TABLE 1. Commercially Available Antibiotic Eyedrops

TABLE 2. Commercially Available Antibiotic Ointments

BLEPHARITIS

The most common type of infectious blepharitis is staphylococcal in origin. The longer the condition is present, the harder it is to eradicate. Patients must be made to realize this fact at the outset to avoid early discouragement. Staphylococcus aureus can be cultured from the lid margin in at least one third of subjects with normal lids.^1,2 The estimate of the incidence of chronic staphylococcal blepharitis (CSB), as well as chronic staphylococcal conjunctivitis, is often inflated by the culture of transient organisms, including Staphylococcus epidermidis; conversely, negative cultures are often obtained after documented CSB associated with recurrent chalazia, a hallmark of CSB. Once topical antibiotics are applied to the lid margins, positive cultures are rarely obtained. While a single hordeolum or chalazion with otherwise clean lids does not presage CSB and needs no antibiotic therapy, multiple recurrent chalazia should be treated as though it were CSB. Treatment of CSB consists of the application of bacitracin ophthalmic ointment, which is rubbed into the lid margins one or two times daily initially for several weeks with a cotton-tipped applicator after the lids have been thoroughly cleaned of dried exudate. Applications should be continued once daily before bedtime over the next 1 to 3 months. It is important to continue nightly applications of bacitracin for 1 month after clinical eradication of the infection to prevent recurrence. Erythromycin is an acceptable second choice; however, staphylococci can rapidly become resistant to this antibiotic. Gentamicin ointment is also effective. As a last resort, vancomycin eyedrops (5 mg/mL)³ may be used for staphylococcal blepharitis infections resistant to other antibiotics. The development of vancomycin-resistant staphylococci should be avoided.

Local hygiene is equally important in helping to eradicate this condition. If the meibomian glands are plugged, they should be expressed periodically as needed. The lid margins should be scrubbed several times weekly with a cotton-tipped applicator minimally moistened with a mild baby shampoo diluted 50% with water. Excessive shampoo causes stinging and results in decreased compliance. If seborrheic blepharitis coexists, selenium sulfide lotion should be similarly applied to the eyelids, guarding against contact of the drug with the conjunctiva and cornea. A concomitant seborrheic scalp condition should also be treated with selenium sulfide shampoo. In recalcitrant cases, systemic antistaphylococcal antibiotics can be of value, as can topical corticosteroids. With the rationale that tetracycline concentrates in meibomian glands, its use has been advocated in the treatment of CSB, recurrent chalazia, and rosacea blepharitis-keratitis. However, only 30% to 50% of staphylococci are sensitive to tetracycline and the salutary effect of the drug is probably, in part, other than antimicrobial. Initial therapy with doxycycline is 100 mg orally twice daily for several weeks. After tapering, I continue to give 100 mg daily for 1 to 3 months. Another oral antistaphylococcal antibiotic may be administered if the use of either tetracycline or erythromycin is proscribed. The chronicity of staphylococcal blepharoconjunctivitis can be partially explained by two factors:

1. Continual seeding by staphylococci that reside in the meibomian glands and are inaccessible to topical antibiotics
   
2. Phagocytosed staphylococci that can remain viable for a protracted period and produce long-standing, smoldering disease.⁴
   

Angular blepharitis, characteristically affecting the skin in the lateral canthal area, is most frequently due to a chronic staphylococcal infection and usually responds to treatment with bacitracin or erythromycin ointment applied several times daily.

CONJUNCTIVITIS

Acute bacterial conjunctivitis is caused most often by Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae (or Haemophilus aegyptius), as well as by Staphylococcus aureus and Staphylococcus epidermidis. Such bacterial infections (except those due to staphylococci and rarely a few gram-negative species, such as Proteus and Moraxella) usually resolve within 1 week with topical antibiotic therapy. Before the antibiotic era, the course of such disease was of longer duration but still relatively benign. Thus, the effectiveness of topical antibiotic therapy is hard to determine for the more common catarrhal types of bacterial conjunctivitis, excluding those due to staphylococci and gonococci.

Standard treatment of an unspecified bacterial conjunctivitis includes antibiotic drops, such as gentamicin, a neomycin-gramicidin-polymyxin B preparation, or antibiotic ointments such as gentamicin or bacitracin-polymyxin B. Although streptococcal species are characteristically resistant to the aminoglycosides, topical gentamycin, in my experience, helps to eradicate the infection within the same time period as other topical antibiotics. This is probably due to our ability to deliver a much greater concentration of drug to the ocular surface than that used in the disc-diffusion assay, which is based on concentrations of drugs achievable in serum. Further, even if the streptococcus is resistant at high concentrations, the average streptococcal conjunctivitis is generally a benign, self-limited disease. The drug should probably not be used in immunosuppressed persons. Excellent but more expensive antibiotics include tobramycin eyedrops and ointment, polymyxin B-trimethoprim eyedrops, and ciprofloxacin-ofloxacin eyedrops. Fluoroquinolone therapy should be reserved for infections unresponsive to the aforementioned antibiotics. Vancomycin eyedrops (5 mg/mL), prepared from the parenteral product, may be employed for staphylococcal infections³ resistant to all other antibiotics. The following should be kept in mind: (1) gentamicin, tobramycin, and the fluoroquinolones are often ineffective against streptococcal species; (2) in rare cases, topical chloramphenicol can cause idiosyncratic bone marrow suppression and death; and (3) neomycin is often toxic to the corneal epithelium on a dose-dependent basis. When staphylococcal conjunctivitis is diagnosed or suspected, topical antibiotics used to treat staphylococcal blepharitis should be instilled into the conjunctival sac, and similar precepts apply. As is well known, staphylococcal infections of lids, conjunctiva, and cornea often occur as a troika. Sulfonamides should not be used to treat bacterial blepharitis or conjunctivitis. This contention is based on two theoretic objections:

1. Sulfa drugs may induce systemic sensitivity.
   
2. Sulfa drugs are bacteriostatic rather than bactericidal; consequently, almost all organisms develop resistance with their use over a period of time. Further, bacteriostatic antibiotics are characteristically less effective than bactericidal drugs in the immunocompromised patient.
   

The fact that many bacterial conjunctival infections clear concomitant with the use of topical sulfonamides may relate to the natural course of a relatively benign disease process or to the fact that these drugs may be bactericidal at high concentrations.

Except for conjunctivitis in the newborn (see later discussion), systemic therapy for bacterial conjunctivitis is reserved for several uncommon entities. These entities include conjunctivitis-otitis syndrome⁵ and Brazilian purpuric fever,⁶ each seen in children and each due to H. influenzae, the latter biogroup H. aegyptius, conjunctivitis due to Neisseria meningitidis, and a group of infectious entities rarely seen in industrialized societies. Oral amoxicillin-clavulanate or trimethoprim-sulfamethoxazole is often effective in treating conjunctivitis-otitis syndrome. Topical therapy of the purulent conjunctivitis, which characteristically precedes the purpura and vascular collapse seen in Brazilian purpuric fever, does not prevent systemic involvement, but early intravenous therapy with antibiotics most effective against the pathogen increases the rate of survival.⁷ Penicillin G, given systemically, remains the drug of choice in treating N. meningitidis.

Conjunctivitis in the Newborn

The three most common types of infectious conjunctivitis in the newborn, in order of frequency, are chlamydial, gonococcal, and staphylococcal. Pseudomonal conjunctivitis in the newborn, an uncommon entity, may presage systemic infection. The infant should therefore be monitored for signs of systemic involvement. Instillation of 1% silver nitrate eyedrops ( Credé used a 2% concentration) is the standard method of prophylaxis against N. gonorrhoeae. With such treatment, the risk of developing gonococcal conjunctivitis is less than 2% for an infant born to an infected mother.⁸ When prophylaxis is not administered, the transmission rate is 50%.⁹ Saline irrigation immediately following prophylaxis is not recommended because it might increase the incidence of infection. Some states in the United States have permitted the substitution of topical antibiotics such as tetracycline or erythromycin, because chlamydial (inclusion) conjunctivitis is more prevalent in the newborn than is conjunctivitis due to N. gonorrhoeae; these drugs are effective in the treatment of inclusion conjunctivitis, whereas silver nitrate is ineffective in eradicating chlamydia. Some authorities have made a case for not employing an antichlamydial prophylactic agent because the development of inclusion conjunctivitis in the newborn permits the detection and treatment of silent and potentially harmful disease in the mother, and permits the administration of systemic antibiotics following detection to prevent overt chlamydial disease in newborn organs (e.g., pneumonitis). Moreover, neonatal inclusion conjunctivitis is easily cured without tissue destruction when treated early. If topical therapy is started before the twelfth day of life, conjunctival and corneal scarring is prevented.¹⁰ Recently, povidone-iodine, administered as a 2.5% solution, was found to be more effective as a prophylactic agent against Chlamydia trachomatis than either silver nitrate or erythromycin. All three agents were equally effective against N. gonorrhoeae.¹¹

Formerly, treatment of gonococcal conjunctivitis consisted of intravenous aqueous crystalline penicillin G (100,000 U/kg given daily in four divided doses for 7 days) and penicillin G eyedrops (10,000 U/mL). The eyedrops, the value of which is questioned by some, are instilled every 15 to 30 minutes for several days and then tapered. Some of the newer cephalosporins have been shown to be very effective against N. gonorrhoeae. Ceftriaxone (25 to 50 mg/kg) as a single intramuscular or intravenous dose has been shown to be effective against gonococcal ophthalmia without the need for concomitant topical antimicrobial therapy. Concurrent saline irrigation of the conjunctiva should be used.^12,13 Inclusion conjunctivitis invariably responds to 1% tetracycline ointment four to six times daily over a 2- to 3-week period. Sulfonamide ointment can serve as an adequate second choice of drug and is administered four to six times daily for 3 weeks. Systemic therapy is important for preventing potential systemic infection, usually pneumonitis, which cannot be prevented by topical therapy. It consists of erythromycin syrup, 40 to 50 mg/kg/day given in four divided doses for 14 days; the failure rate for this treatment is 7% to 19%.⁹ Systemic tetracycline therapy is contraindicated in children younger than 7 to 8 years of age because the drug permanently discolors the teeth and retards bone growth. Other types of bacterial conjunctivitis are occasionally seen in the neonate and should be treated with topical medication as in the adult. Antibiotic ointments are preferable to eyedrops in the neonate, infant, and small child because they have a reduced washout effect.

ADULT CHLAMYDIAL AND GONOCOCCAL DISEASE

An increasing incidence of both diseases parallels current changes in sexual practices. Untreated inclusion conjunctivitis in the adult may persist for long periods. Although usually benign, long-standing chronic cases may induce corneal scarring. Treatment consists of a 3-week course of oral tetracycline (500 mg three times daily) or doxycycline (100 mg twice daily). The US Food and Drug Administration recommends 1 week of therapy. The efficacy of azithromycin as a single 1-g oral dose seems promising, but more data are needed before recommending it as standard therapy. Topical antibiotic is ineffective by itself, and there are no data to indicate that topical and systemic doses of tetracycline have an additive effect. Even when the disease is adequately treated, it may not appear to remit for many weeks after treatment. The use of systemic tetracycline is contraindicated in pregnant women because it may induce acute yellow atrophy of the liver and death. A test for pregnancy before the initiation of therapy is, at times, a judicious procedure. Oral erythromycin, 250 mg given four times daily over a 3-week period, may be employed when tetracycline is contraindicated.

