Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

vessels may encircle or envelop the follicle. Germinal cells (immature lymphocytes) and macrophages compose the central portion; mature cells form the periphery.The conjunctival lymphatic system responds to antigen exposure with hyperplasia of the T lymphocytes contained within the lymphoid germinal center of the follicle. This antigenic response can occur in viral, chlamydial, and certain bacterial infections and after exposure to toxic agents. Follicles may also be observed in young asymptomatic children as an incidental finding. Follicles located in the fornices usually are nonspecific; however, follicles located on the superior tarsus or at the limbus frequently represent disease.

LABORATORY DIAGNOSIS

OF CONJUNCTIVITIS

Indications for Laboratory Analysis

The differential diagnosis of conjunctivitis can sometimes be challenging. Laboratory testing can help both to identify the etiology and to effectively direct treatment. Ideally, in all cases of infectious conjunctivitis, cultures or ocular smears should be obtained to determine the exact etiology. However, in practice this rarely is done. Experienced practitioners typically treat infectious conjunctivitis empirically. In most cases eye care providers can diagnose conjunctivitis accurately and treat it effectively

by assessing the clinical history, signs, and symptoms. With some forms of conjunctivitis the disease severity or increased risk for ocular tissue damage demands ancillary testing as part of the workup and management plan. In other cases laboratory diagnosis is suggested but not mandatory. Conjunctival disorders requiring mandatory laboratory analysis include severe chronic conjunctivitis, hyperacute conjunctivitis, membranous conjunctivitis, ophthalmia neonatorum, Parinaud’s oculoglandular syndrome, conjunctivitis in immunocompromised patients, and in postoperative infections. Laboratory diagnosis is recommended for moderate chronic conjunctivitis, conjunctivitis secondary to canaliculitis or dacryocystitis, conjunctivitis secondary to infectious eczematous or ulcerative blepharitis,and conjunctivitis unresponsive to therapy (Box 25-2).The inexperienced clinician may find laboratory evaluation helpful in confirming clinical judgment.

Cultures

Whenever bacterial or fungal etiologies are suspected, ocular specimens for culture should ideally be plated directly on agar plates containing enriched or selective bacteriologic media. Commercially available transport media may not be sufficient for bacteria or fungi because most ocular specimens may contain diminutive quantities of fastidious microorganisms. However, transport solutions for viruses and chlamydia can effectively maintain

Box 25-2 Indications for Laboratory Diagnosis of Conjunctivitis

Mandatory

Severe chronic conjunctivitis

Hyperacute conjunctivitis

Ophthalmia neonatorum

Membranous conjunctivitis

Parinaud’s oculoglandular syndrome

Postoperative infections

Recommended

Any chronic conjunctivitis

Conjunctivitis secondary to canaliculitis or dacryocystitis Conjunctivitis secondary to infectious eczematous or

ulcerative blepharitis

Conjunctivitis unresponsive to therapy

specimens for laboratory analysis. Inoculating agar plates directly enhances a practitioner’s chances of isolating an offending organism. Solid media plates also enable laboratory technicians to identify the organism’s morphology more efficiently and thus shorten the waiting time for reports. Three types of solid media and one liquid medium are recommended for routine inoculation: blood agar, chocolate agar, and Sabouraud’s agar and thioglycolate broth. The liquid medium provides for transport of any anaerobic microorganisms and permits the laboratory to inoculate additional media plates if necessary. Other selective media may be indicated when isolation of specific microorganisms, such as Neisseria species, is being attempted.

The use of Mini-tip Culturette (Becton Dickinson, Cockeysville, MD) has been compared with traditional culture techniques using a rabbit model as well as community-acquired presumed bacterial keratitis. The sensitivity of the Mini-tip Culturette was 83.3% and the specificity 100%. Detected organisms included group A β-hemolytic Streptococcus, S. aureus, coagulase-negative

Staphylococcus, Serratia marcescens, and Pseudomonas aeruginosa.

Blood agar is an all-purpose enriched medium appropriate for isolating most ocular aerobic or anaerobic pathogens except Haemophilus, Neisseria, and Moraxella species. When incubated under anaerobic conditions, blood agar is useful for isolating most anaerobes, including Actinomyces. This medium is trypticasesoy agar with 5% to 10% sterile defibrinated sheep blood. Blood agar is the standard bacteriologic medium used for cultivating fastidious microorganisms and determining hemolytic reactions that characterize certain bacteria.

Chocolate agar is a polypeptone or beef infusion agar enriched with 2% hemoglobin released from defibrinated heated rabbit’s or sheep’s blood. The blood hemolysis creates the chocolate color. Free hemin and nicotinamide

adenine dinucleotide permit cultivation of Haemophilus, Neisseria, and Moraxella species. Because its usefulness is more limited, chocolate agar cannot take the place of blood agar.

