Therapy of Bacterial Infections of the Eye
TERRENCE P. O'BRIEN and TAE WON HAHN
Table Of Contents
|Topical preparations of antibiotics are those most frequently used in the
clinical practice of ophthalmology; periocular, intraocular, and systemic
injections are used, depending on the site and the severity of
the infection. Topical antibiotic selection should not be determined solely
by the results of susceptibility tests. The laboratory may report
an organism as resistant to a specific antibiotic because the high minimal
inhibitory concentration (MIC) or bactericidal concentrations needed
cannot be safely reached in the serum. However, the infection may
respond clinically to the antibiotic because of the high concentrations
achievable in the tear film and superficial ocular tissues after topical
application. In some instances, the clinician may wish to have
the pharmacy prepare so-called fortified solutions with antibiotic concentrations
that exceed those found in commercial preparations.|
Subconjunctival or sub-Tenon injections of antibiotics may be indicated in keratitis or endophthalmitis as an adjunctive therapy to topical fortified antibiotics. Although such injections can produce higher drug levels in the cornea, the aqueous humor, and the vitreous chamber, they also have the disadvantages of producing subconjunctival hemorrhages and conjunctival and Tenon's capsule scarring, and of increasing the risk of intraocular needle penetration.
Intravitreal injection is the most reliable means of achieving adequate drug levels in the treatment of bacterial endophthalmitis, although potential risks include vitreous hemorrhage and retinal tears, detachments, and toxicity.
Systemic administration of antibiotics may be indicated for infections of the ocular adnexa (lids, lacrimal gland, and drainage system and, at times, conjunctiva), cornea, and intraocular contents.
In conjunction with effective antibiotic therapy, therapeutic surgical procedures such as incision and drainage, mechanical debridement, keratoplasty, and vitrectomy play important roles in the treatment of bacterial infections of the eye.
In contrast to some forms of chronic blepharitis, staphylococcal blepharitis can be cured, but long-term therapy is required to prevent recurrence. Eyelid hygiene and topical antibiotic applications are important components of the therapy. Application of a warm compress with a moist facecloth on the closed eyelids for 5 to 10 minutes is helpful for subsequent removal of secretions with cotton-tipped applicators. Moist, cotton-tipped applicators are used to keep the eyelids clean and to apply a mild, nonirritating soap (e.g., baby shampoo) to the lid margins. After the eyelid scrubs, the soap should be rinsed away. In the initial phase of therapy, patients should be instructed to perform lid scrubs once or twice a day. Eye scrubs are most beneficial in the morning because bacteria and debris has collected on the lids and the lashes during the night. For meibomian gland obstruction, the contents of the congested meibomian glands should be expressed by massaging the eyelid margin against the globe or by compressing the lid margins between the tips of two cotton-tipped applicators.
After the eye scrub, a topical antibiotic ointment should be applied to the eyelids and lash margins once or twice daily, depending on the severity of the inflammatory process. Staphylococcus species- producing blepharitis, including Staphylococcus aureus, are highly susceptible to bacitracin, erythromycin, gentamicin, neomycin, and chloramphenicol.1 Antibiotic resistance has been reported with the use of sulfonamides or tetracycline.2 Topical gentamicin and tobramycin are effective against most eyelid microflora but are frequently not well tolerated in chronic therapy. Topical fluoroquinolones such as ciprofloxacin, norfloxacin, and ofloxacin are also effective.3–8 Bacitracin and erythromycin ophthalmic ointments are those most often used because they have a wide spectrum of activity and are usually well tolerated.
Eyelid scrubs and antibiotic applications are usually required for 2 to 8 weeks for the patient to become free of inflammatory signs; once this goal has been achieved, therapy can be tapered or discontinued. Continued lid hygiene and minimal antibiotic therapy are frequently required to prevent recurrence.
Resistant cases, or those associated with acne rosacea, may benefit from long-term use of oral tetracycline (250 mg, 4 times/day). Patients should be warned to avoid ultraviolet light exposure while taking tetracyclines, and pregnant women and children younger than 12 years should be given erythromycin rather than tetracycline. Doxycycline (100 mg, twice daily) can be substituted if a patient is unable to tolerate tetracycline.
Topical corticosteroid drops are occasionally used for brief periods to decrease ocular surface inflammation; they are beneficial for short periods in patients with rosacea-associated keratitis or during the initial stages of treatment of corneal pannus formation.9 Caution must be exercised to avoid complications from chronic steroid use, including cataract formation, glaucoma, and secondary infections, especially in dry eye syndrome.
Angular blepharitis, a minor infection of the skin at the lateral canthus, is caused by S. aureus or, less commonly, Moraxella lacunata; 1% or 2% silver nitrate can be used for treatment. Cleaning the involved skin with water or a mild soap at night is recommended. After removal of the mucoid discharge, neomycin, sulfacetamide (10%), or chloramphenicol (0.5%) is used three times daily until healing occurs.
An acutely infected internal or external hordeolum or chalazion can be treated with warm compresses until the inflammation subsides; the use of topical antibiotics is ineffective. Systemic antibiotics are usually not needed. Surgical drainage, which is seldom required for an infected hordeolum, has more of a role in a rapidly expanding chalazion.