Trachoma in the adult is treated similarly to adult inclusion conjunctivitis. The use of sulfa drugs carries a moderate risk of allergic reaction. Trachoma in children younger than 8 years old should be treated with topical tetracycline, erythromycin, or sulfa. Because secondary bacterial infection often exacerbates the primary condition, especially in Third World countries, topical antibiotics such as erythromycin ointment administered several times daily should be employed concomitantly. Unfortunately, there are often insurmountable logistic and compliance problems. Currently azithromycin has a promising role in the treatment of trachoma, and it may soon be a drug of choice.¹³

Gonococcal conjunctivitis in the adult, typically described as a hyperpurulent infection, can present as a nondescript catarrhal conjunctivitis. Although corneal ulceration has been reported as a frequent complication, I have rarely seen this complication. The Massachusetts Division of Communicable Diseases has no record of a case of gonococcal corneal ulceration between 1972 and 1986.¹⁴ The treatment of choice for conjunctivitis due to N. gonorrhoeae is ceftriaxone in conjunction with a one-time saline lavage of the conjunctiva. Because of the frequent incidence of coinfection with Chlamydia trachomatis, this regimen should be followed by either a single oral dose of 1 g azithromycin or 100 mg doxycycline, given twice daily for 7 days.¹⁵ The use of penicillin G eyedrops (10,000 U/mL) is controversial. If there is an allergy or resistance to penicillin, 2 g spectinomycin should be administered intramuscularly along with optional tetracycline administered topically. It has been recommended that pregnant women who are allergic to penicillin receive erythromycin (1500 mg orally, and then 500 mg four times daily for 4 days) or spectinomycin. Erythromycin, however, has been shown to be relatively ineffective against gonococcal urethritis.

Cat-scratch (Afipia felis) involvement of the eyelids or conjunctiva may be treated with oral ciprofloxacin as the primary agent or trimethoprim-sulfamethoxazole or gentamicin as secondary agents.

BACTERIAL CORNEAL ULCERS

For the past several years, a small group of investigators, including myself, have begun to question the “standard” approach to the diagnosis and treatment of bacterial corneal ulcers—a standard that has been in place, with minor modifications, for the past two decades. I¹⁶ first suggested the use of cefazolin and gentamicin in 1978 after several years' experience with this combination of antibiotics. Baum¹⁷ presented one approach to the treatment of this infection in 1979, Jones¹⁸ another. I suggested broad antibiotic coverage based on the prevalence of organisms in the local community, and Jones suggested specific antibiotic therapy based on Gram's stain findings. The following excerpt from all the previous editions of this chapter lists the reasons for employing a broad-spectrum approach to the initial therapy of bacterial corneal ulcers. It also serves as background for questioning this “standard” approach:

I believe that bacterial ulcers of the cornea should be treated with “shotgun” antibiotic therapy, based on the prevalence of pathogens known to be producing this disease in the community. I still perform a Gram's stain on every bacterial corneal ulcer to correlate the results of therapy with recovery and sensitivity to the pathogen and to help exclude the possibility of fungal infections. My reasons for this approach include the following:

1. The frequency of poor correlation between Gram's stain and culture identification
   
2. The risk of selecting an inappropriate antibiotic or combination of antibiotics based on an invalid Gram's stain identification
   
3. The ability to deliver bactericidal concentrations of a predetermined combination of antibiotics to which the spectrum of bacteria responsible for almost all bacterial ulcers in the community would be sensitive.
   

In light of the above, I believe we can sterilize bacterial corneal ulcers more effectively using an antibiotic “shotgun” than by use of an antibiotic “bullet” poorly aimed.

Initial Therapy

Factors that have prompted a reevaluation of the “standard” approach to the diagnosis and treatment of bacterial corneal ulcers include the following:

1. Several fluoroquinolone eye drops that are now commercially available can, with few exceptions, cover the spectrum of those gram-positive and gram-negative pathogens more commonly encountered.^19–23 The treatment of streptococcal infections is, in some instances, a cause of concern, but clinical outcomes appear to be less problematic than would appear to be the case based on in vitro susceptibility studies (see earlier section titled Conjunctivitis).
   
2. Data suggest no need for routine laboratory evaluation prior to initial therapy, based on findings that only 4% of ulcers are due to pathogens not adequately covered by empiric therapy consisting of fortified cefazolin-aminoglycoside eye drops.²⁴ Another study reported that only 4% of nonfungal ulcers required modification of therapy after initial cefazolin-aminoglycoside therapy failed.²⁵ In that study, the few treatment failures were all subsequently sterilized on modified therapy.
   
3. There is the potential for a delay in therapy of many hours between the initial clinical diagnosis by the primary ophthalmologist and the commencement of therapy. Delays, often additive, include the following: the time it takes to reach a distant tertiary center, the waiting time at the center before being seen initially, the time between arrival at the center and the collection of specimens for laboratory evaluation, the time between workup by the house staff and presentation to the attending, and the time required to prepare fortified antibiotic eye drops.
   
4. The primary ophthalmologist can diagnose and treat a putative bacterial ulcer immediately in the office using commercially available antibiotic eye drops. Cultures might be forgone or planted and held, to be read only if the ulcer worsened.²⁶
   
5. We can fine-tune therapy by identifying risk factors, including severity and duration of the ulcer, soft contact lens wear (e.g., Pseudomonas), concurrent staphylococcal blepharitis, or a rural setting (e.g., Bacillus cereus).
   

It is difficult at times to differentiate clinically a bacterial corneal ulcer from a fungal ulcer or a sterile infiltrate associated with the use of a soft contact lens. Even with a complete history and expertise in laboratory techniques, the clinician may have difficulty diagnosing a bacterial corneal ulcer. When necessary, Gram's stain evaluation, culture, sensitivity, and initiation of antibiotic therapy should follow in rapid succession.

A decision must also be made whether to hospitalize a patient. The factors influencing the need to hospitalize include the following:

  Ability of the patient or family to comply in delivering frequent topical instillation of antibiotic eyedrops
  Necessity for frequent examination and for subconjunctival injection of antibiotics in some cases
  Presence of a rapidly thinning cornea in danger of perforation

The initial topical antibiotic therapy for bacterial ulcers is detailed in Table 3. Subsequent therapy is found in Table 4. Directions for preparation of selected, fortified topical antibiotics may be found in Table 5. Table 6 contains typical antibiotic concentrations and dosages for various routes of administration. Additional information related to this section may be found elsewhere.^27–29 An important exception to either “standard” therapy or topical fluoroquinolone therapy relates to those patients who wear an extended-wear soft contact lens and develop a suspected bacterial corneal ulcer. For such patients, antipseudomonal therapy should be considered initially, as the incidence of pseudomonal infection in such patients is high and a delay in treating pseudomonal corneal ulcers with appropriate therapy may result in rapid destruction of corneal tissue.²⁷ Based on data that concentrated antibiotic eyedrops are as effective or more effective than subconjunctival injections,³⁰ the standard route of administration of antibiotic for the treatment of bacterial corneal ulcers is topical. Subconjunctival administration of the drug is appropriate when compliance is in question or in treating infants and young children (see later discussion). The role of corneal collagen shields is controversial, and its use for this purpose appears to be decreasing.

TABLE 3. Initial Topical Antibiotic Therapy of Suspected Bacterial Keratitis

1. Low suspicion of pseudomonal involvement
   1. First choice regimens
      1. Ciprofloxacin 3 mg/mL alone
         or
         
      2. Ciprofloxacin 3 mg/mL plus cefazolin* 50 mg/mL
         or
         
      3. Cefazolin* 50 mg/mL plus gentamicin or tobramycin 10–20 mg/mL
         
      
      
   2. Alternatives in patients allergic to:
      1. Cephalosporins (or penicillins) if allergy is of high risk
         1. Vancomycin 25–50 mg/mL
            or
            
         2. Bacitracin 10000 U/mL (poorer penetration)
            
         
         
      2. Aminoglycosides
         1. Ciprofloxacin 3 mg/mL
            or
            
         2. Piperacillin 6–12 mg/mL
            or
            
         3. Ticarcillin 6–12 mg/mL
            
         
         
      3. Fluoroquinolones
         1. Aminoglycosides plus cephalosporins
            
         
         
      
      
   
   
2. High suspicion of pseudomonal involvement
   1. Tobramycin plus an extended spectrum penicillin:
      1. Tobramycin 15–20 mg/mL (not gentamicin)
         plus
         
      2. Ticarcillin or piperacillin 6–20 mg/mL
         or
         
      
      
   2. Tobramycin 15–20 mg/mL plus ceftazidime 50 mg/mL
      
   
   

TABLE 4. Subsequent Therapy of Bacterial Keratitis (see text)*

1. Pseudomonal ulcer
   1. Topical
      1. Tobramycin 15 mg/mL
         and
         
      2. Ticarcillin or piperacillin 6–20 mg/mL
         
      
      
   2. Subconjunctival (see text for indications)
      1. Tobramycin 20–40 mg
         and
         
      2. Ticarcillin or piperacillin 100 mg
         
      
      
   
   
2. Staphylococcal ulcer (penicillin-sensitive)
   1. Topical
      1. Bacitracin 10,000 U/mL
         
      
      
   2. Subconjunctival (see text for indications)
      1. Penicillin G 1 million U
         or
         
      2. If allergic to penicillin
         1. Gentamicin 20–40 mg (first choice)
            or
            
         2. Cefazolin 100 mg (if no severe penicillin allergy)
            
         
         
      
      
   
   
3. Staphylococcal ulcer (penicillin-resistant)
   1. Topical
      1. Bacitracin 10,000 U/ml
         or
         
      2. Vancomycin 25–50 mg/mL
         
      
      
   2. Subconjunctival (see text for indications)
      1. Cefazolin 100 mg (first choice)
         or
         
      2. Methicillin or oxacillin 100 mg
         or
         
      3. Vancomycin 25 mg (conjunctival toxicity)
         
      
      
   
   
4. Gram-negative ulcer (Enterobacter, E. coli, Klebsiella, Proteus)
   1. Topical
      1. Gentamicin 10–20 mg/mL
         or
         
      2. Tobramycin 10–20 mg/mL
         or
         
      3. Ciprofloxacin 3 mg/mL
         
      
      
   2. Subconjunctival (see text for indications)
      1. Tobramycin 20–40 mg
         or
         
      2. Gentamicin 20–40 mg
         
      
      
   
   
5. No organism cultured but ulcer is progressing
   1. Topical
      1. Ceftazidime 50 mg/mL
         plus
         
      2. Vancomycin 25–50 mg/mL
         
      
      
   2. Subconjunctival
      1. Ceftazidime 100 mg
         plus
         
      2. Vancomycin 25 mg (conjunctival toxicity)
         
      
      
   
   
6. Bacillus ulcer
   1. Topical
      1. Gentamicin or Tobramycin 10–20 mg/mL
         plus
         
      2. Vancomycin 25–50 mg/mL
         
      
      
   2. Subconjunctival (see text for indications)
      1. Gentamicin or Tobramycin 20–40 mg
         plus
         
      2. Vancomycin 25 mg (conjunctival toxicity)
         
      
      
   
   
7. High suspicion of anaerobic involvement
   1. Gentamicin or tobramycin 10–20 mg/mL
      plus
      
   2. Additional anaerobic coverage
      1. Ceftazidime 50 mg/mL or penicillin G 100,000 U/mL
         plus
         
      2. Clindamycin 50 mg/mL
         
      
      
   
   

TABLE 5. Preparation of Selected Fortified Topical Antibiotics

TABLE 6. Antibiotic Concentrations and Dosages

The rationale for the use of cefazolin in some patients allergic to penicillin is detailed later in the chapter. Clindamycin or vancomycin may be substituted as eyedrops or as a subconjunctival injection if the use of cephalosporins is deemed unwise in a patient allergic to penicillin. Both are effective against penicillinase-producing staphylococci. Vancomycin may cause severe chemosis of the conjunctiva following subconjunctival injection.

I avoid the use of systemic antibiotics in the treatment of bacterial ulcers of the cornea unless a corneal perforation occurs. Table 6 lists the principal antibiotics usually administered by subconjunctival injection in the treatment of bacterial ulcers of the cornea. Each injection should be delivered in a volume of 0.5 to 1 mL and prepared according to commercial instructions. When employed, daily subconjunctival injections of antibiotics are administered for 4 to 5 days, but more frequent injections (e.g., every 12 hours) may prove more effective.

