrease P. acnes colonization and to lessen the percentage of free fatty acids in surface lipids.52 For more severe acne, systemic antibiotics (erythromycin, clindamycin, or tetracycline) and retinoids (topical and systemic) are added to the therapeutic regimen. Topical antibiotic monotherapy is not recommended because of emergence of bacterial resistance and availability of superior topical alternatives.53

Impetigo Impetigo is caused by Streptococcus pyogenes alone or in combination with S. aureus.58,59 Topical therapy is sufficient for minor localized infection in a well child. Mupirocin has exquisite activity against these organisms and is the topical agent of choice for impetigo.60 Retapamulin 1% ointment, approved by the FDA in 2007 for the treatment of impetigo secondary to S. pyogenes or methicillin-susceptible S. aureus, is a 1% semisynthetic pleuromutilin compound with in vitro activity against most gram-positive bacteria and anaerobes. Pleuromutilin may be active against some mupirocin-resistant S. aureus strains.61 Systemic antibiotic therapy is required for a febrile or ill-appearing child (because of the possibility of bacteremia or toxin-mediated manifestations) or if there are multiple or deep lesions.

Prophylaxis and Treatment of Wounds Although topical antibacterial agents are used commonly for the prophylaxis of minor cuts and abrasions, no study has demonstrated that their use prevents infection. In addition to topical antibiotics, antiseptic agents are used for cleansing and treating wounds. Antiseptic agents comprise a wide variety of substances that are applied to living tissues to inhibit or kill microorganisms. The mechanism of action of most agents is not understood clearly. Because methods of testing are not well standardized and it is difficult to make comparisons of antimicrobial activity between compounds, no quantification of the antimicrobial activity of antiseptic agents has been made. Table 294.8 lists antiseptics commonly used for the treatment of skin infections.57,62–64 Topical agents such as mupirocin have been used intranasally in an attempt to eliminate colonization with S. aureus. Mupirocin is especially advantageous because of efficacy against methicillin-resistant S. aureus (MRSA). Unfortunately, increasing use has been associated with the emergence of mupirocin resistance and failure to eradicate communityacquired MRSA.65,66 Dilute sodium hypochlorite (bleach) baths have been used, alone or concurrently with intranasal mupirocin, in attempt to decrease MRSA colonization, with variable outcomes.67,68

THERAPY FOR BURNS Infections are a leading cause of death in burn victims who are successfully resuscitated. The burn wound is often the source of infection in these patients. Aggressive, early surgical debridement and wound closure, in combination with routine use of topical antimicrobial agents, have contributed immensely to prevention and control of burn wound sepsis. Burn wound infection is defined as bacterial invasion into the underlying viable tissue and usually correlates with more than 105 colony-forming units per gram of tissue. Topical antimicrobial agents do not sterilize the wound, but rather decrease the number of colonizing bacteria and the risk for deeper bacterial invasion into underlying viable tissue. Thus their major role is one of prophylaxis. For established burn wound sepsis, topical therapy is used in conjunction with aggressive surgical debridement and parenteral antibiotic therapy. Many topical agents are used, all differing in their antimicrobial spectrum of activity and side effects, but none is ideal. The characteristics of an ideal agent are listed in Box 294.1. The most commonly used agents are shown in Table 294.9.69–91 The agent used most widely has been silver sulfadiazine because of its broad antibacterial spectrum and relatively minor side effects. Other nonconventional topical agents such as acetic acid, formalin, and honey are used occasionally.36,37,92–96 To some extent, all topical antimicrobial agents inhibit the rate of wound epithelialization, but on balance, their prophylactic efficacy against burn wound infection merits use.97,98 Although susceptibility testing can be performed by several methods (most commonly the Nathan agar well diffusion assay), such methods are poorly

Topical Antimicrobial Agents

294

TABLE 294.7  Topical Antibiotics for Use on Skin Spectrum of Activity Agent (Trade Name)

Mechanism of Action

Gram-Positive Organisms

Gram-Negative Organismsa

Anaerobes

Yeast

Adverse Effects

Bacitracinb 400, 500 U/g (generic)

Inhibits early steps in peptidoglycan biosynthesis, inhibits cell wall synthesis; changes membrane permeability

+++ (group B Streptococcus R)

+ (Enterobacteriaceae R, Pseudomonas spp. R)

++

−

Hypersensitivity skin reactions

Clindamycin, 10 mg/mL (Cleocin)