Sabouraud’s agar is a glucose-peptone agar combination, the pH of which has been adjusted to 6.7 to 7.1 to favor isolation of opportunistic fungi. The addition of antibiotics such as chloramphenicol or gentamicin prevents the growth of bacteria, thus enhancing the growth environment for fungal microorganisms.This medium should not contain cycloheximide, which inhibits saprophytic fungi that may cause ocular infection.

Thioglycolate broth is an enriched trypticase-peptone broth usually containing glucose, hemin, and vitamin K. This medium is favorable for culturing a variety of fastidious aerobic or anaerobic microorganisms. Although it is superior to commercially available bacterial transport media systems for conveying specimens to the laboratory, thioglycolate broth should not be used as the sole medium. Solid media are still superior for isolating and quantifying microorganisms. Extra care must be taken to use an uncontaminated plate because of the relatively low numbers of microorganisms found in most ocular specimens.This contamination increases the risk of overgrowth of unwanted organisms when using a medium that supports multiple microbial species.

Mannitol salt agar is a selective medium for the isolation of Staphylococcus species that ferment mannitol from nonmannitol-fermenting species.The peptone-based agar contains mannitol, with 7.5% sodium chloride and a phenol red indicator dye. The salt concentration inhibits most other bacteria.Thayer-Martin medium is a selective agar for isolating Neisseria gonorrhoeae or Neisseria meningitidis from specimens contaminated with other bacteria and fungi. It consists of an enriched chocolate agar to which vancomycin, colistin, trimethoprim, and nystatin are added to inhibit the growth of other bacteria and fungi. If Neisseria infection is suspected, chocolate agar should be inoculated in conjunction with ThayerMartin medium, because some strains of pathogenic Neisseria species are inhibited by the additives.

Several viral transport systems are available commercially or through medical laboratories. These transport solutions contain antibiotics to inhibit the growth of bacteria and are adequate for maintaining all types of viruses until the laboratory can culture them.

A Dacron-tipped or calcium alginate swab is recommended for obtaining all conjunctival specimens for culture. The use of cotton-tipped swabs should be avoided, because the fatty acids in the cotton material may inhibit the growth of some bacteria. Specimens should also be obtained without the use of topical anesthesia. All topical anesthetics have some antimicrobial effects in addition to preservatives that may inhibit the recovery of some microorganisms. The swab should be moistened with either thioglycolate broth or sterile saline and gently rolled through the full length of the conjunctival

Figure 25-2 Standard convention for streaking agar plates.

fornix, maintaining contact for several seconds. Specimens should be obtained from both eyes, one swab being used for each eye to inoculate all media. Contact with the eyelid margins should be avoided so as not to contaminate the conjunctival specimen. The agar plates are inoculated by streaking (lightly dragging) the swab across the surface of the plate.The swab should be rolled gently during the streaking process.After the conjunctiva has been swabbed, specimens are obtained from the eyelid margins using a second moistened swab. The inoculum from both the conjunctiva and eyelid margins may be placed on the same plate using the standard convention shown in Figure 25-2. After inoculation of the agar plates, the swab should be plunged into the thioglycolate broth and twirled, after which the end that was handled is broken or cut off,allowing the sterile untouched lower portion of the swab to drop into the broth.The same

Table 25-2

Efficacy of Commonly Used Topical Antibacterial Agents

procedure used with thioglycolate broth is followed for inoculating the viral or chlamydial transport media. However, dry swabs may be used to collect these samples. The practitioner is strongly advised to wear disposable gloves when obtaining ocular specimens with swabs or other ophthalmic instruments.

Until the laboratory reports the results of the cultures, empirical therapy is initiated on the basis of clinical findings.The results of most aerobic bacterial cultures usually are known in 24 to 48 hours, anaerobic cultures in 3 to 7 days, and fungal cultures may take up to 1 to 2 weeks. Antibiotic sensitivity testing should be routinely ordered for all culture specimens. This testing allows for proper management of the conjunctivitis after receipt of the laboratory report. Antibiotic sensitivity testing either confirms the appropriateness of the initial empiric therapy or indicates organism resistance, requiring the selection of another anti-infective agent (Table 25-2).

Sensitivity testing usually is performed by a microbroth dilution method and should encompass all categories of antibiotics. Zones of inhibition around antibioticcontaining drugs indicate relative sensitivity.The agents to be tested may vary based on availability of antibiotic discs, geographic prevalence rates of infection, or practitioner preference (Box 25-3).