Following the instillation of proparacaine, the injection is performed using a tuberculin syringe with a 25-gauge, 1.6-cm needle. To relieve pain, lidocaine (Xylocaine), 1% to 2%, 0.25 mL, may be injected subconjunctivally before the antibiotic is administered; this does not cause antibiotic inactivation.³¹

The subconjunctival bleb should be created as close to the ulcer as possible to ensure the highest concentration of antibiotic near the lesion. When more than one type of antibiotic is administered, the second drug should be injected at a separate site with a second syringe to reduce the potential for inactivation of one agent by the other.

Some ophthalmologists avoid the use of subconjunctival injections in small children because general anesthesia may be necessary to ensure the safety of the injection, and the anesthetic risk may be considered too great or the value of the injection not worth the effort. Considering the low risk of general anesthesia today and the greater risk of undertreating a bacterial corneal ulcer, the use of general anesthesia is warranted and reasonable in most situations. When eyedrops are administered to the flailing, crying child who squeezes the eyes shut, undertreatment is a possibility. Not only does the medication miss its mark, but the flood of tears may reduce the concentration of antibiotic to an ineffective level.

Subconjunctival administration of antibiotics should be accompanied by supplemental concentrated eyedrops at intervals of 15 to 30 minutes. The preparation of such concentrated eyedrops is described in Table 5. Ointments are not used because the ointment base may impair the corneal penetration of an eyedrop used concomitantly. Antibiotics available for parenteral use be added to commercially available artificial tears in squeeze-type plastic bottles.³² It has also been determined that many of these antibiotic-artificial tear preparations can be kept at bedside for periods up to a week at room temperature without significant loss of antibiotic activity.³³ Penicillin G, however, decays by 25% and 75% after 3 and 7 days, respectively.

Modification of Initial Therapy

Initial antibiotic therapy should be changed only if it is determined that the pathogen is resistant to the antibiotics initially employed and there is progression of the corneal ulcer. An acute or subacute bacterial corneal ulcer is “getting better” and responding to specific therapy if it does not appear to be “getting worse.” At times, a favorable clinical response may be noted despite laboratory reports indicating “resistance” of the organism to the antimicrobial agent. This kind of discrepancy reflects the fact that susceptibility testing in the clinical laboratory is extrapolated from antibiotic concentrations readily achievable in serum; the test does not generally take into account situations such as this, in which extremely high concentrations of drug can be applied directly to a relatively superficial lesion. Different subconjunctival and topic antibiotics are used if, subsequent to initial therapy, the ulcer continues to worsen and the laboratory reports a pathogen resistant to the initial combination of antibiotics.

Evidence suggests a previously unsuspected incidence of corneal ulcers induced by anaerobic bacteria.³⁴ Penicillin G remains one of the most active antibiotics against many of these organisms. Clindamycin is also quite effective, and its use should be considered when a patient is allergic to penicillin. Other antibiotics, such as the aminoglycosides and some of the cephalosporins (e.g., ceftazidime), are variably effective. The true incidence of these infections is difficult to uncover because we are, at times, unsure whether the organisms cultured are pathogens or commensals.

The use of topical corticosteroids in the treatment of bacterial corneal ulcers is controversial. Their proven ability to limit the consequences of inflammation must be weighed against their retardation of collagen formation, their posing an increased risk of perforation, their prolongation of infection (especially by Pseudomonas), and their enhancement of pseudomonal extension to the sclera. Minimal use of these agents after sterilization of the ulcer encourages reepithelialization, retarded by stromal inflammation.

BACTERIAL ENDOPHTHALMITIS

The management of postoperative bacterial endophthalmitis is based on our understanding of the ocular pharmacokinetics of antibiotics, the availability of effective antibiotics (see later discussion), and the results of clinical ocular studies.

Although various reports have documented bacterial growth from anterior chamber aspirates in cases of bacterial endophthalmitis, Forster and co-workers,^35–37 in a series of articles between 1974 and 1986, recognized the importance of the vitreous humor as the primary focus of bacterial replication and suggested obtaining cultures from aspirates of both aqueous and vitreous humors. These publications also clarified the need to create therapeutic concentrations of drug in the vitreous. It has been repeatedly demonstrated that only intravitreal delivery can reliably achieve therapeutic concentrations of antibiotic for the initial treatment of bacterial endophthalmitis due to all but a few pathogens. Further, when initial therapy commences, the genus and species of the pathogen has yet to be determined, necessitating delivery of antibiotics, usually two, that encompass both the gram-positive and gram-negative spectrum.

Until 1987, standard treatment of postoperative bacterial endophthalmitis consisted of vitrectomy and the administration of antibiotic by intravitreal, intravenous, subconjunctival, and topical delivery.^38,39 In that year, Paven and Brinser⁴⁰ boldly forwent the use of the intravenous route and concluded that the efficacy of treatment was unchanged when this route was eliminated from standard therapy. This finding, together with the fact that the role of vitrectomy had not been studied systematically, promoted the recent Endophthalmitis Vitrectomy Study (EVS).⁴¹ In this study, intravitreal injections included 0.4 mg amikacin and 1 mg vancomycin. Vancomycin, ceftazidime, and dexamethasone phosphate were administered subconjunctivally. Ceftazidime and amikacin were given intravenously (Table 7). Because such a study may not be repeated for at least a generation, the group's findings deserve full attention and include the following:

TABLE 7. Initial Antibiotic Therapy for Postoperative and Traumatic Bacterial Endophthalmitis

1. No difference in visual outcome whether or not a vitrectomy was performed in patients whose initial visual acuity was hand motion or better
   
2. A significantly better final visual acuity and greater media clarity in a subset that included vitrectomy if the initial vision was light perception only
   
3. No difference in final vision acuity or media clarity whether or not systemic antibiotics were used
   

In a separate analysis of the same parent study, gram-positive bacteria were isolated in 94.2% and gram-negative organisms were found in 6.5% of cases.⁴² Seventy percent of total isolates were gram-positive, coagulase-negative micrococci; 10% were Staphylococcus aureus. All gram-positive isolates were susceptible to vancomycin. Of the gram-negative isolates tested, 89% were susceptible to both amikacin and ceftazidime, and 11% were resistant to both. Secondary or anterior chamber lens implantations were associated with a greater number of infections due to gram-positive bacteria other than coagulase-negative micrococci.

The EVS' advocacy for intravitreal amikacin administration is tempered by questions as to the safety of intravitreal administration of an aminoglycoside after a documented case of macular infarction and severe visual loss.⁴³ A decade earlier, a comparative study demonstrated amikacin to be less toxic than either gentamicin or tobramycin.⁴⁴ The effect of gravity and positioning may also play a role.⁴⁵ Campochiaro and Green⁴⁶ suggested that ceftazidime be considered a substitute for amikacin. This suggestion is supported by the apparent safety,^47,48 the in vitro sensitivities,⁴² and early clinical endophthalmitis efficacy^47,49,50 of ceftazidime. After recognition of these studies, Flynn and colleagues (see Table 7) at the Bascom Palmer Eye Institute in Miami now advocate the intravitreal administration of vancomycin and ceftazidime for acute bacterial postoperative endophthalmitis, postoperative endophthalmitis associated with conjunctival filtering blebs (streptococcus and H. influenzae), and endophthalmitis following penetrating trauma. For delayed-onset postoperative endophthalmitis, they suggest the use of intravitreal vancomycin. In cases of endophthalmitis associated with a bleb, topical therapy to treat the infected bleb is also required. As can be seen from the EVS, the recommendations by Flynn and co-workers, and anecdotal practice patterns elsewhere, vancomycin has largely replaced cefazolin for intravitreal delivery as coverage of those gram-positive organisms associated with the infection that were becoming more resistant to cefazolin.^51–54 Vancomycin is also characteristically nontoxic when delivered intravitreally at a dose of 1 mg (Table 8).

TABLE 8. Maximum Nontoxic Doses of Antibiotic and Antifungal Agents for Vitrectomy Infusion Fluid for Endophthalmitis

The importance of rapid diagnosis and therapy of postoperative bacterial endophthalmitis and the achievement of therapeutic intraocular concentrations of antibiotic cannot be stressed too strongly. A delay in the institution of appropriate drug therapy, even for a few hours, may jeopardize the prognosis for visual recovery. It is during those first hours after early clinical detection—before severe tissue destruction, and while the organisms are in the early logarithmic phase of multiplication—that therapy is most effective. Antibiotic therapy, if necessary, is modified based on both the clinical condition and the results of the culture and sensitivity report of the anterior chamber and vitreous tap. When an anaerobic infection is suspected,³⁴ penicillin G can be administered. If there is a history of allergy to penicillin, clindamycin is often effective (see section titled Bacterial Corneal Ulcers). A steroid-sensitive, delayed-onset, postoperative endophthalmitis after extracapsular cataract extraction caused by Propionibacterium acnes was reported in 1986,⁵⁵ and its present treatment, 1 mg intravitreal vancomycin, was suggested shortly thereafter.⁵⁶ Bacillus cereus endophthalmitis, a fulminant infection usually seen after trauma, has a dismal prognosis. In past years, however, eyes have been salvaged after intravitreal clindamycin and gentamicin therapy, and more recently with intravitreal vancomycin and ceftazidime (see Table 8). When subsequent intravitreal antibiotic administration is required, relevant pharmacokinetic data pertaining to drug half-life is of value (Table 9).^57,58

TABLE 9. Regimens for Intravitreal Injection in Humans (Pharmacokinetic Data Estimated from Data in Rabbits)

Experimental studies described later in this chapter suggest that there is little difference in subconjunctival and retrobulbar routes of administration.

Prognosis for recovery of good vision can be divided arbitrarily into two categories: (1) that following staphylococcal and Propionibacterium acnes infections; and (2) that following infection with most other bacteria. Staphylococcal and Propionibacterium acnes infections can be eradicated in many instances with very low (2 μg/mL) concentrations of proper antibiotic in the vitreous. Most other bacteria are not susceptible. Reasons for a continued poor prognosis in the latter group include a delay in initial therapy; a failure to maintain a therapeutic intravitreal antibiotic level; inadequate knowledge, in many instances, of the toxic level and half-lives of intravitreal antibiotics; and the possibility of continued retinal damage by toxic bacterial products, even after sterilization of the infected tissues. Data related to the peak vitreal concentrations and estimated half-lives of those antibiotics used for intravitreal administration may be found elsewhere²⁸ and in Table 9.

The weight of clinical evidence supports the use of corticosteroids in the treatment of bacterial endophthalmitis,⁵⁹ and both the recent EVS⁴¹ and the Bascom Palmer group concur.^54,60 The ophthalmologist might want to consult a specialist in infectious disease or an internist familiar with the administration of high-dose aminoglycoside therapy. Patients receiving a parenteral aminoglycoside should be monitored every 24 hours for nephrotoxicity (serum creatinine) and ototoxicity (clinical evaluation of hearing and equilibrium). It is also wise to obtain serum levels of drug twice weekly immediately before and 1 hour after administration, especially in patients with renal impairment. In cases of renal impairment, the dosage schedule should be adjusted. Transscleral iontophoresis, a novel modification of an old technique, moves small ions through the sclera and into the vitreous by means of a low electrical current.⁶¹ Since first employed for antibiotics,⁶² its clinical use has yet to be reported, probably because the range of drug delivery into the vitreous remains wide. If delivery of a known quantity can be ensured, this technique may yet prove valuable for administrating antibiotic subsequent to the initial vitreal dose, assuming the vitreal half-life is known.