Inhibits protein synthesis

+++

−

+++

−

Pseudomembranous colitis has been reported with topical use

Erythromycin, 2%, 3% (many preparations)

Inhibits protein synthesis

+++

++

−

−

Fusidic acid, 2% (Fucidin)

Inhibits protein synthesis

+++

+ (Enterobacteriaceae R, Pseudomonas spp. R)

++

−

Gentamicin, 0.1%

Inhibits protein synthesis

+

+++

−

−

Meclocycline, 1% (Meclan)

Inhibits protein synthesis

+

++ (Pseudomonas spp. R)

Metronidazole, 0.75% (MetroGel)

Interacts with bacterial DNA; precise mechanism unknown

−

−

+++ (Propionibacterium acnes R)

−

Mupirocin, 2% (Bactroban)

Inhibits protein synthesis by acting on bacterial isoleucyl transfer RNA synthetase

+++

+/−

−

−

Application to open wound can cause pain

Neomycin, 3.5 mg/gb (many)

Inhibits protein synthesis

+

++ (Pseudomonas spp. R)

−

−

Hypersensitivity reactions (rash)— uncommon

Polymyxin Bb

Attaches to cell membrane, with disruption of osmotic properties leading to cell death

−

+++ (Proteus spp. R, Serratia spp. R)

+ (Bacteroides fragilis R)

+/− (in high concentrations)

Hypersensitivity reaction; renal toxicity if absorbed

Retapamulin 1% ointment (Altabax, Altargo)

Inhibits protein synthesis (novel site of action on SOS ribosomal subunit)

+++

−

+

−

Rare allergic contact dermatitis; localized irritation (pruritus)

Sulfacetamide, 10% (Novacet, Sulfacet-R)

Inhibits folic acid synthesis

++

++ (Pseudomonas spp. R)

−

−

Absorption can causes Stevens-Johnson syndrome

Tetracycline, 2.2 mg/mL (Topicycline)

Inhibits protein synthesis

+

++ (Pseudomonas spp. R)

+

−

Photosensitivity

Resistance develops during therapy; not available in the United States

+

a

Gram-negative organisms include Haemophilus spp., Neisseria spp., Enterobacteriaceae, and Pseudomonas spp., unless otherwise specified. Many commercial preparations combine bacitracin, neomycin, and polymyxin B. +++, excellent activity and spectrum; ++, good activity and spectrum; +, fair activity and spectrum; −, no activity; R, resistant. Data from references 8, 10, 50–57.

b

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PART IV  Laboratory Diagnosis and Therapy for Infectious Diseases SECTION B  Anti-Infective Therapy

TABLE 294.8  Antiseptics Used on Skin Spectrum of Activitya Gram-Positive Organisms

Gram-Negative Organismsb

Acid electrolytic water (AEW)

S

S

Benzalkonium chloride (Lanax, Zephiran, many brands)

S

Sc

Benzethonium chloride (many brands)

S

S

Benzoyl peroxide (many brands)

S

Chlorhexidine gluconate, solutions 2% and 4% (Hibiclens)

S

Clioquinol (Vioform)

S

Hexachlorophene (pHisoHex)

S

Phenol (Castellani Paint, Anbesol, CamphoPhenique)

S

S

Povidone-iodine (Betadine)

S

S

Triple dye (brilliant green, proflavine hemisulfate, gentian violet)

S

Can be deleterious to wound healing

Triclosan

S

Limited against gram-negative bacilli; may lead to Pseudomonas aeruginosa overgrowth

Agent (Trade Name)

Anaerobes

Yeast

Adverse Effects

S

Nosocomial gramnegative bacilli and yeast infections from open contaminated solutions

S

Irritation and dryness S

S

Possible CNS toxicity if broad application to neonate

CNS toxicity if broad application to neonate

S

S

Hyperbilirubinemia in neonates; ? carcinogenic potential

S

Excessive area of application can cause thyroid dysfunction

a

S, susceptible; blanks indicate resistance or insufficient data. Gram-negative organisms include Haemophilus spp., Neisseria spp., Enterobacteriaceae, and Pseudomonas spp. c Pseudomonas is frequently resistant. CNS, central nervous system. Data from references 57, 62–64. b