LACRIMAL APPARATUS INFECTIONS
Acute suppurative dacryadenitis is rare, and S. aureus is the most common pathogen. Streptococci, gonococci, and Chlamydia species are less frequently encountered. An intravenous (IV) antibiotic, such as oxacillin or cefazolin, is necessary for about 5 to 7 days. If an orbital abscess forms, surgical drainage is necessary.
Canaliculitis can occur secondary to dacryocystitis or obstruction within the nasolacrimal passage, or after instrumentation of the nasolacrimal passages or implantation of materials such as plastic tubing or silicone.10,11 Isolated bacterial infections of the canaliculi are rare. The most common pathogen is Actinomyces israelii and less commonly, Nocardia and Streptomyces species, Propionibacterium propionicus, and Eikenella corrodens.12–15 Antibiotic irrigation of the canaliculi combined with use of topical antibiotic eyedrops is an effective treatment. Penicillin G (160,000 U/ml as an irrigant, 60,000 U/ml as drops) is used for P. propionicus and Actinomyces species. Systemic penicillin, erythromycin, or cephalosporins should be part of the treatment regimen in cases caused by P. propionicus.15,16 When concretions are present, they should be removed by external pressure, curettage, or canaliculotomy. The canaliculus should then be reconstructed; silicone intubation may be needed.17 Large diverticula should be excised or marsupialized.
Dacryocystitis in adults is usually caused by stenosis of the duct opening into the nasopharynx. In acute dacryocystitis, warm compresses and systemic antibiotics should be given. If it is possible to get material from the lacrimal sac by expression or aspiration, antibiotics should be chosen on the basis of microbiologic results; otherwise, empirical therapy is indicated. Ciprofloxacin and trimethoprim/sulfisoxazole have been suggested.18 Staphylococcus species (S. aureus, Staphylococcus epidermidis, Staphylococcus sacrophyticus) are the most common pathogens,18,19 and are best treated with a penicillinase-resistant penicillin or cephalosporin.15,20 If Streptococcus pyogenes is isolated or suspected, topical and oral penicillin are used.15 Unusual organisms, such as Pasteurella multocida21 and Aeromonas hydrophila,22 have been reported. After the acute infection has been controlled, the patient should be taught to perform digital massage of the lacrimal sac, and the use of topical antibiotic drops should be continued. Medical treatment is rarely beneficial in chronic dacryocystitis. If epiphora persists, a dacryocystorhinostomy is needed to obtain adequate tear drainage.
Acute dacryocystitis occurs infrequently in childhood; when it does, and Streptococcus pneumoniae is the predominant cause.23 Parents of infants with nasolacrimal duct obstruction should be taught to massage the lacrimal sac area firmly several times daily; topical antibiotic eyedrops may be used as well. These conservative treatments are effective in approximately 95% of affected infants.24,25 If symptoms persist for 6 to 8 months, the lacrimal drainage apparatus should be irrigated and possibly probed. Probing is more successful in lacrimal duct obstruction caused by to membranous obstruction than in narrowing of the duct. If the initial probing is unsuccessful, repeat probing is performed a few months later. Silicone intubation of the drainage apparatus is performed if the repeat probing also fails.26
In patients with preseptal cellulitis due to trauma or local infection, (e.g., hordeola, acute chalazia, acute dacryocystitis, or impetigo) cultures from the wound or primary focus of infection should be obtained, if possible, for appropriate antibiotic selection; S. aureus and beta-hemolytic streptococci are the main causative organisms,27,28 Polymicrobial infections may occur if wounds remain open for several days after injury. Anaerobes, such as Peptostreptococcus and Bacteroides species, are associated with infections from human or animal bites.29
Management of post-traumatic preseptal cellulitis includes clinical assessment of the eye and orbit. A computed tomographic (CT) or magnetic resonance imaging (MRI) scan may be needed. Tetanus anaphylaxis should be considered. Incision and drainage are necessary, in addition to antibiotic therapy, in cases of abscess formation. The IV antibiotics chosen depend on the results of Gram's stains. If gram-positive cocci are observed, IV nafcillin or oxacillin is recommended. In mild cases, oral cloxacillin or dicloxacillin may be used; IV cefazolin or oral cephalexin may be administered to nonanaphylactic penicillin-allergic patients. If there is a history of anaphylactic penicillin allergy, IV vancomycin is recommended. For preseptal cellulitis in children, IV cephalosporins, such as cefuroxime or ceftriaxone, which are effective against Hemophilus influenzae, streptococci species, (including S. pneumoniae) and S. aureus are recommended.IV antibiotics are continued until the child has improved clinically and been afebrile for 24 hours, after which switching to oral antibiotic therapy (e.g., amoxicillin-clavulanate or trimethoprim-sulfamethoxazole) is possible. If gram-negative rods are observed on diagnostic smears, an IV third-generation cephalosporin or oral ciprofloxacin (depending on the severity of the cellulitis) may be administered. If anaerobic bacteria are isolated in the cultures, clindamycin may be the therapy of choice. Antibiotic therapy should be continued in all infections for a minimum of 5 days, or as long as needed, until there is resolution of suppuration.