DACRYOADENITIS

Acute bacterial dacryoadenitis is a rare entity. In most cases, Staphylococcus aureus is the pathogen and produces a suppurative infection. Streptococci and gonococci are less frequently encountered. Patients usually present with fever, localized pain or tenderness, the typical S-shaped eyebrow, and swelling with a palpable mass in and under the upper lid laterally. In its early stages, it may be difficult to differentiate from orbital cellulitis. The patient usually requires hospitalization and treatment with an intravenous antibiotic effective against the suspected pathogen for approximately 4 to 7 days in conjunction with hot packs. Abscess formation and spontaneous drainage may ensue. Acute dacryoadenitis may also be due to mumps or infectious mononucleosis. It has been rarely associated with other viral disease, scarlet fever, erysipelas, and typhoid. Chronic dacryoadenitis is almost always associated with noninfectious systemic disease.

DACRYOCYSTITIS

Both acute and chronic dacryocystitis often occur either secondary to or concomitant with stasis of the lacrimal outflow system and persist or recur unless the obstruction is relieved. There are anecdotal data to suggest that in bacterial infections of the lacrimal sac, the organisms are located in the sac wall during the acute phase and in the lumen when the infection is chronic. Acute bacterial dacryocystitis is almost always due to a gram-positive organism. Staphylococcus aureus is the prime pathogen. Streptococcal infections (including pneumococcus) are seen less frequently. There is a low rate of bacterial recovery when the disease is acute, and antibiotic therapy should be empiric. Depending on the severity of the disease and the age of the patient, an oral or parenteral penicillin or cephalosporin active against penicillinase-producing staphylococci should be employed. Chronic bacterial dacryocystitis may be induced by a plethora of organisms, including the anaerobic bacterium Actinomyces. Positive identification by cultures is problematic. Material regurgitated through the punctum following pressure on the sac should be cultured. An anaerobic culture should also be employed to identify Actinomyces. I do not employ systemic antibiotics in the treatment of chronic dacryocystitis. Depending on the culture report, an appropriate antibiotic is irrigated through the lacrimal outflow system several times weekly for several weeks. Irrigation with a penicillin G solution is appropriate when an Actinomyces infection is diagnosed. If the patient is allergic to penicillin, a 10-mg/mL clindamycin solution may be employed. It must be remembered that eradication of the infection is difficult, if not impossible as long as obstruction to tear outflow persists. Occasionally, relief of obstruction alone results in spontaneous eradication of infection.

UVEITIS

Those infectious entities affecting the uveal tract and retina that are susceptible to antibiotic therapy include bacterial endophthalmitis, tuberculosis, syphilis, Lyme disease, and toxoplasmosis. Iritis secondary to culture-proven Listeria monocytogenes previously treated with penicillin now responds more readily to ampicillin, alone or in combination with gentamicin.⁶³ Intraocular inflammation associated with Whipple's disease often responds to systemic tetracycline therapy. Tuberculosis and syphilis are best treated in concert with an internist with expertise in infectious disease. These entities and Lyme disease will not be discussed here. The treatment of bacterial endophthalmitis was discussed earlier. The therapeutic regimen for ocular toxoplasmosis is outlined elsewhere in this volume.

MECHANISMS OF ANTIBIOTIC ACTION

Antibiotics usually act in one of two ways: (1) by breaking down the cell wall of bacteria; or (2) by interfering with ribosomal protein synthesis within the bacterial cytoplasm. Those antibiotics that interfere with cell wall synthesis include the penicillins, the cephalosporins, bacitracin, and vancomycin. Antibiotics affecting bacterial protein synthesis include the aminoglycosides (gentamicin, tobramycin, amikacin, neomycin, streptomycin, and kanamycin), erythromycin, chloramphenicol, the tetracyclines, clindamycin, and spectinomycin. Within the bacterial cell wall is a cytoplasmic membrane. Colistin and polymyxin break down this membrane, a third mechanism of antibiotic action.

Other antibiotics affect deoxyribonucleic acid (DNA). Metronidazole inhibits the synthesis of DNA, while rifampin binds to DNA-dependent ribonucleic acid (RNA) polymerase and blocks the formation of RNA. The fluoroquinolones, typified by norfloxacin, ciprofloxacin, and ofloxacin, interfere with both the structure and function of bacterial DNA by blocking an essential bacterial enzyme, DNA gyrase. This enzyme is responsible for maintaining superhelical twists in DNA.⁷⁰

ANTIBIOTIC RESISTANCE

There are four main mechanisms of resistance:

1. The antibiotic may not be able to interact with the target.
   
2. The antibiotic may fail to reach the target. For example, narrow-spectrum penicillins fail to reach the internal target within gram-negative bacteria because they cannot penetrate their complex shells. Chemical modifications of these drugs have produced broad-spectrum penicillins such as ampicillin, carbenicillin, and ticarcillin. These antibiotics pass through the cell wall and membrane of gram-negative bacteria, affect the internal target, and have proved effective in certain gram-negative infections.
   
3. The bacteria may produce enzymes that inactivate the antibiotic. Examples include the penicillinases and cephalosporinases (β-lactamases) produced by organisms such as Staphylococcus aureus that break down (hydrolyze) the β-lactam ring of these antibiotics. Bacteria acquire the ability to produce antibiotic-destroying enzymes in one of three ways:
   1. Bacteria take up extracellular DNA from their environment (transformation).
      
   2. A virus picks up bacterial DNA from one bacterium and transfers it to another (transduction).
      
   3. Plasmids (self-replicating pieces of extrachromosomal DNA) possessing genes for antibiotic resistance (R factors) are transferred to antibiotic-sensitive bacteria after sexual mating of the bacteria (conjugation). Gram-negative organisms acquire resistance primarily by conjugation.
      
   
   
4. The bacteria may have an increased ability to transport the antibiotic out of itself actively, via an “efflux pump.”
   

Clinically, antibiotic resistance may have a different connotation for the ophthalmologist than for the nonophthalmologist. In the treatment of a surface or near-surface infection, such as a bacterial corneal ulcer, a favorable clinical response may be noted despite a laboratory report indicating “resistance.” This apparent discrepancy reflects the fact that susceptibility testing is extrapolated from antibiotic concentrations easily achievable in serum. In the treatment of bacterial corneal ulcers, extremely high concentrations of drug can be applied directly to a relatively superficial lesion.

PROPHYLACTIC ANTIBIOTICS

Although the use of prophylactic antibiotics after trauma or surgery is at times discouraged in general medicine, ophthalmologists appear justified in prescribing a topical antibiotic for even a minor corneal abrasion, rather than risking development of a bacterial corneal ulcer. A de-epithelialized cornea is more susceptible to infection, especially in a patched eye. Such a cornea is vulnerable not only to pathogens contaminating the foreign body that produced the abrasion, but also to potential pathogens indigenous to the normal conjunctival flora. The ability to deliver milligram levels of antibiotic topically may be a factor enhancing the prophylactic effect. The use of prophylactic periocular injections or systemic administration of antibiotic after intraocular surgery is controversial. I do not employ systemic antibiotics prophylactically because of what I consider an adverse risk-benefit ratio; however, I do administer a subconjunctival injection of 40 mg gentamicin after repair of a ruptured globe and occasionally after a long intraocular procedure associated with excess tissue manipulation, especially in a patient with decreased host resistance. With meticulous attention directed toward avoiding scleral perforation and securing wound closure, I have yet to encounter macular infarction. I also administer 100 mg cefazolin subconjunctivally after intraocular surgery in patients who have received prolonged treatment for chronic staphylococcal blepharitis and have responded sufficiently to allow surgery. Such surgery is not performed until two consecutive lid margin cultures are negative after antibiotic therapy has been withheld for 1 to 2 weeks.

The rationale for the use of preoperative antibiotic eye drops before intraocular surgery to reduce eyelid margin and ocular surface flora⁷¹ and documentation that these tissues host potential pathogens, most often staphylococcal species,⁷² combine to validate preoperative topical antibiotic prophylaxis, a concept documented in 1974 by Allen and Mangiaracine.⁷³ Povidone-iodine, administered topically as a 5% solution immediately before surgery, reduces the colony count in cultures taken from the ocular surface,^74,75 and its use is fast becoming standard. Further, in a single but important report,⁷⁶ prophylactic use of povidone-iodine was reported to result in a decreased incidence of endophthalmitis. The need for delivery of antibiotic to the anterior chamber immediately after anterior segment surgery, administered in past years by means of a subconjunctival injection, has been strengthened by data documenting culture growth of gram-positive organisms from aqueous humor specimens in 22% of patients immediately after cataract and other intraocular surgeries.⁷⁷ Further, these organisms were identical in type and had matching antibiotic sensitivities to those isolated from the eyelids and conjunctiva. There is currently a trend to withhold a subconjunctival antibiotic injection after cataract surgery, relying rather on an antibiotic, commonly vancomycin, in the irrigating solution. The use of vancomycin for this purpose, however, needlessly encourages the emergence of vancomycin-resistant enterococci (VRE) and facilitates the potential for transmission of this resistance to methicillin-resistant Staphylococcus aureus (MRSA). Whether a subconjunctival injection encourages less resistance than the use of intraocular irrigating solutions containing antibiotics is debatable. However, the use of vancomycin or those antibiotics soon to arrive that are effective against VRE and MRSA is to be discouraged.

There is a need to develop susceptibility testing based on antibiotic concentrations achievable in ocular tissues and fluids, rather than on maximal levels achievable in serum.

Due largely to misuse and overuse of antibiotics and the ingenuity of bacteria, through genetic engineering, to develop resistance to even the newer, most effective broad-spectrum antibiotics,⁷⁸ there has been a recent emergence of VRE and a potential transmission of such resistance to staphylococci, especially MRSA. Current pressure to develop new antibiotics and mechanisms to deal with the threat, after a lull in development in the 1980s, has resulted in the formulation of new molecules and reason for cautious optimism. Quinupristin-dalfopristin (Synecid), effective against VRE and MRSA⁷⁹ and other gram-positive cocci, including pneumococci,⁸⁰ is now available commercially for systemic delivery. If, however, the organism is resistant to erythromycin, there will probably be a poor kill rate with this drug combination. Several synthesized agents of a new class of compounds with a new chemical structure, the oxazolidinones, have been found to be highly effective against VRE and MRSA in experimental studies.^81,82 Newly engineered variants of vancomycin (glycopeptides LY333328 and LY307599, Lilly) also appear to be very effective against VRE and MRSA.^83,84 Neither the oxazolidinones nor the glycopeptides are commercially available at present.

ROUTES OF ADMINISTRATION AND INTRAOCULAR PENETRATION OF ANTIBIOTICS

This section represents a summary of many experimental studies. Certain basic principles of antibiotic delivery to the eye are discussed. These generalizations are set forth in relation to each route of administration and pertain, for the most part, to serious ocular infections, such as corneal ulcers and intraocular infections.

1. Topical Administration
   1. The average medicated eyedrop is 0.025 to 0.040 mL; drops larger than 0.025 mL overflow the lid margin.^85,86
      
   2. Eyedrops should be instilled frequently, probably every 15 to 30 minutes to ensure therapeutic concentrations in the cornea.^87,88 A more convenient regimen for the patient, hospital staff, and family is to instill one drop of the first drug every minute for five doses, and then wait 5 minutes (to avoid a washout effect). The next step is to give the second drug similarly and then wait 45 minutes. Continue this regimen around the clock for 24 to 48 hours, or until culture report and clinical condition suggest a change.
      