BOX 294.1  Characteristics of an Ideal Topical Antimicrobial Agent

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GENERAL

PERTINENT TO BURN WOUNDS

Painless on application Nonallergenic No systemic absorption Long lasting Ease of use Inexpensive

Penetrates burn wounds to a sufficient depth Prevents desiccation Does not impair the ability to examine wounds Controls bacterial proliferation Does not promote bacterial resistance Does not inhibit re-epithelialization Does not injure viable cells

Topical Antimicrobial Agents

294

TABLE 294.9  Topical Antimicrobial Agents Used in the Treatment of Burns Antimicrobial Activity Agent (Trade Name)

Mechanism of Action

Gram-Positive Organisms

Gram-Negative Organismsa

Anaerobes

Yeast

Acetic acid

Unknown

ND

Pseudomonas aeruginosa

ND

ND

Bacitracin, 400, 500 U/g (generic)

Inhibits early steps in peptidoglycan biosynthesis resulting in inhibition of cell wall synthesis; also changes cell membrane permeability

+++ (Group B Streptococcus R)

+

++

−

Allergic reaction (rare)

Cerium nitrate, 2.2%

Unknown

+++

+++

ND

+++

Methemoglobinemia (rare); ? inactivates silver sulfadiazine

Chlorhexidine

Unknown

+++

+++

ND

+

Possible central nervous system toxicity if broad application

Fusidic acid, 2% (Fucidin)

Inhibits protein synthesis

+++

+ (Enterobacteriaceae, Pseudomonas spp. R)

++

−

Resistance develops during therapy; not available in the United States

Gentamicin, 0.1% (Garamycin)

Inhibits protein synthesis

+ (Synergy for Staphylococcus aureus and Enterococcus spp.)

+++

−

−

High rate of systemic absorption with neuro/ ototoxicities; resistance develops during therapy with possible cross-resistance to silver sulfadiazine

Mafenide acetate, 11.1% cream, 5% solution (Sulfamylon)

Unknown

+

+++

+++

+

Allergic reaction in 10%; painful on application; electrolyte disturbances; metabolic acidosis

Mupirocin, 2% (Bactroban)

Inhibits protein synthesis by irreversibly binding to bacterial isoleucyl transfer RNA synthesis

+++

+/− (Pseudomonas spp. R)

+/−

−

Some MRSA resistant

Neomycin, 3.5 mg/g

Inhibits protein synthesis

+

++ (Pseudomonas spp. R)

−

−

Allergic reaction in 6%–8%; renal toxicity; neuromuscular blockade

Nitrofurazone, 0.2% cream, solution (Furacin)

Inhibits several bacterial enzymes involved in carbohydrate metabolism

+++

+++

++

−

Contact dermatitis in 1%; fatal hypersensitivity (rare); fungal overgrowth; mild pain on application secondary to vehicle

Polymyxin B, 5000, 10,000 U/g

Attaches to cell membrane, with disruption of osmotic properties leading to cell death

−

+++ (Proteus spp. R; Serratia spp. R)

+/− (Bacillus fragilis R)

+/− (In high concentrations)

Allergic reaction (rare)

Povidone-iodine, 5% cream, 10% ointment (Betadine)

Unknown

+++

+++

++

++

Allergic reaction in 20%; inactivated by wound exudate; absorption of iodine leads to thyroid dysfunction; short antibacterial effect requires frequent reapplication

Adverse Effects

Continued

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PART IV  Laboratory Diagnosis and Therapy for Infectious Diseases SECTION B  Anti-Infective Therapy

TABLE 294.9  Topical Antimicrobial Agents Used in the Treatment of Burns—cont’d Antimicrobial Activity Agent (Trade Name)

Mechanism of Action

Gram-Positive Organisms

Gram-Negative Organismsa

Anaerobes

Yeast

Adverse Effects

Silver nitrate, 0.5% solution

Silver ion inhibits DNA replication; modifies cell membrane

+

++

+

+

No penetration of burn eschar; causes a decrease in serum osmolality, sodium, potassium, chloride, and calcium; methemoglobinemia (rare); staining

Silver sulfadiazine, 1% cream (Silvadene, Thermazene)

Silver ion inhibits DNA replication; modifies cell membrane

++

+++

++

++

Allergic reaction in 5%; transient, reversible leukopenia in 5%–15% (probably due to margination); moderate penetration into burn eschar; causes “pseudoeschar,” a proteinaceous exudate confused with purulence; resistance of gram-negative bacilli (especially Pseudomonas spp.) develops; serum hyperosmolality secondary to propylene glycol in cream base