In preseptal cellulitis arising from contiguous spread from the eyelid skin, therapy is both local and systemic. The former consists of thorough scrubbing of the involved lids with soap and water two or three times daily, and application of a topical antibiotic ointment, such as bacitracin (500 U/mg). For systemic treatment of impetigo, oral cloxacillin or cefaclor is usually effective. IV nafcillin is recommended in severe cases and in infants. Systemic therapy should be continued for at least 10 days. In patients with erysipelas, IV penicillin G is usually given for 48 to 72 hours or until clinical signs improve. Oral penicillin V may then be substituted.
In the absence of trauma or skin infections, preseptal cellulitis in children younger than 6 years is caused almost exclusively by H. influenzae type B or S. pneumoniae27 H. influenzae type B infections in children between the ages of 6 months and 2 years can be especially severe. Children should be hospitalized and treated with IV antibiotic agents because of the potentially rapid progression of the infection and the risk of consecutive meningitis. Because of the increasing incidence of beta lactamase-producing type B strains, ampicillin is no longer recommended as first-line therapy. A second-generation cephalosporin, cefuroxime (75 to 100 mg/kg/day), is the preferred initial drug as it is effective against both H. influenzae and aerobic gram-positive cocci. Blood and bilateral conjunctival cultures should be obtained. Nasopharyngeal cultures can be misleading because of the normal flora. Lumbar puncture should be performed if meningeal signs are present. Cefotaxime or ceftriaxone are the drugs of choice in patients with meningitis because of their better penetration of the cerebrospinal fluid. Chloramphenicol is used in patients allergic to cephalosporins. Surgical drainage of the orbit or sinuses is usually not required in Hemophilus preseptal cellulitis.
Orbital cellulitis requires urgent hospitalization and appropriate IV antibiotics; vision and other ocular signs should be monitored closely. A CT scan is of great value in the initial assessment and management of all forms of orbital cellulitis. Consultation with an otolaryngologist may be necessary for drainage of paranasal sinus abscesses. The bacterial agents most commonly responsible are H. influenzae and S. pneumoniae, followed by Bacillus catarrhalis, S. aureus, S. pyogenes, and Streptococcus viridans. Polymicrobial infection by a mixture of aerobic and anaerobic bacteria may occur,30 and orbital cellulitis from unusual anaerobes (e.g., E. corrodens) has been reported.31 Selection of initial antibiotics is based on the assumption that these organisms are probably the sinus pathogens. The most frequently used combination has been IV nafcillin and chloramphenicol. In cases of penicillin allergy, vancomycin may be used.32–34 In young children, S. pneumoniae and H. influenzae are the most common pathogens.35–37 Because H. influenzae is a common cause of orbital cellulitis in children, cefuroxime has become the drug of choice while waiting for culture and susceptibility results to be available38–39 (Table 1, Table 2). Progression of the infection and clinical deterioration, despite what seems to be adequate IV antibiotic therapy, is probably related to the development of a subperiosteal or orbital abscess. If an abscess is found, a repeat CT scan and surgical drainage are imperative.40–42 Material obtained from such drainage should be sent for microbiologic evaluation. In cases of radiographically suspected subperiosteal abscesses that seem to be responding to treatment, surgery may be deferred, but the inflammatory signs may persist much longer than if treated by drainage.43–46 In cases of orbital cellulitis after trauma or surgery, S. aureus is the most common pathogen. Tetanus prophylaxis should be administered in post-traumatic cases and the selection of initial IV antibiotics can be aided by Gram's stain evaluation of any purulent drainage.
(IM, intramuscularly; IV, intravenously; PO, by mouth.
Most types of mild bacterial conjunctivitis are self-limited and probably require no treatment in immunocompetent individuals. However, a pretreatment microbiologic evaluation is the best guide for antibiotic therapy and should be considered for neonates, immunocompromised patients, and any patient with severe conjunctivitis.
In general, broad-spectrum topical antibiotics initially can be chosen either empirically or pending microbiologic evaluation. Several single or combined agents are available. A combination of trimethoprim sulfate/polymyxin B sulfate, or of bacitracin/polymyxin B sulfate provides broad-spectrum coverage and a low incidence of adverse reactions.47–48 Aminoglycoside eyedrop preparations containing neomycin, tobramycin, or gentamicin, and erythromycin ophthalmic ointment are other useful agents. Topical fluoroquinolones such as ciprofloxacin, norfloxacin, and ofloxacin are highly effective against a broad spectrum of bacteria; these agents should probably be reserved for severe conjunctivitis.49,50
After observing Gram's-stained microscopic slides of diagnostic smears, topical gentamicin, tobramycin,51 ciprofloxacin, norfloxacin, or ofloxacin can be prescribed for gram-negative rod infections; erythromycin, bacitracin, polymyxin B/trimethoprim, or neomycin/polymyxin can be prescribed for gram-positive infections. These agents are usually given every 2 to 4 hours for 7 to 10 days.49,52–56 Conjunctivitis caused by H. influenzae, Neisseria gonorrhoeae, or Neisseria meningitidis requires systemic antibiotic therapy to prevent serious extraocular complications. An approach to initial antibacterial therapy based on Gram's stain interpretation is shown in Table 3.