   3. Eyedrops containing a viscous vehicle aid ocular penetration.⁸⁶,⁸⁹
      
   4. Fat-soluble antibiotic eyedrops and ointments, such as chloramphenicol and various tetracyclines, penetrate the cornea better than water-soluble antibiotics.^90,91
      
   5. At least 5 minutes should be allowed between two different types of eyedrops to avoid a washout effect.⁸⁶
      
   6. Compared with eyedrops, ointments increase retention time and possibly corneal penetration.^92,93
      
   7. An ointment, once applied, retards subsequent eyedrop drug penetration.
      
   8. Eyedrops administered to a crying child are quickly washed out.
      
   9. When antibiotic eyedrops are administered to an eye containing a soft contact lens, the lens may initially and preferentially absorb the antibiotic, thus tending to reduce the amount of antibiotic available to the eye (hypothetically). After the lens becomes saturated with antibiotic, it serves as a depot and probably aids in increasing the level of antibiotic in the cornea.^94,95
      
   
   
2. Periocular Injection
   1. Higher concentrations of antibiotic can be obtained in ocular tissue by a periocular injection than by a much larger dose given parenterally.^96–98
      
   2. Ocular tissue and fluid antibiotic levels are approximately the same after a subconjunctival (anterior sub-Tenon) or retrobulbar (posterior sub-Tenon) injection.⁹⁹
      
   3. Patient discomfort is eased when lidocaine is preinjected or injected concomitantly. The anesthetic does not decrease the activity of antibiotics.³¹
      
   4. Ocular inflammation may decrease ocular tissue and fluid antibiotic levels after a periocular injection.^100,101
      
   5. Higher concentrations of antibiotics for a given tissue are found in the immediate vicinity of the periocular injection site.^100–102
      
   6. Two different drugs should always be administered from separate syringes at different locations unless it has been demonstrated that one drug does not decrease the activity of the other.
      
   7. It is difficult to achieve a high level of antibiotic in the vitreous after periocular injections.^{96,97,99,100,103–107}
      
   
   
3. Oral and Parenteral Administration
   1. There is no evidence to support the use of oral administration of antibiotic for the initial treatment of bacterial corneal ulcers or endophthalmitis.
      
   2. In general, higher serum and hence higher ocular tissue levels are achieved after intravenous injections than are achieved after intramuscular injections. Aminoglycosides, however (e.g., gentamicin, tobramycin, amikacin) may be given by either route.
      
   3. Probenecid decreases renal excretion of the penicillins and cephalosporins, thus raising serum and ocular tissue concentrations of drug. In addition, probenecid has a direct effect on the ciliary body and aids retention of penicillins and cephalosporins within the eye.^103,108,109
      
   4. Parenteral administration of antibiotic may augment ocular tissue levels achieved by periocular injections.¹¹⁰
      
   5. Ocular inflammation decreases the blood-ocular barrier and aids penetration of antibiotic administered parenterally.^97,110
      
   6. It is difficult to achieve a high level of antibiotic in the vitreous after high-dose parenteral administration,^{96,97,104,105,111} but intravenous supplementation after vitrectomy may be of value in certain instances.¹¹²
      
   
   
4. Intravitreal Injection
   1. This route of administration has the obvious advantage of delivery of antibiotic to a locus that is relatively inaccessible to antibiotics by other routes of administration.^39,113
      
   2. The use of various antibiotics has proved both safe and effective. Amikacin has been shown to be less toxic to the retina than either gentamicin or tobramycin (see section titled Bacterial Endophthalmitis).⁴⁴
      
   3. Removal of vitreous shortens the half-life of drugs in the vitreous.^114,115
      
   
   

PENICILLINS

Penicillins have a thiazolidine ring connected to a β-lactam ring. The side chain, attached to the β-lactam ring, determines many of the characteristics of an individual penicillin.

Penicillin G (Benzyl)

ACTIVITY. This drug is active against many gram-positive and a few gram-negative bacteria. Up to 85% of Staphylococcus aureus and Staphylococcus epidermidis organisms are resistant.

MODE OF ACTION. Bactericidal action occurs when organisms are dividing. The drug inhibits the biosynthesis of mucopeptides in the bacterial cell wall.

EXCRETION. Penicillin G is excreted through the kidney tubules and pumped out of the eye via active transport in the ciliary body. Tubular excretion and probably ciliary body excretion can be partially blocked by 0.5 g probenecid, given orally four times daily. Probenecid should not be used in children younger than 2 years of age.

RESISTANCE. Staphylococcal resistance is usually due to inactivation of antibiotic by penicillinase produced by some staphylococci. Resistant strains of gonococci have now appeared.

USES. Penicillin G is used in gonococcal and streptococcal (including pneumonococcal) infections when these organisms are penicillin sensitive. It is no longer the drug of choice for gonococcal infection. It is the drug of choice for anaerobic infections other than those caused by Bacteroides fragilis and for actinomycosis infection.

ADVERSE REACTIONS. Allergy is the primary reaction. There is no relation between dose and allergic effect. Hyperkalemia is a potential problem in certain patients when high doses are administered intravenously.

Semisynthetic Penicillins

The group of semisynthetic penicillins includes methicillin, oxacillin, cloxacillin, dicloxacillin, and nafcillin.

ACTIVITY AND PHARMACOLOGY. These drugs are resistant to staphylococcal penicillinase. There is little difference among oxacillin, dicloxacillin, nafcillin, and methicillin when administered parenterally. However, the marked acid liability of methicillin could affect its stability in many intravenous solutions.

USES. These drugs are used mainly for staphylococcal infections.

ADVERSE REACTIONS. The adverse effects are similar to those of penicillin G. Methicillin produces interstitial nephritis more commonly than the others and causes more pain on injection than does oxacillin. Dicloxacillin may induce tissue necrosis when administered subconjunctivally. Nafcillin is the most expensive drug in this group and has no clear advantage over the others.

Extended-Spectrum Penicillins

Extended-spectrum antibiotics, which comprise ampicillin, amoxicillin, carbenicillin, ticarcillin, piperacillin, mezlocillin, and bacampicillin, are active against some gram-negative bacilli. They are ineffective against penicillinase-producing staphylococci, as well as other gram-negative organisms that produce penicillinase. Numerous studies have documented synergism between members of this group and the aminoglycosides. Ampicillin, amoxicillin, and bacampicillin exhibit activity against aerobic gram-negative bacteria, including Neisseria (from β-lactamase-producing strains); Haemophilus (non-β-lactamase-producing strains); Escherichia coli; Proteus mirabilis; Salmonella; and Shigella. Carbenicillin, ticarcillin, mezlocillin, and piperacillin have a further extended gram-negative spectrum that includes Pseudomonas aeruginosa, Proteus vulgaris, Enterobacter sp., Serratia marcescens, Morganella morganii, and Klebsiella pneumoniae (piperacillin). Piperacillin or ticarcillin, when used in conjunction with tobramycin, is highly effective against Pseudomonas aeruginosa.

More recently, several of the extended-spectrum penicillins have been combined with a β-lactamase inhibitor, either clavulonic acid (naturally occurring) or sublactam (semisynthetic). Each acts as a competitive inhibitor of β-lactamase and potentiates the action of the antibiotic. Commercially available combinations include amoxicillin-clavulanic acid, ticarcillin-clavulanic acid and ampicillin-sublactam. Cellulitis, including preseptal, and infections of the orbit respond well to these agents when the pathogen is susceptible.

AMPICILLIN. The outstanding characteristic of ampicillin has been its activity against H. influenzae infections, such as preseptal and orbital cellulitis; however, more strains are becoming resistant, and it is no longer the drug of choice. The pharmacodynamics and adverse effects are similar to those of penicillin G. Approximately 20% is bound to serum protein.

CARBENICILLIN. Used chiefly in ophthalmology against Pseudomonas infections, carbenicillin is also effective against indole-producing strains of various Proteus species. Approximately 50% is bound to serum proteins. It is usually used in conjunction with gentamicin in severe Pseudomonas infections. Adverse effects include a similar allergic effect in patients allergic to penicillin, hemorrhagic manifestations in patients with renal failure, or if daily dose approaches 300 mg/kg, sodium overload and hypokalemia. Carbenicillin inactivates gentamicin and tobramycin if mixed in the same bottle with either of these.

TICARCILLIN. Ticarcillin, a parenteral semisynthetic penicillin, is similar to carbenicillin, except that ticarcillin has a greater activity against Pseudomonas and a lower total daily dosage. Strains of Pseudomonas resistant to carbenicillin are almost always resistant to ticarcillin. The adverse effects of ticarcillin are similar to those of carbenicillin. Experimental tobramycin nephrotoxicity has been attenuated by ticarcillin.¹¹⁶

PIPERACILLIN. Piperacillin, a semisynthetic parenteral penicillin, is similar to carbenicillin and ticarcillin, except that piperacillin seems to be more active in vitro against Pseudomonas aeruginosa that these two antipseudomonal antibiotics. Piperacillin, like its mirror image, mezlocillin, has one of the broadest spectra of activities among the penicillins and is generally well tolerated. Thrombophlebitis has been the most common side effect (4%). Aminoglycosides are inactivated when the drugs are mixed together.¹¹⁷

CEPHALOSPORINS

Over the past two decades, the proliferation of cephalosporins, while a boon in controlling and eradicating bacterial disease, has been indigestible for most clinicians.

Structure

A β-lactam ring is common to the penicillins, cephalosporins, cephamycins, and oxa-β-lactams, and all members of these groups are known as β-lactam antibiotics. The penicillins derive from 6-aminopenicillamic acid, the cephalosporin nucleus from 7-aminocephalosporanic acid. The cephamycins differ from the cephalosporins in that they possess a 7-α-methoxy group, making them more resistant to certain β-lactamases.

Classification and Activity

It is convenient to classify these family members by generations (Table 10). First-generation drugs have a narrower spectrum of antibacterial activity, but are more active against gram-positive cocci than are second- or third-generation antibiotics. However, methicillin-resistant staphylococci are resistant to all available cephalosporins. Second-generation cephalosporins have a broader spectrum against gram-negative bacteria than do first-generation antibiotics, and third-generation drugs have yet a broader spectrum. Enterococci (Streptococcus faecalis) are resistant to all cephalosporins. N. gonorrhoeae is sensitive to the cephalosporins in general and in particular to cefoxitin and third-generation drugs. Many second- and third-generation, but not (first-generation, antibiotics are effective against H. influenzae. In general, Pseudomonas aeruginosa is resistant to all cephalosporins except for a few third-generation members, such as ceftazidime and cefoperazone, and their activity is variable.

TABLE 10. Antibacterial Drugs of Choice

Mode of Action

Until recently, cephalosporins were thought to act only by inhibiting the enzymatic action necessary for the production of a stable bacterial cell wall. We now know that members of this group of antibiotics also bind to proteins (β-lactam-binding proteins) associated with the cellular membrane. Such binding, which may differ with certain antibiotics, initiates a complex chain of events affecting permeability and protein synthesis and causing a release of autolysins. Cephalosporins possess a high but variable degree of resistance to β-lactamase (penicillinase, cephalosporinase) enzymes of both gram-positive and gram-negative bacteria.

Pharmacology

Only those cephalosporins that are resistant to acid hydrolysis (cephalexin [Keflex], cefadroxil [Duricef, Ultracef], and cefaclor [Ceclor]) can be given orally. Those administered parenterally can be given intravenously or intramuscularly. Protein binding varies from 20% to 80%, but such binding seems to be unrelated to therapeutic effect and to be of no clinical significance. Many, but not all, cephalosporins and cephamycins penetrate the aqueous humor in therapeutic concentrations when administered intravenously, but a therapeutic concentration is achieved intravitreally only in instances in which the bacteria are highly sensitive to the antibiotic (e.g., staphylococci). One study surprisingly showed a dramatically high intravitreal concentration of ceftriaxone (43 μg/mL) after subconjunctival administration of drug to the rabbit eye.¹¹⁸ The cephalosporins are eliminated unchanged mainly through the kidneys by a combination of glomerular filtration and proximal tubular secretion. Probenecid blocks renal transport for first- and second-generation antibiotics, but for only two third-generation drugs thus far studied (cefotaxime and ceftizoxime). Like the penicillins, the cephalosporins have a relatively short half-life in the vitreous because they are pumped out of the eye through the retina by an active transport process.¹¹⁹ Systemically administered probenecid was found to increase the intravitreal half-life of cefazolin in the monkey.¹⁰⁸ A more detailed evaluation of the ocular pharmacokinetics of cephalosporins and other antibiotics may be found elsewhere.²⁸

Uses

Even though second- and third-generation antibiotics may be of occasional value, the first-generation drug cefazolin, used in combination with an aminoglycoside, is still (but less commonly) employed for the initial treatment of a suspected bacterial corneal ulcer that is presumed not to be due to Pseudomonas aeruginosa. Synergy has been reported between the cephalosporins and the aminoglycosides¹²⁰; piperacillin or ticarcillin, when used in combination with tobramycin, has proved to be a highly effective topical therapy in the treatment of bacterial ulcer due to Pseudomonas aeruginosa. There has been, however, an increase in staphylococcal and streptococcal ocular infections resistant to cefazolin. A cephalosporin may be employed in many instances when the patient is allergic to penicillin, although it should be remembered that some patients who are allergic to penicillin also will be allergic to cephalosporins (see later discussion).