Smears and Scrapings

Conjunctival smears and scrapings are used to investigate exudative discharge or to perform a cytologic analysis of

Box 25-3 Suggested Agents for Antibiotic Sensitivity Testing

Ampicillin

Bacitracin

Carbenicillin

Cefazolin

Ciprofloxacin

Colistin (polymyxin E)

Erythromycin

Gatifloxacin

Gentamicin

Levofloxacin

Moxifloxacin

Neomycin

Ofloxacin

Polymyxin B

Tetracycline

Tobramycin

Trimethoprim

Vancomycin

Note: If Neisseria gonorrhoeae is suspected, test ceftriaxone and penicillin G.

conjunctival tissue. These techniques provide more immediate information regarding the disease process than do cultures.A Kimura platinum spatula is the instrument of choice for obtaining conjunctival scraping specimens. After the conjunctiva has been anesthetized with two drops of 0.5% proparacaine solution, the spatula is used to scrape the inferior palpebral conjunctival epithelial surface. Although some conjunctival blanching may occur,care should be taken to avoid any bleeding.The material is spread in a thin layer onto a clean glass microscope slide; it then is fixed either with a commercial fixative

Table 25-3

Ocular Smear Interpretation for Gram and Giemsa Stains

solution or methyl alcohol or is air-dried. Next, the smear is stained to inspect for the presence of bacteria or inflammatory cells. Gram stain identifies bacteria as gram positive (stains blue or purple) or gram negative (stains pink). This information aids the practitioner in selecting the initial antibiotic for therapy until the culture report has been received. A conjunctival scraping often reveals a definitive inflammatory cell response indicating a particular disease process. Staining with Giemsa solution is the most useful method, because Giemsa stains inflammatory cells, epithelial cells, fungi, and chlamydial inclusion bodies present in the smear (Table 25-3). Wright’s solution or the Diff-Quik system stains conjunctival inflammatory cells, but chlamydial inclusion bodies are not stained adequately. Papanicolaou stain is superior for eliciting viral intranuclear inclusion bodies as well as cytologic examinations for premalignant lesions or malignancies. The clinician is advised to consult standard ocular microbiology and cytology texts for additional information on standard stain preparation techniques.

Direct fluorescent antibody smears have become a more efficient method than Giemsa stains or tissue cultures for identifying chlamydia. Commercially prepared kits make specimen collection convenient, and results are available in approximately 24 hours. Good results, however, depend on obtaining an adequate specimen. Fluoresceinlabeled monoclonal antibodies in the staining reagent specific for Chlamydia trachomatis outer membrane proteins bind to the C. trachomatis in the smear. Studies that compare direct fluorescein antibody techniques with tissue culture results have found acceptable sensitivity and specificity values.

Newer techniques have equal sensitivity and greater specificity. Enzyme-linked immunosorbent assay (ELISA) tests can identify C. trachomatis, HSV-1 and -2, and adenoviruses through the detection of microbial antigens. In the direct ELISA, an enzyme is covalently linked to an antigen-specific monoclonal or polyclonal antibody.

444 CHAPTER 25 Diseases of the Conjunctiva

The antigen then is mixed with serial dilutions of the enzyme-labeled antibody. A chromogenic substrate mixed with the conjugated enzyme yields a water-soluble product, the absorbency of which can be measured by a spectrophotometer. Recent technology has led to the development of rapid tests that do not require intact cells, live organisms, or cell cultures. ELISAs using monoclonal antibody techniques for the rapid detection of HSVs, adenoviruses, and C. trachomatis are highly sensitive and specific.

Polymerase chain reaction testing is a nucleic acid amplification test (NAAT) that amplifies the number of copies of a specific region of DNA to produce enough DNA to be adequately tested. It has been used to identify a variety of ocular pathogens, including C. trachomatis, adenoviruses, HSV-1 and -2, varicella-zoster virus, EpsteinBarr virus, and cytomegalovirus. Specimen DNA is denatured, specific primers are attached to the strand, and a new DNA strand is synthesized in an elegant expression of applied practical molecular biology. With each round the number of DNA strands is doubled, allowing more than a million-fold amplification. Polymerase chain reaction testing is both sensitive and specific and can be used with clinical samples containing minuscule amounts of the pathogen, such as tears. Combining two or more primers into one multiplex test for detection of several pathogens may replace individual tests and, consequently, decrease costs and erroneous results, especially when the clinical picture is confusing. Ongoing developments in microand nanotechnology and electronics will likely lead to diminutive, likely handheld, in-office microbiological diagnostic devices.