Topical corticosteroids and antibiotic-corticosteroid combinations have little, if any, role in the treatment of conjunctivitis because corticosteroids may aggravate the infection owing to local immune suppression. Topical anesthetic agents should never be prescribed for ocular discomfort because they retard epithelial healing.
Patients who wear contact lens should be instructed to discontinue wearing the lenses until the infection has completely resolved and treatment has been discontinued. If contaminated contact lens solution is suspected to be the cause or the result of conjunctivitis, obtaining a culture of the solution may help identify the organism and its antibiotic sensitivities.57,58
ACUTE BACTERIAL CONJUNCTIVITIS
In severe conjunctivitis, diagnostic Gram's-stained microscopic slides and cultures become more important. Treatment should be prompt and specific for the causative pathogen to prevent corneal involvement or systemic complications.
N. gonorrhoeae is the most common cause of hyperacute conjunctivitis and requires systemic therapy. Topical therapy is only adjunctive and is used to prevent corneal infection. Topical ciprofloxacin is more effective in vitro against gonococcus than are the other fluoroquinolones.65,66 Most investigators do not recommend topical antibiotics in patients receiving adequate systemic therapy.67,68 The Centers for Disease Control (CDC) recommends the following: Adult and children over 20 kg with nonsepticemic gonococcal ophthalmia should be treated with a single injection of ceftriaxone (1 g administered intramuscularly [IM]). Irrigation of the eyes with saline or buffered ophthalmic solutions may be useful adjunctive therapy to eliminate discharge and dilute local virulence factors. Infants without overt gonococcal conjunctivitis who were born to mothers with gonococcal infections should receive a single injection of cefriaxone (50 mg/kg IV or IM, not to exceed 125 mg). Infants with gonococcal conjunctivitis require ceftriaxone (25 to 50 mg/kg/day IV or IM) in a single daily dose for 7 days, or cefotaxime (25 mg/kg IV or IM every 12 hours for 7 days.
In adults, if the gonococcal isolate is proven to be susceptible to penicillin, crystalline penicillin G may be given (100,000 U/kg/day in two equal doses for 7 days).59 Beta lactam-allergic patients could alternately receive spectinomycin (e.g., 2 gm IM either as the one-time dose for adult gonococcal conjunctivitis or every 12 hours for keratoconjunctivitis or disseminated infections). However, because of the increasing incidence of penicillinase-producing60,61 and of chromosomally penicillin-resistant strains,62 penicillin G is no longer a preferred initial therapeutic agents. The fluoroquinolones, such as norfloxacin,63 ciprofloxacin, and ofloxacin may eventually be preferred as effective and less costly (i.e., oral) therapies for adults. However, additional clinical trials are necessary.
Because gonococcal and chlamydial infections often coexist,64 patients may require treatment for both, and an additional antibiotic must be given (e.g., oral tetracycline, doxycycline, or erythromycin). Tetracycline and doxycycline deposit in and discolor teeth and bone; these antibiotics should only be used in nonpregnant women. If initial Gram's stain and Giemsa stain results are positive or equivocal for chlamydia, the infant should receive oral erythromycin (such as erythromycin ethylsuccinate, 40 to 50 mg/kg/day in four divided doses) for 2 to 3 weeks to treat conjunctivitis and to prevent chlamydial pneumonia.
N. meningitidis is a rare cause of conjunctivitis in both children and adults. Primary meningococcal conjunctivitis is associated with a systemic meningococcal infection, such as septicemia or meningitis, in approximately 18% of cases,70–72 thus systemic antibiotic therapy should be considered immediately. Parenteral penicillin G (300,000 U/kg/day) is recommended as soon as the organism is identified.
Conjunctivitis due to H. influenzae is common in children and also occurs in adults. Treatment of childhood Hemophilus conjunctivitis should include systemic as well as topical antibiotic agents because of the risks of dissemination and subsequent meningitis. Topical ciprofloxacin or trimethoprimpolymyxin eyedrops are usually recommended. H. influenzae type B vaccine may provide some protection against the conjunctivitis and its sequelae73 but does not seem to be effective in every case.74
Conjunctivitis-otitis media syndrome, most commonly seen in children and often caused by H. influenzae or S. pneumoniae, also requires systemic treatment. Combinations of amoxicillinclavulanate, trimethoprim/sulfamethoxazole, or erythromycin/sulfisoxazole are recommended for initial therapy because of the high incidence of ampicillin-resistant H. influenzae.75,76
Corynebacterium diphtheriae uncommonly causes a purulent conjunctivitis. Systemic effects from the exotoxin73,77 requires treatment with diphtheria antitoxin parenterally in a dose of 10,000 to 100,000 U. Systemic penicillin or erythromycin is used to eradicate the carrier state and to abolish secondary infections.78,79
For nongonococcal neonatal bacterial conjunctivitis, erythromycin 0.5% ointment four to six times per day or sulfacetamide ointment may be used.69 B. catarrhalis may cause a purulent conjunctivitis in newborns and occasionally, in adults. Bacillus subtilis is rarely the causative agent of conjunctivitis.80 If Bacillus species is identified by Gram's stain or in culture, fortified topical gentamicin (11 to 15 mg/ml) or clindamycin (50 mg/ml) is usually effective.