Adverse Reactions

Up to 5% of patients experience allergic reactions to the cephalosporins that are similar in type and degree to penicillin hypersensitivity. A patient with a known allergy to penicillin has a 5% to 16% risk of allergy to the cephalosporins (mean, 8%). It is probably wise to avoid all cephalosporins in patients with a past history of immediate hypersensitivity to penicillin (anaphylaxis, giant urticaria); however, milder delayed reactions to penicillin do not constitute a contraindication to the use of cephalosporins. Administered either subconjunctivally or by the retrobulbar route, the cephalosporins induce varying degrees of tissue irritation; cefazolin induces the least irritation. Before administering any of these drugs, the ophthalmologist should become familiar with its adverse effects.

HYPERSENSITIVITY TO THE PENICILLINS AND CEPHALOSPORINS

The incidence of hypersensitivity reactions to the penicillins ranges from 1% to 10%. Many of these reactions are mild (e.g., eosinophilia, fever, morbilliform skin rash), but more severe (e.g., serum sickness) or life-threatening (e.g., anaphylaxis) reactions may ensue. Until recent years, a history of penicillin allergy constituted good reason to avoid this antibiotic. It is now known that intradermal skin testing with penicillin reagents is the best predictor of current allergic status, as opposed to the patient's history. Up to 75% of patients with an allergic history to penicillin will be able to tolerate penicillin again in the future. These skin tests are used to identify patients who will develop serious IgE-mediated reactions and risk death if penicillin or any of its congeners are administered. Skin tests do not predict the occurrence of other penicillin reactions, including hemolytic anemias, serum sickness, drug fever, interstitial nephritis, and exfoliative dermatitis. At present, there is no satisfactory way of identifying patients who might develop these reactions.

The reagent penicilloyl polylysine, when administered as a skin test, is more closely identified with urticaria and the minor determinant mixture reagent with anaphylaxis, although there are exceptions. Both reagents are now available commercially. Patients with a history of penicillin allergy should receive a scratch test with both reagents before intradermal testing. The details of how and when to use skin testing for penicillin reactions may be found elsewhere.¹²¹ If both skin tests are negative the patient may be given penicillins or cephalosporins, as there is less than a 1% risk of anaphylaxis or giant urticaria.

Between 5% and 16% of penicillin-allergic patients will have allergic reactions to the cephalosporins. If there is a history of giant urticaria or anaphylaxis associated with penicillin or its congeners, cephalosporin therapy should not be instituted. Cephalosporins may be given, however, when there is a history of minor allergic penicillin reactions such as fever, eosinophilia, or morbilliform skin rash.

OTHER β-LACTAM ANTIBIOTICS

Imipenem and aztreonam, each classified as a carbapenem and having a β-lactam structure, are newer agents that are neither penicillins nor cephalosporins. Although they are effective against a wide variety of gram-positive and gram-negative organisms, their role in the treatment of ophthalmic infections has yet to be defined.

AMINOGLYCOSIDES

Many compounds in this group have rarely, if ever, been used in the treatment of ophthalmic disease. Those of service (in chronological order) include neomycin (1949), gentamicin (1963), tobramycin (1967), and amikacin (1972). Neomycin is administered only topically. No aminoglycoside is absorbed well after oral delivery.

STRUCTURE. Amino sugars are linked to another moiety by a glycoside bond.

MODE OF ACTION. These antibiotics affect bacteria in a complex fashion. They bind irreversibly to ribosomes and block the “recognition” step in protein synthesis, causing a “misreading” of the genetic code. The ribosomes separate from messenger RNA, and cell death ensues. These drugs are bactericidal at conventional doses. They also have a “postantibiotic effect”: that is, a residual bactericidal effect that continues after serum levels of drug fall below the minimum inhibitory concentration.

ACTIVITY. Gentamicin, tobramycin, and amikacin are generally used in treating gram-negative aerobic infections, and their action against most gram-positive pathogens is weak. Pneumococcus and Streptococcus pyogenes are highly resistant. Sensitive organisms usually include Pseudomonas aeruginosa, Proteus, Klebsiella, Salmonella, Shigella, E. coli, H. influenzae, and Serratia. The activity of tobramycin is similar to gentamicin except that strains of Pseudomonas are sensitive to tobramycin at one half the concentration of gentamicin. Serratia may be less sensitive to tobramycin than to gentamicin. Amikacin is active and more effective against a higher proportion of gram-negative aerobic bacilli than gentamicin or tobramycin. Organisms resistant to gentamicin and tobramycin may be susceptible to amikacin, but the reverse is not true. Staphylococcus aureus and Staphylococcus epidermidis, including penicillinase-producing strains, are usually susceptible to gentamicin, tobramycin, and amikacin. β-Hemolytic streptococci (group A), pneumococci, and enterococci are notoriously resistant. Activity against the gonococci is variable. Aminoglycosides have a synergistic effect with the penicillins and cephalosporins (e.g., with piperacillin or ticarcillin against Pseudomonas).

PHARMACOLOGY. Aminoglycosides are absorbed well by intramuscular injection but may be given intravenously. They are absorbed poorly after oral administration, are weakly bound to serum protein, and are excreted by renal glomerular filtration. These antibiotics concentrate in renal cortical tissue.

USES. The aminoglycosides have been a mainstay over the years in the treatment of serious ocular disease, such as bacterial corneal ulcers and endophthalmitis. They are usually used in combination with a penicillinase-resistant penicillin-type antibiotic or a cephalosporin in treating such diseases. Such a combination exhibits synergy; however, because of the emergence of resistant strains, their use has been decreasing. Amikacin has been shown to be less toxic to the retina than either gentamicin or tobramycin.⁴⁴ An aminoglycoside in combination with either piperacillin or ticarcillin is the treatment of choice for a Pseudomonas infection. It can be administered parenterally, subconjunctivally, retrobulbarly, or topically. Tobramycin should be used exactly as gentamicin.

ADVERSE REACTIONS. The most serious potential adverse effects of the aminoglycosides are nephrotoxicity and ototoxicity. These reactions correlate roughly with the length of treatment, degree of preexisting renal impairment, and the age of the patient. Gentamicin, tobramycin, and amikacin produce mild changes in the proximal tubular cells of the kidney in approximately 8% to 25% of recipients and more severe effects in 2% to 3%. The renal damage is usually reversible if the drug is discontinued at the first signs of renal dysfunction (a rising serum creatinine). These aminoglycosides may be employed, even when there is evidence of renal failure, by adjusting the dosage schedule to the following formula: a loading dose of 2 to 2.2 mg/kg, followed by 0.8 mg/kg every half-life of the serum antibiotic concentration. The serum half-life is dependent on the degree of renal abnormality and may be calculated by multiplying serum creatinine by 3 to 4. For example, if the serum creatinine is 4 mg/dL, the dose should be 0.8 mg/kg every 12 to 16 (4 × 3 to 4) hours.

Patients receiving parenteral aminoglycosides must be monitored every 24 to 48 hours for nephrotoxicity by measuring serum creatinine. It is wise to obtain serum levels of aminoglycosides immediately preceding and 1 hour after administration. Even the best nomogram is not fully predictive. An attempt should be made to achieve a serum peak of 5 to 8 μg/mL. A valley of 1 to 2 μg/mL is “desirable,” but in renal failure this value can be achieved only by letting the serum level fall for several half-lives. Ototoxicity is manifested by hearing loss or vestibular impairment. The true incidence is unknown and ranges from 2% to 25%, with approximately 50% of cases being reversible. When an ophthalmologist administers an aminoglycoside parenterally, it is wise, if not mandatory, to obtain a consultation by an internist familiar with antibiotic pharmacology; pretherapeutic kidney function tests that are maintained throughout and after the treatment period and periodic measurements of serum drug levels have been described earlier. Even with these precautions, however, some patients will need renal dialysis.

Less common or rare adverse effects include malabsorption, elevations of serum glutamic pyruvic transaminase, alkaline phosphatase, neurotoxicity (pain or paresthesia), blurring of vision, or an acute organic brain syndrome and optic neuritis. Neomycin, administered topically, is associated with a high incidence of punctate epithelial keratitis.

CHLORAMPHENICOL

STRUCTURE. Chloramphenicol is a derivative of bichloroacetic acid and contains a nitrobenzine moiety. Originally derived from a Streptomyces species, it is now prepared synthetically.

MODE OF ACTION. This agent inhibits protein synthesis by blocking polypeptide linkage on the messenger RNA-ribosome complex and may also inhibit the binding of messenger RNA to bacterial ribosomes. It is bacteriostatic.

ACTIVITY. Chloramphenicol is active against E. coli, some Klebsiella, Salmonella, Shigella, Proteus sp., H. influenzae, Corynebacterium diphtheriae, L. monocytogenes, streptococci, and pneumonococci and is moderately active against Staphylococcus aureus and Staphylococcus epidermidis.

PHARMACOLOGY. Absorption is rapid and complete after oral administration, and peak serum levels are reached in 1 to 2 hours. Inactivated in the liver, chloramphenicol and its metabolites are excreted rapidly (80% to 90% of the dose) in the urine. Because of its lipid solubility, it penetrates well into all tissues including the eye. From 45% to 60% is bound to serum proteins.

USES. Although chloramphenicol has been used in past decades to treat serious ocular infections, its use has declined because of the introduction of more effective antibiotics and its potential for inducing severe systemic adverse reactions. It was, in past years, used in the treatment of “garden-variety” bacterial conjunctivitis (excluding staphylococcal) and as either a preoperative or postoperative topical antibiotic. However, because of the risk of fatal idiosyncratic aplastic anemia after the topical administration of chloramphenicol,^122,123 such usage is proscribed unless the pathogen is resistant to all other antibiotics that can be administered topically.

ADVERSE REACTIONS. The most important adverse effect of chloramphenicol is bone marrow suppression. Chloramphenicol-associated pancytopenia occurs in two forms: dose-related and idiosyncratic. Dose-related bone marrow suppression occurs when serum concentrations exceed 25 μg/mL, with daily doses of 4 g or more, or with prolonged therapy. Recovery usually occurs within 3 weeks after the antibiotic has been discontinued. Idiosyncratic aplastic anemia (see Conjunctivitis section) is rare (1:30,000 to 40,000) and unrelated to dose. Other side effects include nausea, diarrhea, and superinfection. Rare complications include prolonged bleeding time and optic neuritis. Chloramphenicol should not be used with other drugs known to produce hematologic side effects. It should generally not be given with penicillin.

CLINDAMYCIN

STRUCTURE. Clindamycin is a 7-deoxy-7-chloro semisynthetic derivative of lincomycin, which is an amino acid attached to a sulfur-containing octose.

MODE OF ACTION. Protein synthesis is inhibited by binding ribosomes to competitively inhibit access to transfer RNA-amino acid complexes to the messenger RNA-ribosome complex.