INFECTIOUS CONJUNCTIVITIS

Mechanisms of Infection

The conjunctiva has several nonimmune defense barriers that protect it from infection. These natural defenses include the intact mucous membrane surface and glycocalyx, rapid epithelial cell turnover, cool temperature due to tear evaporation, mechanical action of the eyelids, and the flushing action of the tears and lacrimal system. The normal bacterial flora and tear film constituents, such as lactoferrin, β-lysine, and lysozyme, have antibacterial action and supplement the anatomic barriers. Additional antibacterial proteins from inflamed blood vessels may play an adjunctive role during dry eye states when normal tear proteins are diminished. The prominently vascularized conjunctiva has highly active immunologic barriers. All cellular components of the immune system, except basophils and eosinophils, typically are found in the conjunctival substantia propria. These barriers work harmoniously to protect against infection. Conjunctivitis may result from a disruption in any of the barriers, leading to invasion by a pathogen or overgrowth of endogenous flora.

Irregular eyelid margins or function, irregular blinking, disturbed ocular surface innervation, or abnormal tear film may compromise the epithelial surface. When an inoculum of sufficient quantity invades the conjunctiva, over-colonization by the infectious organism may result either from overwhelming normal flora or because the antimicrobial capabilities of the tear constituents have been exceeded.

For example, tear lysozyme is not effective against S. aureus. Once an infectious conjunctivitis becomes established, the severity of the infection depends on several factors, including the organism’s virulence, invasiveness, and level of toxin production; environmental elements such as temperature; pH; and the function and effectiveness of existing active nonimmune barriers and immune defenses.

Principles of Therapy

In theory, antimicrobial therapy for infectious conjunctivitis should be specific for the infecting organism; however, in current practice such is rarely the case. Most commonly, treatment is based on the patient’s history, signs, and symptoms rather than on laboratory analysis of ocular cultures or smears. The advent of effective broadspectrum topical antibiotics made empiric treatment of presumed bacterial conjunctivitis commonplace, despite the still accepted belief that pathogen-specific therapy selected on the basis of known antibiotic sensitivity characteristics of the infecting microorganism is preferred (see Table 25-2).The introduction of the fluoroquinolones reinforced empiric treatment, and the even broader spectrum fourth-generation fluoroquinolones have furthered this now well-accepted clinical practice. Nonetheless, clinical experience tempered by appropriate scientific evidence remains the most important guide to selecting an appropriate antibiotic for empiric treatment of conjunctivitis.

Severe infection such as gonococcal conjunctivitis requires systemic therapy, which may be used in conjunction with topical agents. Treatment of viral infections often is directed at relieving patient symptoms, because specific antiviral agents do not currently exist in most cases. Chlamydial disease requires systemic therapy frequently combined with adjunctive topical therapy.

Acute Bacterial Conjunctivitis

Etiology

Acute bacterial conjunctivitis is the most frequently encountered ocular infection in optometric practice,especially among the pediatric population. Both gram-positive and gram-negative organisms can cause acute bacterial conjunctivitis.As is the case with most ocular infections, gram-negative bacterial conjunctivitis is generally more severe than conjunctivitis induced by gram-positive organisms. S. aureus, S. pneumoniae, and H. influenzae

Figure 25-3 Acute bacterial conjunctivitis with typical mucopurulent discharge (arrow).

A

are most frequently associated with acute bacterial conjunctivitis. S. aureus is the most common infectious agent in patients of all ages. Less common causative organisms include S. epidermidis, Moraxella lacunata, Corynebacterium diphtheriae, Serratia marcescens, and P. aeruginosa. S. pneumoniae and H. influenzae occur more commonly in pediatric patients.

Diagnosis

Acute bacterial conjunctivitis usually begins suddenly in one eye with hyperemia and a mild to moderate mucopurulent or purulent discharge (Figure 25-3). The discharge may be trapped beneath the upper eyelid and expel upon lid eversion or manipulation (Figure 25-4A). Patients initially complain of unilateral tearing and vague irritation. Associated mild to moderate eyelid edema and erythema may give the appearance of pseudoptosis. No preauricular lymph node swelling or tenderness occurs. The hyperemia may be either diffuse or localized to a particular sector—often nasally because of the higher accumulation of organisms and elaborated toxins in this region due to tear drainage. The hyperemia tends to be

B

446 CHAPTER 25 Diseases of the Conjunctiva

more intense toward the fornix and diminishes at the limbus. A velvety papillary reaction is frequently seen on the tarsal conjunctiva (Figure 25-4B). Exudative material may accumulate on the eyelashes, prompting complaints that the patient’s eyelids stick together on awakening.The fellow eye may become involved 2 to 3 days after the first eye. In some cases, a diffuse superficial punctate keratitis (SPK) may be present, caused by microbial exotoxins. Pseudomembrane or membranes may form, typically when Streptococcus pyogenes, S. aureus, or C. diphtheriae causes the conjunctivitis. Conjunctival cultures and smears assist in the diagnosis and treatment of moderately severe or severe acute bacterial conjunctivitis.