CHRONIC BACTERIAL CONJUNCTIVITIS
Patients with chronic or recurrent staphylococcal conjunctivitis may have an underlying chronic blepharoconjunctivitis caused by colonization of the anterior lid margins (treatment of this condition was discussed in the Eyelid Infections portion of this chapter). M. lacunata is a frequently encountered pathogen of chronic bacterial conjunctivitis. Regular lid scrubs and topical bacitracin, erythromycin, or sulfacetamide ointments are beneficial. Chronic conjunctivitis due to oral anaerobes is rare, but is seen in patients with severe periodontal disease81; it usually does not respond to topical antibiotic therapy. A combination of oral metronidazole (750 mg/day) and amoxicillin (1.125 g/day for 7 days) has been shown to be effective.
PROPHYLAXIS OF OPHTHALMIA NEONATORUM
There is considerable debate over the relative efficacy of 1% silver nitrate versus topical antibiotics, such as 0.5% erythromycin or 1% tetracycline. Although tetracycline-resistant N. gonorrhoeae occur, tetracycline probably remains effective because of the high drug concentrations achieved with topical application. Silver nitrate is effective against gonococcal infection but has little impact on the increasing incidence of chlamydial infections and has the possible side effect of producing a chemical conjunctivitis. Topical erythromycin seems effective in preventing chlamydial conjunctivitis.82 The CDC has recommended that one of these three prophylactic regimens be instilled into the eyes of every neonate as soon as possible after delivery, and definitely within 1 hour after birth. In infants born to mothers with genital chlamydial infection, topical erythromycin ointment is effective against chlamydia in the conjunctiva, but systemic erythromycin estolate is preferred because it will treat any nasopharyngeal colonization.83,84
Most bacterial keratitis patients are treated as outpatients. However, because of the potential rapid evolution to ulceration and perforation, virulent pathogens may require hospital admission. The high frequency of administering antimicrobial therapy often requires the assistance of nursing personnel.
Aggressive antibiotic therapy using high concentrations at frequent intervals is the mainstay of keratitis treatment. The possible routes of administration include topical drops and ointments, continuous lavage, soaked collagen corneal shields or soft contact lenses, iontophoresis, subconjunctival injections, and systemic administration.
The objectives of therapy are to eliminate the infecting organism rapidly, to reduce the inflammatory response, to prevent structural damage to the cornea, and to promote healing of the epithelial surface. When a bacterial origin to the keratitis is suspected, the clinician has the option of initiating antimicrobial therapy or deferring treatment pending the results of laboratory investigation. In general, because of the potential rapid destruction of corneal tissue that may accompany bacterial keratitis, the patient should be treated before a definitive diagnosis is made.
Signs of clinical improvement are based on frequent slit-lamp examination. Improvement may be difficult to appreciate early in the course of therapy because of the irritative effects of both the diagnostic corneal scraping and the frequent topical antibiotic drops. After the first 48 hours, the frequency of antibiotic administration can usually be gradually decreased. The therapeutic endpoint in ulcerative keratitis is epithelial healing, yet concentrated antibiotics may retard re-epithelialization. Highly concentrated antibiotic solutions may be converted to commercial-strength drops after several days.
CHOICE OF ANTIBIOTICS
Therapy of keratitis begins with microscopic analysis of Gram's stains from smears of corneal scrapings85 (Table 4). If a single type of bacterium is observed and the patient has not been undergoing antecedent therapy, a single antibacterial agent is selected. If two or more bacteria are present on Gram's stain results, combinations of antibacterial agents may be recommended. If a single type of bacterium is observed on Gram's stain results, and the patient has received previous therapy, a different broad-spectrum antibacterial regimen than that previously used is recommended.
IM, intramuscularly; IV, intravenously
*Use only for corneal perforation or scleral suppuration.
†Based on trimethoprim component; consider use of oral trimethoprim/sulfamethoxasole for mild suppuration.
‡Consider addition or substitution of ceftazidime (topical 50 mg/ml; subconjunctival, 100 mg).
(Modified from Abbot RL, Kremer PA, Abrams MA, Bacterial corneal ulcers. In Tasman W, Jaeger EA [eds]: Duane's Clinical Ophthalmology, p 20. Vol. 4. Philadelphia, Lippincott, 1994.)