ACTIVITY. Clindamycin is active against Staphylococcus aureus and Staphylococcus epidermidis, including penicillinase-producing staphylococci, βhemolytic streptococci, and pneumococcus; H. influenzae; and anaerobes including Bacteroides sp., Actinomyces, and Bacteroides fragilis.

PHARMACOLOGY. Clindamycin absorption is good after oral administration, but parenteral administration produces higher serum levels. It may be administered either subconjunctivally or retrobulbarly. It is metabolized by the liver and excreted in inactive form in the urine, and approximately 25% is bound to plasma protein.

USES. Clindamycin is most commonly used against gram-positive anaerobic infections when penicillin and cephalosporins cannot be administered, or in the treatment of Bacillus cereus endophthalmitis or ocular toxoplasmosis. It is also often effective against non-methicillin-resistant staphylococcal species and some streptococci, including pneumococcus, Streptococcus pyogenes and Streptococcus viridans.

ADVERSE REACTIONS. Diarrhea occurs in approximately 2% to 20% of patients. The diarrhea is secondary to bowel flora changes in 10% and to pseudomembranous enterocolitis in 0.1% to 10%. Fatalities have been reported. Occasionally skin rash, pruritus, and hypersensitivity reactions have occurred.

TETRACYCLINES

The tetracyclines consist of chlortetracycline, oxytetracycline, demeclocycline, minocycline, and doxycycline.

MODE OF ACTION. These bacteriostatic antibiotics inhibit microbial ribosomal protein synthesis. However, in contrast to most other antibiotics, the tetracyclines are also capable of interfering with mammalian protein synthesis.

ACTIVITY. Tetracyclines are broad-spectrum antibiotics with activity against bacteria, including Rickettsia, Chlamydia, Actinomyces, and even protozoa. Because of widespread resistance, the tetracyclines cannot be relied on as initial therapy for infections due to most gram-positive cocci, gram-negative facultative bacilli, or anaerobes. A minority of strains of gonococci are sensitive, whereas 90% of strains of H. influenzae remain sensitive to doxycycline. Sixty-five percent of Staphylococcus aureus strains remain susceptible. The tetracyclines are active against many spirochetes, including Borrelia burgdorferi (Lyme disease).

PHARMACOLOGY. Absorption is good throughout the gastrointestinal tract, but it is incomplete and shows individual variation. It is diminished by the presence of iron, magnesium, calcium, and alkalis and increased by phosphate; therefore, milk and some antacids interfere with absorption. The tetracyclines differ substantially in their modes of elimination: chlortetracycline, minocycline, and doxycycline are eliminated largely by nonrenal routes; the others are mainly excreted in the urine. These antibiotics are lipid soluble and penetrate the eye readily. Minocycline and doxycycline are the most lipid soluble, whereas oxytetracycline is the least lipid soluble. Serum protein binding is approximately 55% to 82% for all congeners except oxytetracycline, which is 30% bound. This group of antibiotics should generally be avoided in patients with renal insufficiency, although doxycycline (and perhaps minocycline) does not enhance renal insufficiency.

USES. The tetracyclines should be avoided, if possible, in pregnant women and in children younger than 8 years of age, as well as in patients with liver disease. In general, the tetracyclines should not be used as the first-line drugs in bacterial infections. In contrast, they are the drugs of choice for certain nonbacterial organisms (e.g., Chlamydia, Mycoplasma) and rosacea keratitis. Although there have been no comparative in-depth studies, doxycycline, because of its lipid solubility, would seem to be the congener of choice for systemic administration, if desired.

ADVERSE REACTIONS. Nausea, vomiting, anorexia, and “unpleasant taste” are the most common side effects of the tetracyclines. Candidiasis is not infrequent. Phototoxicity, hepatotoxicity, and pseudotumor cerebri may also be seen at times. The tetracyclines may bind to the calcium in teeth and bones, and can cause mottling of the teeth. As stated earlier, these antibiotics should be avoided in children younger than 8 years of age. Pregnant women on these drugs have a higher risk of hepatotoxicity. Minocycline has the unique potential to cause vestibular toxicity, more often in women than in men. The symptoms (ataxia, dizziness, nausea, and vomiting) usually abate 1 to 2 days after the drug is discontinued.

MACROLIDES (ERYTHROMYCIN, AZITHROMYCIN, CLARITHROMYCIN)

MODE OF ACTION. These drugs prevent microbial protein synthesis by binding to the 50s ribosomal unit, which prevents elongation of the peptide chain. They are bacteriostatic, but bactericidal at higher doses.

ACTIVITY. The spectrum of erythromycin embraces gram-positive organisms, and is effective against Staphylococcus aureus, S. epidermidis, S. pyogenes, pneumonococcus, Streptococcus viridans, Streptococcus faecalis, Corynebacterium diphtheriae and Actinomyces israelii. It is also effective in treating infection due to some gram-negative bacteria, including N. gonorrhoeae, N. meningitidis, and H. influenzae. Strains of staphylococci resistant to erythromycin are also characteristically resistant to the other macrolides. When sensitive, clarithromycin exhibits better activity than erythromycin. It is also more active against strains of streptococci than erythromycin. Azithromycin, however, is less active against gram-positive bacteria than erythromycin but is more active than the other two congeners against H. influenzae. Its prime role in ophthalmology may lie in its high activity against chlamydiae. Preliminary data suggest it is more effective than erythromycin in eliminating inclusion conjunctivitis.

PHARMACOLOGY. Erythromycin is absorbed well by mouth, but activity is reduced by gastric acid; therefore, it is given as enteric-coated tablets or as erythromycin stearate or estolate. Although intramuscular injections are very painful and intravenous injections may cause severe thrombophlebitis, it can be given by injection as the ethylsuccinate intramuscularly or as the gluceptate or lactobionate by slow intravenous injection. Because there are more effective antibiotics for the treatment of severe ocular infections due to gram-positive organisms, there is little need to administer erythromycin parenterally. Excretion is primarily in the bile. Between 20% and 40% is bound to serum protein. Azithromycin possesses unique pharmacokinetic properties in its extensive tissue distribution and high drug concentrations in most tissues.

USES. Although erythromycin is effective against many gram-positive organisms, it is seldom the drug of choice for parenteral use because other antibiotics, especially the penicillinase-resistant penicillins and cephalosporins, are more effective in treating serious ocular bacterial infections, such as corneal ulcers and endophthalmitis. Oral administration may be used in combination with topical therapy to treat recalcitrant staphylococcal blepharitis, especially when recurrent chalazia do not respond to topical therapy. It is useful in the treatment of conjunctivitis induced by gram-positive organisms and chlamydia. As stated earlier, azithromycin may play its most important role in the treatment of chlamydial disease if preliminary data are confirmed.14 A single treatment has been shown to eradicate presumed chlamydial urethritis.

ADVERSE REACTIONS. Erythromycin has perhaps one of the lowest rates of local side effects, toxic or allergic, of any of the antibiotics applied topically to the eye. It also has a low rate of side effects when administered systemically. Gastrointestinal irritation is perhaps the most common side effect following oral administration. Diarrhea and vomiting occasionally occur. The estolate may cause liver damage with jaundice and skin eruptions if treatment is continued for more than 10 to 12 days. The drug should not be given to patients known to have liver disease. Estolate may rarely induce cholestatic hepatitis and eosinophilia. Adverse reactions from the two newer macrolides seem to mirror those of erythromycin, but more data are needed.

BACITRACIN

MODE OF ACTION. Bacitracin inhibits protein synthesis by preventing the incorporation of amino acids and nucleotides into the bacterial cell wall. It is bactericidal.

ACTIVITY. Bacitracin is very active against many of the gram-positive organisms and some gram-negative organisms, including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus faecalis, pneumococcus, Corynebacterium diphtheriae, Actinomyces israelii, H. influenzae, Clostridia, and Bacillus anthracis.

PHARMACOLOGY. Because of its severe nephrotoxicity, the drug is rarely, if ever, given systemically.

USES. This drug in ointment form is perhaps the most effective topical antibiotic commercially available for the treatment of staphylococcal blepharoconjunctivitis. It is very effective against penicillinase-producing staphylococci and rarely produces hypersensitivity.

POLYMYXIN B

MODE OF ACTION. Polymyxin B is absorbed by the bacterial cell membrane and alters its permeability, allowing the escape of intracellular substances. It is bactericidal.

ACTIVITY. Polymyxin B is active in vitro against nearly all species of gram-negative bacteria (except Proteus and Neisseria) and has variable activity in vivo. Gram-positive bacteria are resistant to it. This antibiotic is effective against E. coli, Klebsiella, H. influenzae, and Pseudomonas aeruginosa.

PHARMACOLOGY. Ophthalmologists do not prescribe polymyxin B for systemic use.

USES. Polymyxin B is used in commercial topical preparations, usually in combination with an antibiotic effective against gram-positive organisms. It may cause tissue necrosis when administered by subconjunctival injection.

POLYMYXIN E (COLISTIN)

This antibiotic has an antibacterial spectrum similar to polymyxin B. It is seldom used in ophthalmologic therapy. Before the advent of newer antibiotics, it was used to treat ocular infections induced by Pseudomonas. Colistin sulfate is more active by weight than sodium colistimethate and is more suitable for topical administration. The colistimethate is less toxic by weight than the sulfate and is used for parental administration. Compared with the sulfate, colistimethate is less irritating when administered via subconjunctival injection.

SPECTINOMYCIN

Spectinomycin is used almost exclusively for infections caused by N. gonorrhoeae when the organism is resistant to penicillin or when the patient has a penicillin allergy.

MODE OF ACTION. Spectinomycin is an aminocyclitol and is related to the aminoglycoside antibiotics, but differs structurally from them. It acts at the 30s ribosomal subunit to inhibit protein synthesis in the bacterial cell.

ACTIVITY. Spectinomycin is variably active against many gram-positive and gram-negative organisms; however, as just stated, the only clinical application of this antibiotic is its use against N. gonorrhoeae.

PHARMACOLOGY. It is poorly absorbed from the gastrointestinal tract and should be administered intramuscularly. A single 2-g dose results in blood levels of approximately 100 μg/mL 1 hour after intramuscular injection. The drug is excreted in the urine in an active form. There are no significant studies regarding administration via a subconjunctival injection.

ADVERSE REACTIONS. Spectinomycin is relatively nontoxic. There has been no demonstration of ototoxicity or nephrotoxicity. There is no cross-allergenicity with the penicillins.

VANCOMYCIN

MODE OF ACTION. Vancomycin inhibits the biosynthesis of the major structural cell-wall polymer peptidoglycan. It is bactericidal.

ACTIVITY. This narrow-spectrum antibiotic is active against some gram-positive bacteria, including Staphylococcus aureus (especially methicillin-resistant Staphylococcus aureus), Staphylococcus epidermidis, Streptococcus pyogenes pneumococcus, Streptococcus viridans, Streptococcus faecalis, Corynebacterium sp., and Clostridium sp.; mycobacteria and fungi are resistant. There is no cross-resistance between vancomycin and other antibiotics, and resistance is not common.

PHARMACOLOGY. Vancomycin is not given orally or intramuscularly because of poor intestinal absorption and localized pain at the site of injection, respectively.

USES. Vancomycin is almost exclusively used in the treatment of staphylococcal or enterococcal infections. It is used for patients in whom the semisynthetic penicillins and cephalosporins are contraindicated, or when the organism is resistant to these antibiotics (methicillin-resistant staphylococci and penicillin-resistant pneumococci). Because of emerging resistance, its use in ophthalmology should be limited largely to those instances in which eyesight or life is threatened by a pathogen resistant to other antibiotics. Exceptions include its use as part of the initial intravitreal regimen in the treatment of bacterial endophthalmitis, or for a serious adnexal infection unresponsive to other antibiotics.