Acute S. aureus conjunctivitis occurs less commonly than does chronic staphylococcal conjunctivitis. It is usually characterized by inferior palpebral conjunctival hyperemia with a mucopurulent discharge. In many cases the bulbar conjunctiva beneath the eyelid is more hyperemic than is the exposed bulbar conjunctiva. The presence of staphylococcal exotoxins may cause SPK and marginal corneal infiltrates that frequently accompany the conjunctivitis (Figure 25-4C).

S. pneumoniae is a common cause of acute bacterial conjunctivitis in children (Figure 25-5). Concurrent upper respiratory tract infections and otitis media, especially in children younger than 4 years, are common. In moderate climates S. pneumoniae is often the cause of acute bacterial conjunctivitis epidemics. This condition commonly presents with diffusely scattered petechial hemorrhages, especially on the superior bulbar conjunctiva, a mucopurulent discharge in the lower fornix, and transient marginal corneal infiltrates. Pseudomembranes may form.

Before the development of an effective vaccine, H. influenzae was another frequent cause of acute bacterial conjunctivitis in children that concurrently

Figure 25-5 Streptococcus pneumoniae conjunctivitis with petechial hemorrhages.

caused upper respiratory infections and otitis media. Conjunctivitis caused by Haemophilus species tends to occur more frequently in warmer climates and last longer than S. pneumoniae infections. The clinical presentation consists of bulbar and palpebral hyperemia with occasional petechial hemorrhages, mucopurulent discharge, and marginal corneal infiltrates. H. influenzae biogroup aegyptius causes a severe conjunctivitis that may precede the life-threatening pediatric disease, Brazilian purpuric fever. Young children with severe or improperly treated Haemophilus infections may present with periorbital bluish discoloration and edema suggestive of preseptal cellulitis or incipient orbital cellulitis.

Management

Many cases of mild bacterial conjunctivitis are selflimiting and resolve without treatment. However, antibiotic therapy often lessens the patient’s anxiety and ocular symptoms, shortens the duration of the disease, and prevents recurrence or spread to the fellow eye. Contagion is also a significant risk. Several severe bacterial conjunctivitis outbreaks have been reported. Among the more common requests in ophthalmic practice are releases permitting patients who had conjunctivitis to return to work or school. Epidemiologic data support the clinical and public health benefits of early treatment.

Current initial treatment for bacterial conjunctivitis is application of a broad-spectrum topical antibiotic. With the introduction of the highly effective fourth-generation fluoroquinolones many clinicians have adopted these agents as a first choice for treating bacterial conjunctivitis. Benefits of the fourth-generation fluoroquinolones include enhanced tissue penetration, a generally better dosing profile (moxifloxacin), reduced likelihood for causing resistant strains, and excellent gram-positive, gram-negative, and atypical mycobacterium coverage.The fourth-generation fluoroquinolones are also effective against many organisms resistant to previous generation fluoroquinolones.

Alternatively, antibiotics such as trimethoprimpolymyxin B (Polytrim), gentamicin, or tobramycin solution, instilled as one drop four times daily for 5 to 7 days, or prior generation fluoroquinolones such as ciprofloxacin, ofloxacin, or levofloxacin, dosed four times daily for 5 to 7 days, may be prescribed. Bacitracin-polymyxin B (Polysporin), erythromycin, gentamicin, tobramycin, or ciprofloxacin ointment may be used at bedtime as supplemental therapy or four times daily in children or other patients who are not comfortable with eyedrops.

Moderate conjunctivitis may require a more frequent initial dosage, up to six to eight times daily, tapering to four times daily over 7 to 10 days depending on the antibiotic used. In moderate to severe bacterial conjunctivitis, conjunctivitis with pseudomembrane or membrane formation, or cases of drug resistance, a fourth-generation fluoroquinolone is currently the initial drug of choice.These antibiotics may be applied as often as six to eight times

daily initially and then tapered as the condition responds to therapy.

To minimize the possibility of overgrowth of resistant strains in more severe or recalcitrant conjunctivitis, a bactericidal dose of antibiotic should be maintained until the therapy is discontinued. For most topical ophthalmic antibiotics, this is generally at least four times daily if not more frequently. Moderate to severe conjunctivitis often requires antibiotic therapy for 7 to 14 days to achieve complete resolution.

Severe acute bacterial conjunctivitis with risk of preseptal cellulitis or conjunctivitis associated with otitis media requires concurrent oral antibiotic therapy, especially in children with severe Haemophilus infections. Possible systemic agents include amoxicillin or Augmentin, cefdinir, cefpodoxime, cefotaxime, cefuroxime, or cefaclor with dosages appropriate for the patient’s age and body weight (see Chapter 23). Azithromycin or clarithromycin are alternatives. Empiric treatment should ideally be based on in vitro activity against locally prevalent organisms. In adults treatment with systemic fluoroquinolone antibiotics may be appropriate for severe infection. Resistance is an ongoing concern in treating conjunctivitis and related diseases with both topical and systemic agents.