If the initial antibiotic therapy is to depend on the results of the Gram's stain, either the clinician or laboratory personnel must be technically proficient.86 If the Gram's stain results are equivocal or there is uncertainty in its interpretation, broadspectrum antibiotic coverage should be initiated in all cases of severe suppurative keratitis because the consequences of inappropriate or inadequate therapy can be devastating.87
Factors that frequently guide the choice of an antibiotic for a systemic infection are not necessarily applicable to topical ocular therapy. MIC testing in vitro is based on achievable serum levels and does not apply to topical therapy. Other pharmacokinetic factors important in systemic therapy, such as bioavailability, distribution compartments, modes of metabolism, and excretion, are also not directly applicable. The antimicrobial agent selected for initial therapy should have bactericidal activity against the common corneal pathogens, a low rate of acquired resistance, favorable solubility characteristics to enhance penetration, and minimal toxicity to ocular tissues.
Initial broad-spectrum therapy for suspected bacterial keratitis has traditionally been a topical first-generation cephalosporin (e.g., cefazolin) and an aminoglycoside (gentamicin, tobramycin, or amikacin), although this combination is not effective against some aminoglycoside-resistant Pseudomonas and methicillin-resistant Staphylococcus and Neisseria species. Second- and third-generation cephalosporins are usually not used as topical medications because of the lack of stability of their beta lactam rings in solution. Hence, their efficacy is in question.
Many classes of antibiotic compounds have been used for the specific therapy of bacterial keratitis (Table 5). Gram-positive keratitis, especially from staphylococci, is most often treated with topical cephalosporins. If there is suspected resistance of staphylococci to either the cephalosporins or the semisynthetic penicillins, topical vancomycin should be considered.88
IM, intramuscularly; IV, intravenously.
* Use only for corneal perforation or scleral suppuration.
† Consider oral clarithromycin (250–500 mg/day).
‡ Use undiluted IV preparation.
§ Based on trimethoprim component; consider use of oral trimethoprim/sulfamethoxazole for mild suppuration.
|| Consider addition or substitution of ceftazidime (topical, 50 mg/ml; subconjunctival, 100 mg).
Penicillin G has been the initial drug of choice for gram-negative coccal infections, but ceftriaxone should be used for N. gonorrhoeae until susceptibility to penicillin is proven. Most gram-positive rods, both aerobic and anaerobic, are still susceptible to penicillin G or cefazolin. Penicillin G is the therapy of choice for pneumococcal keratitis and is also effective against Actinomyces species.
Gentamicin has been the therapy of choice for other gram-negative causes of keratitis and can be administered by topical, subconjunctival, and parenteral routes. Tobramycin is more active than gentamicin against Pseudomonas aeruginosa but less active against Serratia marcescens. The aminoglycosides may act synergistically with ticarcillin or piperacillin against Pseudomonas and Proteus species but some combinations are physically incompatible and are inactivated if mixed and allowed to stand in the same solution.
Fluoroquinolone antibiotics have been used topically and have shown excellent activity against both gram-negative and gram-positive ocular pathogens.89,90 Ciprofloxacin, norfloxacin, and ofloxacin have been successfully used in the therapy of bacterial keratitis.91,92 Fortified topical antibiotics and topical ciprofloxacin have proven to be highly effective in both experimental and clinical studies.93–95 Ciprofloxacin has been recommended as a useful single agent for initial therapy. However, resistance has emerged and some streptococci and enterococci treatments have failed.89,91–92,96–100
Sulfonamides have been replaced by more effective antibiotics in the treatment of bacterial keratitis, but they remain indicated for infections caused by Nocardia101 species.
ROUTES OF ADMINISTRATION
Topical antibiotic agents are the most effective and usually the preferred means of treating bacterial keratitis. The optimal frequency is unknown, but it is generally accepted that drops should be given every 15 to 30 minutes for the first few days and then tapered. Solutions are preferred over ointments because higher concentrations can be achieved in the tear film, resulting in higher concentrations in the cornea. Hospital pharmacies can readily prepare these concentrated (fortified) solutions by using commercially available ocular antibiotic or lubricant solutions, to which are added parenteral antibiotic formulations.102
Subconjunctival administration of antibiotics cannot be repeated indefinitely. They can provide a transient, high drug concentration within the corneal stroma. However, equivalent drug levels can be attained with concentrated topical antibiotic solutions administered frequently. Topical therapy alone is as therapeutically effective as the combination of topical and subconjunctival therapy.103,104
Parenteral administration of antibiotic compounds does not appear to augment the intracorneal antimicrobial effect of topical or subconjunctival antibiotics.105 Parenteral antibiotics are reserved for so-called keratitis plus (e.g., keratitis with corneal perforation or impending perforation, keratitis with scleral involvement, and keratitis caused by Neisseria or Hemophilus species).
Supportive therapy in the treatment of infectious keratitis can include topical cycloplegics, enzyme inhibitors, therapeutic soft contact lenses or collagen corneal shields, and topical corticosteroids.
Because severe anterior chamber inflammatory reactions may occur with bacterial keratitis, cycloplegics are administered to prevent the formation of synechiae and to relieve the discomfort of ciliary spasm.
Metalloproteinase inhibitors seem to be effective especially in Pseudomonas keratitis by preventing enzymatic degradation of the corneal stroma.106 However, further investigations are needed before its routine use can be recommended.