+++, excellent activity and spectrum; ++, good activity and spectrum; +, fair activity and spectrum; −, no activity; MRSA, methicillin-resistant Staphylococcus aureus; ND, no or limited data; R, resistant. a Gram-negative organisms include Haemophilus spp., Neisseria spp., Enterobacteriaceae, and Pseudomonas spp., unless otherwise specified.Data from references 36, 37, 69–91.

standardized for topical antimicrobial testing and results have varied widely.70,71,99–101 Selection of topical agents is based on known or expected colonizing organisms and their presumed susceptibilities, timing of injury, knowledge of organisms indigenous to the burn unit, and possible adverse reactions of agents. Occasionally, preparations of systemically administered antibacterial and antifungal agents are made extemporaneously for topical use when an infection is due to organism resistant to available topical agents or when cultured autografts are used because many routine preparations can be toxic to keratinocytes. Such use must be restricted and for short periods as resistance develops rapidly (precluding future use of that agent systemically). The toxicity of antibiotics on cultured skin and skin substitutes varies extensively, and the choice of agents should be based on the manufacturer’s guidelines and the antimicrobial susceptibility of the organisms isolated. All references are available online at www.expertconsult.com.

KEY REFERENCES 19. Williams L, Malhotra Y, Murante B, et al. A single-blinded randomized clinical trial comparing polymyxin-B-trimethoprim and moxifloxacin for treatment of acute conjunctivitis in children. J Pediatr 2014;162:857–861.

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25. David M, Rumelt S, Weintraub Z. Efficacy comparison between povidone iodine 2.5% and tetracycline 1% in prevention of ophthalmia neonatorum. Ophthalmology 2011;118:1454–1458. 26. Moore DL, MacDonald NE, Canadian Pediatric Society, Infectious Diseases and Immunization Committee. Preventing ophthalmia neonatorum. Paediatr Child Health 2015;20:93–96. 29. Gentile RC, Shukla S, Ritterband DC, et al. Microbiological spectrum and antibiotic sensitivity in endophthalmitis: a 25-year review. Ophthalmology 2014;121: 1634–1642. 30. Lemley CA, Han DP. Endophthalmitis: a review of current evaluation and management. Retina 2007;27:662–680. 34. Roland PS, Belcher BP, Bettis R, et al. A single topical agent is clinically equivalent to the combination of topical and oral antibiotic treatment for otitis externa. Am J Otolaryngol 2008;29:255–261. 49. van Dongen TM, van der Heijden GJ, Venekamp RP, et al. A trial of treatment for acute otorrhea in children with tympanostomy tubes. N Engl J Med 2014;370: 723–733. 53. Eichenfield LF, Krakowski AC, Piggott C, et al. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics 2013;131(suppl 3): 163–186. 57. Lipsky BA, Hoey C. Topical antimicrobial therapy for treating chronic wounds. Clin Infect Dis 2009;49:1541–1549. 66. Patel JB, Gorwitz RJ, Jernigan JA. Mupirocin resistance. Clin Infect Dis 2009;49:935–941.

Topical Antimicrobial Agents

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Moore DL, MacDonald NE, Canadian Pediatric Society, Infectious Diseases and Immunization Committee. Preventing ophthalmia neonatorum. Paediatr Child Health 2015;20:93–96. 27. Rettig PJ. Conjunctivitis and keratitis. In: Nelson JD (ed) Current Therapy of Pediatric Infectious Diseases. Toronto, BC Decker, 1986. 28. Sharma N, Goel M, Bansal S. Evaluation of moxifloxacin 0.5% in treatment of nonperforated bacterial corneal ulcers: a randomized controlled trial. Ophthalmology 2013;120:1173–1178. 29. Gentile RC, Shukla S, Ritterband DC, et al. Microbiological spectrum and antibiotic sensitivity in endophthalmitis: a 25-year review. Ophthalmology 2014;121:1634–1642. 30. Lemley CA, Han DP. Endophthalmitis: a review of current evaluation and management. Retina 2007;27:662–680. 31. Riddell J IV, Comer GM, Kauffman CA. Treatment of endogenous fungal endophthalmitis: focus on new antifungal agents. Clin Infect Dis 2011;52:648–653. 32. Agius AM, Pickles JM, Burch KL. 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