Topical steroids are not indicated for most cases of acute bacterial conjunctivitis. The exception is acute conjunctivitis accompanied by severe inflammation or pseudomembranes or true membranes. Concurrent topical antibiotic–steroid therapy hastens resolution of inflammatory response; however, caution is prudent in cases in which the infectious agent has not been definitively identified and until the infection has clearly responded to antibiotic therapy.

Sulfonamide, chloramphenicol, and tetracycline antibiotics generally are no longer used for treating bacterial conjunctivitis. The sulfonamides have a broad spectrum of activity against gram-positive and gram-negative organisms, but they are bacteriostatic agents that require intact immune responses to eliminate infection. Because S. aureus often is resistant to these agents, sulfonamides may actually delay resolution of the infection or initiate a low-grade chronic conjunctivitis. The anti-infective activity of the sulfonamides is also inhibited by paraaminobenzoic acid, found in purulent exudate. Although largely obsolete drugs, topical 10% sodium sulfacetamide and 4% sulfisoxazole may be effective in mild cases of acute bacterial conjunctivitis when little or no mucopurulent discharge is present. The sulfonamides also are contraindicated in patients with allergies to these drugs that may lead to erythema multiforme. Although uncommon, erythema multiforme has reportedly followed topical application of 10% sodium sulfacetamide.

Although seldom used in the United States, chloramphenicol has a broad spectrum of activity against S. pneumoniae and many gram-negative organisms. Because of the potential for adverse reactions, other readily available

anti-infective agents that are equally or more effective have largely replaced it. Chloramphenicol has been linked to numerous cases of aplastic anemia, although the actual risk is subject to significant debate. The reaction is not dose related and typically occurs weeks or months after completion of therapy.

Topical tetracycline may be used as an adjunctive therapy for chlamydial infections but not for initial treatment of acute bacterial conjunctivitis. Numerous organisms are resistant to tetracycline.

Trimethoprim is a bactericidal agent effective against most gram-positive and gram-negative organisms, except P. aeruginosa.When combined with polymyxin B, which is effective against Pseudomonas species, it provides broad-spectrum antimicrobial activity for the initial treatment of acute bacterial conjunctivitis. The usual dose of the solution is one drop four times daily. Studies indicate that trimethoprim is a safe and effective agent for treating conjunctivitis caused by a variety of organisms in patients of all ages older than 2 months.Trimethoprim-polymyxin B (Polytrim) has been found to be effective and well tolerated in both adults and children. It is particularly useful in the pediatric population because of its antimicrobial activity against S. pneumoniae and H. influenzae.However, reports of growing resistance suggest that caution should be used with empiric treatment, especially in children, where fourth-generation fluoroquinolones may be a more effective choice.

In decreasing favor since the emergence of the fluoroquinolones, the aminoglycosides gentamicin and tobramycin are bactericidal against most gram-negative bacteria, especially P. aeruginosa, and some gram-positive bacteria, particularly S. aureus. H. influenzae and Neisseria species are variably susceptible to the aminoglycosides. Anaerobes, S. pneumoniae, and the α-hemolytic streptococci are resistant to the aminoglycosides. The usual dose frequency for these agents is four times daily, whether in solution or ointment. Potential adverse effects include a toxic epitheliopathy, SPK, and hypersensitivity reactions. The risk of adverse reactions is greater when the drugs are applied more often than six times daily or are applied as ointments. Other rarely occurring adverse events reported with gentamicin are pupillary mydriasis, conjunctival paresthesia, and neuromuscular blocking activity. Pseudomembranous conjunctivitis has been reported after treatment with topical gentamicin. Aminoglycosides should be used cautiously in patients with myasthenia gravis, because these patients are more susceptible to the potential neuromuscular blocking action of such agents, which may lead to respiratory failure.

Neomycin is a topical aminoglycoside widely used for skin wounds and in otolaryngology. Its antibacterial activity resembles that of gentamicin and tobramycin, except that P. aeruginosa, S. pneumoniae, and the α-hemolytic streptococci are generally resistant. Neomycin’s usefulness for treating acute bacterial conjunctivitis is limited

448 CHAPTER 25 Diseases of the Conjunctiva

by the relatively high rate of hypersensitivity reactions. Allergic reactions occur in nearly 6% to 8% of patients treated and are often more severe than the original infection. For these reasons most clinicians avoid neomycin and combination drugs containing neomycin for routine use in treating acute bacterial conjunctivitis.