Soft hydrophilic contact lenses and collagen corneal shields have been used as drug delivery systems to achieve more sustained and higher intraocular drug concentrations than can be obtained with frequent topical administration.107,108 If corneal ulceration is marked, the temporary use of a therapeutic soft contact lens or “bandage” lens may facilitate stromal repair and promote re-epithelialization by protecting the corneal surface from the mechanical trauma of lid movement. Topical medications may be continued after contact lens insertion, enhancing the drug delivery to the cornea. Alternatively, the argument has been made that lenses should not be used during the active infectious stage because they may interfere with both the penetration of the drugs in eyedrops and the removal of degradative enzymes and tissue debris.
Collagen corneal shields soaked in antibiotic solutions seem to increase ocular penetration of antibiotics more effectively than therapeutic soft contact lenses.109,110 Although the value of collagen corneal shields has been experimentally documented,111 no controlled clinical trials documenting efficacy and safety have been completed.
Devices that provide continuous lavage of the cornea with antibiotic solutions112 have the advantage of increasing drug levels113 and reducing the dependency on nursing personnel to instill them. These devices have several disadvantages, such as the possibility of further corneal epithelial mechanical injury, potential systemic toxicity, and prolonged patient immobilization. Other strategies to improve drug delivery to the cornea include placement of temporary occlusion plugs in the puncta and conjunctival sac and sustained-release inserts, either of which will maintain more antibiotic in the preocular tear film. Iontophoresis of antibiotics will also enhance corneal drug concentrations.114
The use of topical corticosteroids in the management of bacterial keratitis is controversial. Corticosteroids may be appropriate if the causative organism has been identified and an effective microbial drug is used concurrently.115 Experimental studies suggest that corticosteroids may minimize the inflammatory sequelae of bacterial keratitis without adversely affecting the efficacy of antibiotic therapy in bacterial keratitis.116–118 However, Pseudomonas species keratitis requires long-term high-dose antibiotic therapy before cautious introduction of corticosteroid therapy; Pseudomonas species ulcers have recurred when topical corticosteroids were used.119
Successful outcome of the management of infectious endophthalmitis requires a low threshold for diagnosing the condition. Acute bacterial endophthalmitis represents an ophthalmologic emergency, and effective therapy requires early diagnostic aspirates; immediate initial broad-spectrum antimicrobial coverage; antibiotic modifications based on microbial culture results, susceptibility testing, and clinical response;120–123 and finally, appropriate therapy to reduce any harmful aspects of the host immune and anti-inflammatory responses.
Animal and human studies have demonstrated that visual outcome is greatly influenced by the virulence of the infectious etiologic agent. At one end of the spectrum are relatively low-grade virulent organisms such as S. epidermidis and Propionibacterium acnes. S. epidermidis endophthalmitis, which appears to be increasing in frequency, responds well to relatively conservative therapy with vancomycin, with or without corticosteroids.121,124 Effective treatment of chronic endophthalmitis from P. acnes infection after cataract surgery may require removal of all residual lens material and capsule, potentially sequestering the organism, 125 plus intravitreal and systemic antibiotic therapy. Although the organism is susceptible to a wide variety of agents, including penicillin and cephalosporins, reliable and rapid diagnosis can sometimes be challenging. At the other end of the spectrum are the highly virulent pathogens. Destruction of the eye by P. aeruginosa, Bacillus cereus, and S. aureus may occur within 24 hours. Although aggressive therapy appears warranted if these organisms are suspected, there is currently no consensus on what constitutes appropriately aggressive therapy. It may include early mechanical vitrectomy;126–129 intravitreal antibiotics;130 early systemic, topical, and perhaps intravitreal corticosteroids;121 and IV broad-spectrum antibiotics (most commonly including a third-generation cephalosporin). Pars plana surgical removal of infected vitreous may facilitate both diagnosis and cure. A prospective, randomized clinical study (the Endophthalmitis Vitrectomy Study [EVS]) conducted to evaluate the efficacy of vitrectomy and of systemic antibiotics for the treatment of endophthalmitis,131,132 found that: (1) early vitrectomy was no more effective than administration of early intraocular antibiotics alone if the presenting visual acuity were hand motion or better, (2) if the presenting visual acuity was light perception, vitrectomy was of value in improving the final visual acuity, and (3) systemic antibiotic use or nonuse did not alter the final visual acuity.
The rationale for the use of early corticosteroids is based on recognition of the visually destructive secondary processes that can occur from host inflammatory and immune responses to the causative organism. Unlike various extraocular infections, effective elimination of the organism is not the only criterion for successful treatment of endophthalmitis. If vision is to be retained, control of the inflammatory and immune responses and elimination of the organism is crucial.