Bacitracin is bactericidal for most gram-positive organisms, especially Staphylococcus and Streptococcus species. It is particularly useful when combined with polymyxin B in an ophthalmic ointment. Bacitracin-polymyxin B ointment (Polysporin) provides broad-spectrum antibacterial activity for patients who require nighttime therapy or who are not comfortable with eyedrops. Bacitracinpolymyxin B ointment is particularly effective in the pediatric population because of the high incidence of Streptococcus infection.The usual dose frequency is three to four times daily.Although adverse events are rare,hypersensitivity reactions can occur. Additionally, bacitracin can sometimes be uncomfortable.

Polymyxin B is bactericidal for most gram-negative organisms, especially Haemophilus and Pseudomonas species. Neisseria and Proteus species, however, are resistant. Combining polymyxin B with bacitracin or trimethoprim achieves broad-spectrum antibacterial activity for treating acute bacterial conjunctivitis. Because it is not absorbed through mucous membrane or skin tissue, polymyxin B is used primarily for superficial infections.Adverse reactions are rare.

Erythromycin is bacteriostatic for many gram-positive organisms, such as S. aureus and S. pneumoniae. Erythromycin may have some bacteriostatic activity against Haemophilus and Neisseria, but it is not a drug of choice for these organisms. Resistant strains of S. aureus may be encountered. Because of its low incidence of adverse reactions, erythromycin is extremely well tolerated, particularly by children. It is used primarily as adjunctive therapy at bedtime.

The fluoroquinolone antibiotics are potent agents with strong dose-dependent bactericidal and variable bacteriostatic activity against most gram-negative organisms. They evolved from nalidixic acid, which was approved by the U.S. Food and Drug Administration in 1963. Modern fourth-generation fluoroquinolones have expanded gram-positive activity and enhanced antibiotic characteristics. Several studies have shown the fluoroquinolones to be equally or more effective than earlier generation antibiotics used in ophthalmic practice. Fluoroquinolones usually are prescribed for moderate to severe acute bacterial conjunctivitis, although the broader spectrum of the fourth-generation fluoroquinolones has prompted wider use. The usual initial dose for secondand third-generation fluoroquinolones is six to eight times daily, tapering to four times daily over 5 to 7 days. With the fourth-generation fluoroquinolones, moxifloxacin is prescribed three times daily for 7 days, whereas gatifloxacin requires 2-hour dosing for the first 2 days followed by four times daily for an additional 5 days.

Despite the safety and effectiveness of the fluoroquinolones and their reduced potential for inducing resistance, their use in routine therapy still remains somewhat controversial.

Emergent resistance to the secondand third-genera- tion fluoroquinolones has been of significant concern. Resistance to the prior generation fluoroquinolones is likely due to one or more of the following three possible mechanisms: alterations in bacterial quinolone enzymatic targets (DNA gyrase), decreased outer membrane permeability, and the development of efflux mechanisms. Newer fourth-generation fluoroquinolones target two enzymatic systems responsible for DNA manipulation, DNA gyrase (topoisomerase II) and topoisomerase IV. This dual mechanism of action increases lethality, minimizes survival of resistant organisms, and effectively treats organisms that have already become fluoroquinolone resistant. Five topical fluoroquinolones are currently available: ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Norfloxacin is no longer distributed.

Ciprofloxacin is still relatively effective against many gram-negative and some gram-positive organisms, including aminoglycoside-resistant Pseudomonas, methicillin-resistant Staphylococcus, Neisseria species, and C. trachomatis. However, S. pneumoniae infections are more likely to be resistant. More aggressive dosing achieves higher tissue concentrations and can effect satisfactory resolution of infection in some cases. Reports that indicate increasing resistance to ciprofloxacin among some strains of Pseudomonas, Staphylococcus, and Streptococcus are of growing concern. Ciprofloxacin does not exhibit any significant epithelial toxicity, as is common with aminoglycosides; the white drug precipitate seen in 16% of the patients receiving keratitis therapy may serve as an active drug depot and does not generally occur in the treatment of acute bacterial conjunctivitis. Ciprofloxacin appears to possess more rapid bacterial kill times than does ofloxacin. Although of less significance in treating conjunctivitis, rapid kill rates are important in preoperative and perioperative prophylaxis.

Ofloxacin has a bactericidal potency and spectrum similar to ciprofloxacin. It has relatively strong antibacterial activity against a wide spectrum of gram-negative and gram-positive organisms, including S. pneumoniae, but more frequent dosing should be used when infection with Streptococcus species is suspected. It is not as effective against Pseudomonas as ciprofloxacin.As compared with gentamicin, ofloxacin had a greater clinical (98% vs. 92%) and microbiological (78% vs. 67%) resolution in a study of 198 patients. Only 3.2% reported side effects for ofloxacin, as compared with 7.1% for gentamicin. Ofloxacin achieved better clinical resolution than did tobramycin in a multicenter study on days 3 to 5 after initiation of treatment, but the efficacy of the two agents was relatively equal at day 11.Additionally,when compared with ciprofloxacin and norfloxacin, ofloxacin has a higher level of corneal penetration and attained aqueous levels four times greater than

Figure 25-6 Conjunctival pharmacokinetics of topical antibodies. (From Wagner RS, Abelson MB, Shapiro A, Torkildsen G. Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin,ofloxacin,and levofloxacin concentrations in human conjunctival tissue.Arch Ophthalmol 2005;123:1282–1283.)

the other agents. More recent data show comparatively lower penetration of ofloxacin compared with other fluoroquinolones (Table 25-6).Twice-daily dosing of ofloxacin has been shown to be as effective as four-times-daily dosing in treating external ocular infection; however, emergent resistance is a concern, with less than four-times-daily dosing not recommended.

Levofloxacin, a third-generation fluoroquinolone, is approved for topical ophthalmic use in treating conjunctivitis. Dosing for adults and children 1 year of age and older is one to two drops every 2 hours for the first 2 days followed by one to two drops every 4 hours for the next 5 days. Levofloxacin shows enhanced activity against gram-positive species, including S. pneumoniae, S. aureus, and Enterococcus species, as well as good activity against

Mycoplasma and Chlamydia species.

Gatifloxacin is a synthetic broad-spectrum 8-methoxy- fluoroquinolone that,like many other ophthalmic anti-infec- tive agents, derives from prior systemic use. Commonly classified as a fourth-generation fluoroquinolone, gatifloxacin interferes with both DNA gyrase and topoisomerase IV activity. The result is broader antibacterial spectrum with clinically similar activity to prior generation fluoroquinolones against gram-negative organisms and significantly improved gram-positive coverage. This dual activity also results in decreased likelihood of creating resistant organisms. Gatifloxacin is approved for the treatment of bacterial conjunctivitis in children over 3 years of age as well as adults.

Moxifloxacin is a broad-spectrum fourth-generation 8-methoxyfluoroquinolone. In ophthalmic use, moxifloxacin is indicated for treatment of conjunctivitis in children over 1 year of age and adults and noted for a

simplified dosing regimen of one or two drops three times a day for 7 days. Moxifloxacin is particularly effective against S. pneumoniae, which has been linked to epidemics of conjunctivitis. Isolates of S. pneumoniae from three patients were exposed to moxifloxacin 0.5%, tobramycin 0.3%, gentamicin 0.3%, and polymyxin B 10,000 IU-trimethoprim 1.0%. All medications were diluted 1:100 and 1:1,000 to emulate tear concentrations. Moxifloxacin killed actively growing S. pneumoniae faster and to a greater extent than did the other three antibiotic products when tested at concentrations corresponding to tear film levels 5 to 10 minutes and 30 to 60 minutes after instillation of the products. Numerous studies report significantly greater penetration of moxifloxacin compared with gatifloxacin into ocular tissues. As a result higher concentrations of moxifloxacin have been reported in the anterior chamber, the cornea, and the conjunctiva (see Figure 25-6).

Preservatives have been a differentiating point for the ophthalmic fourth-generation fluoroquinolones. In the United States gatifloxacin ophthalmic solution is preserved with benzalkonium chloride 0.005%, whereas moxifloxacin drops contain no preservative. Although several studies have attributed advantages or disadvantages related to the preservatives (or lack thereof), clinically no differences have been found.

Topical azithromycin 1.5% (Astern) is currently undergoing testing for bacterial conjunctivitis with good results reported. Introduction to the United States is expected by the fourth quarter of 2007.

Since the 1980s, when methicillin-resistant S. aureus emerged in the United States, vancomycin has been the last uniformly effective antimicrobial agent available for treatment of serious and, in some cases, life-threatening S. aureus infections. Sporadic cases of vancomycin-resistant S. aureus have been reported.Despite concerns expressed by the Centers for Disease Control and Prevention (CDC) in Atlanta and recommendations regarding the prevention of the spread of vancomycin resistance, vancomycin is being used with increasing frequency for ocular therapy and prophylaxis. Use of topical vancomycin at a concentration of 31 mg/ml has been successful in treating patients with chronic S. epidermidis and methi- cillin-resistant S. aureus infection. However, because of the possibility of fostering resistance to this last-line antibiotic, vancomycin should be considered for use only after commercially formulated agents have failed and sensitivity testing indicates likely effectiveness. The fourth-generation fluoroquinolones are generally effective against methicillin-resistant S. aureus; however increased resistance has been reported.

Hyperacute Bacterial Conjunctivitis

Etiology

Hyperacute bacterial conjunctivitis most commonly results from N. gonorrhoeae and, less frequently, from