Direct intravitreal injection of antibiotics has been considered a mainstay of therapy in endophthalmitis.130 This method provides high intraocular concentrations of antibiotics experimentally,133–135 and can result in successful clinical cure.136–138
Selection of the optimal agent for intravitreal administration includes a consideration of maximizing efficacy against the suspected pathogen(s) and minimizing potential ocular drug toxicity. The presence of certain organisms is relatively predictable given the clinical setting of the endophthalmitis. Broad-spectrum coverage should be administered before culture results are available. The most widely recommended combination of antibiotic agents for intravitreal injection (and the one chosen for the EVS) is vancomycin (1 mg) and amikacin (0.4 mg).131 This combination has proven to be effective clinically. Although amikacin is believed to be less toxic than other aminoglycosides,139 there has been a trend toward use of the third-generation cephalosporin, ceftazidime, for coverage against gram-negative pathogens because of the potential severe retinal toxicity from aminoglycosides.140,141 Ceftazidime not only produces excellent results when used against gram-negative organisms, including Pseudomonas species, but is also active against staphylococci. An intraocular dose of ceftazidime (2.25 mg) caused no retinal toxicity in primate experiments.142 Vancomycin is effective against gram-positive organisms, including Staphylococcus species, the most common cause of postoperative endophthalmitis. In one animal study, intravitreal injection of as much as 2 mg vancomycin was found to be nontoxic in both phakic and aphakicvitrectomized eyes.143 Vancomycin may be the agent of choice because of the increased incidence of methicillin-resistant staphylococci in endophthalmitis cases.144 Vancomycin also covers streptococci, which often cause filtering bleb-associated endophthalmitis. Bacillus species are frequent pathogens in cases of post-traumatic endophthalmitis and, although sensitive to vancomycin in in vitro sensitivity testing, clinical experience is limited. Therefore, clindamycin, a drug known to be effective against Bacillus species, should be considered in posttraumatic endophthalmitis.145
Each of these antibiotics should be injected slowly in small, (0.1 ml) volumes into the anterior vitreous, with the bevel of the needle facing anteriorly.146 Table 6 shows several injection concentrations of antibiotics that are believed effective and relatively safe. Separate syringes should be used in combination antibiotic therapy if there is the possibility of physical incompatibility (as occurs with the mixing of vancomycin and ceftazidime).147
Although a repeat intravitreal injection of antibiotics between 48 and 96 hours after the first was administered, repeated injections in animal studies resulted in increased retinal toxicity.148
The IV administration of antibiotics has gradually assumed a less important role in the treatment of endophthalmitis. This route of administration usually provides poor penetration into the vitreous of uninflamed eyes. Repeated IV administration of cefazolin achieved intravitreal drug levels above the MIC for organisms in experimental endophthalmitis.149 Penetration may be increased during inflammation, but so, too, is the binding by serum proteins, which also leak into the eye. Successful treatment of exogenous bacterial endophthalmitis has been reported without the use of systemic antibiotic therapy.150 IV antibiotics are more and more frequently considered as an adjunctive therapy to intravitreal antibiotics.
The optimal choice of a systemic antibiotic agent for the treatment of endophthalmitis is controversial. A combination of amikacin and ceftazidime was chosen for IV therapy in the EVS131 because of its antibacterial spectrum and its ability to penetrate the vitreous151; no benefit to final visual acuity was found. However, a significant percentage of the most common gram-positive organisms (coagulase-negative staphylococci and streptococci) that causes endophthalmitis is resistant to both of these antibiotic agents.144,152 Although vancomycin has excellent efficacy against the spectrum of gram-positive organisms, its intravitreal concentration after IV injection is below the therapeutic level.153 Oral ciprofloxacin reaches vitreous concentrations above the MIC in human eyes.154,155 Although staphylococci and streptococci can develop resistance, oral ciprofloxacin has the advantages of providing a broad spectrum of activity, being well tolerated by patients, and not requiring hospitalization for administration.
Retrospective studies of therapeutic vitrectomy for endophthalmitis have reported conflicting results. Investigators reported that visual outcomes were worse,152,156 similar,144 or better with vitrectomy.157,158 Because the data from these nonrandomized clinical studies were difficult to assess, the prospective randomized EVS clinical trial was conducted.131,132 The EVS study has only partially clarified the role of vitrectomy. Early vitrectomy was no more effective than IV injection of antibiotics alone if the presenting visual acuity was hand motion or better, but if the vision was light perception, vitrectomy plus intravitreal antibiotics produced visual results superior to those of intravitreal antibiotics alone. Therapeutic vitrectromy later in the course of the disease may be of value for fungal endophthalmitis or bacterial endophthalmitis with progressive severe vitritis that does not improve after initial intraocular antibiotic therapy.
Intravitreal dexamethasone (360 to 440 μg) is commonly used in conjunction with intravitreal antibiotics in acute postoperative endophthalmitis unless fungal infection is suspected. Histopathology of experimental endophthalmitis suggests that the destruction of vision by the inflammatory process is minimally affected by intraocular antibiotics with or without vitrectomy, and suggests that further evaluation of corticosteroids is necessary.133 Several animal studies of endophthalmitis indicate that intravitreal injection of 440 μg of dexamethasone is safe and may improve visual outcome.159 Meredith and colleagues160 compared the effects on inflammation of several different therapies and reported that the best results were observed with combined vitrectomy, intraocular antibiotics, and corticosteroids. Although concern has been expressed about the possibility of potentiating or prolonging intraocular infections by the use of intraocular steroids, one clinical study has shown that using intraocular dexamethasone as part of the initial treatment of endophthalmitis did not have an adverse influence on the final visual outcome.156
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