ADVERSE REACTIONS. Vancomycin may cause sloughing after subconjunctival injection. After intravenous administration, the major adverse effects are neurotoxicity, ototoxicity, and nephrotoxicity. There are numerous other side effects that are rarely encountered.

RIFAMPIN

MODE OF ACTION. Rifampin inhibits bacterial DNA-dependent RNA polymerase and is bactericidal.

ACTIVITY. Rifampin is active against Mycobacterium tuberculosis and many of the other mycobacteria, including Mycobacterium fortuitum. Other sensitive organisms include Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus faecalis, pneumococcus, Clostridium perfringens, Bacillus anthracis, H. influenzae, N. gonorrhoeae, Mycobacterium leprae, E. coli, and Brucella species. Other partially sensitive organisms include Aerobacter aerogenes, K. pneumoniae, and Proteus species.

PHARMACOLOGY. Rifampin is well absorbed orally and is excreted in the bile and urine. Probenecid elevates serum levels. The rate of protein binding is 75% to 80%.

USES. Rifampin is primarily used in the treatment of tuberculosis in combination with other drugs, and its use is uncommon in clinical ophthalmologic practice; however, its potential has not been thoroughly explored. It has been used to treat eye infections due to methicillin-resistant staphylococci.

ADVERSE REACTIONS. Dyspeptic symptoms and loss of appetite may occur. Urine and sweat may become reddish brown. Anemia, thrombocytopenia, leukopenia, and acute renal failure have been rarely noted. Hepatotoxicity may occasionally occur. It is well tolerated as a 1% subconjunctival injection in rabbits.

SULFONAMIDES

I do not favor the use of sulfonamides alone in treating ocular infections. These antimicrobial agents are not considered first-line agents except when more effective antibiotics are contraindicated. Sulfonamides may prove effective, however, in combination with pyrimethamine for the treatment of ocular toxoplasmosis and nocardia keratitis.

MODE OF ACTION. Sulfa drugs prevent uptake of para-aminobenzoic acid, which is an essential bacterial metabolite required for the synthesis of folic acid, without which growth and reproduction cease. They are bacteriostatic, but may be bactericidal in high concentrations. Trimethoprim competitively inhibits the conversion of dihydrofolic acid to tetrahydrofolic acid by blocking the action of bacterial dihydrofolate reductase.

ACTIVITY. Sulfa drugs have a very broad spectrum with activity against both gram-positive and gram-negative organisms. In addition, they are somewhat effective against chlamydial agents that produce trachoma and inclusion conjunctivitis. Toxoplasma, Actinomyces, and Nocardia sp. may also be sensitive.

PHARMACOLOGY. Most sulfonamides are rapidly absorbed after oral administration to give adequate blood levels. They are bound to serum proteins in varying degrees (1% to 98%) and excreted mainly by glomerular filtration. Unless the urine is kept alkaline, certain sulfonamides may crystallize out in the urine. Conversely, when alkali is given to the patient to protect against crystallization, excretion is enhanced and blood levels are decreased.

USES. In ophthalmology the use of these agents is primarily limited to treating ocular toxoplasmosis, chlamydial disease, and superficial infections of the conjunctiva. The sulfonamides are almost as effective as tetracycline therapy in the treatment of trachoma and inclusion conjunctivitis, but these agents may be better treated with a macrolide antibiotic.

ADVERSE REACTIONS. The overall incidence of toxic reactions is approximately 5% to 10%. The most common reactions include nausea, vomiting, dizziness, headache, drug fever, and sensitization manifesting with many types of skin rashes. Erythema multiforme may follow sulfonamide therapy, although in recent years the incidence of this disease associated with long-acting sulfonamides has been questioned. Hematologic complications such as hemolytic anemia, agranulocytosis, aplastic anemia, and thrombocytopenia have been reported. The main toxic reaction of the sulfonamides is crystallization of the drug in an acid urine. This results in renal tubular obstruction and its subsequent complications. If good fluid intake and output are ensured and if alkali are given (bicarbonate) to ensure alkalinization of the urine, the risk of tubular obstruction is minimal if not eradicated completely when sulfisoxazole or triple sulfas are used.

TRIMETHOPRIM-SULFAMETHOXAZOLE

Although trimethoprim is commercially available as a single agent, it is almost always used in combination with sulfamethoxazole when administered systemically and in combination with polymyxin B when employed as an eyedrop for bacterial conjunctivitis.

MODE OF ACTION. Trimethoprim and sulfamethoxazole act independently at sequential steps of the enzymatic pathway for the synthesis of tetrahydrofolic acid, resulting in a strong synthesis of the agents and a decreased bacterial resistance against the combination compared with each drug individually.

ACTIVITY. The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole, but the former is 18 to 200 times more effective than the latter. A large variety of gram-positive organisms are susceptible to the combination. The bacteria that are usually resistant include Pseudomonas aeruginosa, enterococci, and Bacteroides fragilis.

USES. Trimethoprim in combination with polymyxin B is used as a broad-spectrum eyedrop for suspected bacterial conjunctivitis. Trimethoprim-sulfamethoxazole eyedrops have also been used to treat nocardia keratitis.

FLUOROQUINOLONES

There has been a decade-long drive to explore the clinical potential of a unique family of antibiotics, the 4-quinolone-3-carboxylates, whose parent compounds—nalidixic and oxolinic acids, discovered years ago—have lain relatively dormant. The newer, synthesized, well-tolerated congeners display an exciting spectrum of activity and intensity of action. The early representatives of this family of compounds, designated the fluoroquinolones,^124,125 include norfloxacin, ofloxacin, ciprofloxacin, amifloxacin, enoxacin, pefloxacin, sparfloxacin, lomefloxicin, and fleroxacin.

STRUCTURE. These agents derive from a 4-quinolone nucleus and a carboxylate substituent at position 3. Each has a 6-fluoro and 7-piperazino substituent. Individual characteristics of each drug are largely determined by substituents at the 1-nitrogen position of the quinolone nucleus and the para position of the piperazino group, although structural differences elsewhere affect drug action.

MODE OF ACTION. Although complex and still partially undetermined, the fluoroquinolones interfere with the both structure and function of bacterial DNA by blocking an essential bacterial enzyme, DNA gyrase. This enzyme is responsible for maintaining superhelical twists in DNA.

ACTIVITY. Although there are individual differences, the fluoroquinolones demonstrate strong activity against a wide variety of both gram-positive and gram-negative bacteria. Ciprofloxacin appears to be the most active drug. The spectrum of activity includes staphylococci (including methicillin-resistant staphylococci), Pseudomonas aeruginosa, the Enterobacteriaceae, Klebsiella, Proteus, Morganella, Citrobacter, Serratia, Acinetobacter, Brucella, Chlamydia, Legionella, and Mycobacteria (including Mycobacterium fortuitum and Mycobacterium chelonei). Pseudomonas maltophilia is relatively resistant, and streptococci are generally more resistant than are gram-negative organisms.

PHARMACOLOGY. The fluoroquinolones, in general, are well absorbed after oral administration and produce therapeutic serum levels after administration by this route. Peak serum levels after oral or intravenous administration of pefloxacin or enoxacin differ little, but norfloxacin and ciprofloxacin are less well absorbed from the gastrointestinal tract than other fluoroquinolones. Relatively long half-lives in serum for group members allow less frequent (8- to 12-hour) dose intervals in some cases. The rate of binding to serum proteins is relatively low for each congener (14% to 30%). The fluoroquinolones are excreted largely through the kidneys, except for pefloxacin, which is excreted through the liver. Metabolic studies, thus far scant, suggest varying degrees of parent drug degeneration among family members. There is evidence for hepatic metabolism of ciprofloxacin and norfloxacin. Fluoroquinolones appear to distribute widely in bodily fluids and demonstrate excellent tissue penetration. Ocular penetration data are lacking, but meningeal penetration for pefloxacin seems good.

CLINICAL USES. Ciprofloxacin and ofloxacin are commercially available as eyedrops and are commonly used to treat bacterial conjunctivitis and corneal ulcers (see earlier discussion). Nonocular clinical studies demonstrate the effectiveness and, in some instances, the superiority of the fluoroquinolones to other antibiotics or antibiotic combinations in treating gram-negative infections. Because members of this family of antibiotics are effective against staphylococci and Pseudomonas aeruginosa, the potential for further use of these drugs in treating serious ocular infections is bright. Both ciprofloxacin and ofloxacin penetrate the cornea well after topical administration, although it is unclear which of the two antibiotics produces higher concentrations of drug in the stroma.^126,127 Susceptibility and clinical effectivity studies for corneal ulcers have been cited earlier.

ADVERSE EFFECTS. Ocular studies demonstrate little significant toxicity. Systemically administered fluoroquinolones are generally well tolerated. Infrequent, and often minor, gastrointestinal and central nervous system symptoms have been reported. Joint swelling and tendonitis have occurred rarely. Bone and cartilage toxicity and central nervous system abnormalities (e.g., seizures, pseudotumor cerebri) are well-known adverse effects of the parent compound, nalidixic acid. Whether such toxicity will occur with the newly synthesized compounds is unknown.

1. Goodner EK: Routine preoperative and postsurgical management. Int Ophthalmol Clin 3:119, 1963

2. Allansmith M, Anderson RP, Butterworth M: The meaning of preoperative cultures in ophthalmology. Trans Am Acad Ophthalmol Otolaryngol 73:683, 1969

3. Fleischer AB, Hoover DL, Khan JA et al: Topical gentamicin formulation for methicillin-resistant Staphylococcus epidermidis blepharoconjunctivitis. Am J Ophthalmol 101:283, 1986

4. Mudd S, Shayegani M: Delayed-type hypersensitivity to S. aureus and its uses. Ann NY Acad Sci 236:244, 1974

5. Harrison CJ, Hedrick JA, Block SK, Gilchrist MJ: Relation of the outcome of conjunctivitis and the conjunctivitis-otitis syndrome to identifiable risk factors and oral antimicrobial therapy. Pediatr Infect Dis J 6:536, 1987

6. Brazilian Purpuric Fever Study Group: Brazilian purpuric fever: Epidemic purpura fulminans associated with purulent conjunctivitis. Lancet 2:757, 1987

7. Brazilian Purpuric Fever Study Group: Haemophilus aegyptius bacteremia in Brazilian purpuric fever. Lancet 2:761, 1987

8. Armstrong JH, Zacarias F, Rein MF: Ophthalmia neonatorum: A chart review. Pediatrics 57:884, 1976

9. de Toledo AR, Chandler DW: Conjunctivitis of the newborn. Infect Dis Clin North Am 6:807, 1992

10. Mordharst CH, Dawson C: Sequelae of neonatal inclusion conjunctivitis and associated disease in parents. Am J Ophthalmol 71:861, 1971

11. Isenberg SJ, Apt L, Wood M: A controlled trial of povidone-iodine as prophylaxis against ophthalmic neonatorum. N Engl J Med 332:562, 1995

12. Laga M, Naamara W, Brunham RC et al: Single-dose therapy of gonococcal ophthalmia neonatorum with ceftriaxone. N Engl J Med 315:1382, 1986

13. Bailey RL, Arullendran P, Whittle HC, Mabey DC: Randomized controlled trial of single-dose azithromycin in treatment of trachoma. Lancet 342:453, 1993

14. Fiumara N: Personal communication, October 1978

15. Centers for Disease Control and Prevention: Sexually transmitted disease treatment guidelines. MMWR 42(suppl RR-14):47, 1993

16. Baum JL: Current concepts in ophthalmology: Ocular infections. N Engl J Med 299:28, 1978

17. Baum JL: Initial therapy of suspected microbial ulcers: I. Broad antibiotic therapy based on prevalence of organisms. Surv Ophthalmol 24:97, 1979

18. Jones DB: Initial therapy of suspected microbial ulcers: II. Specific antibiotic therapy based on corneal smears. Surv Ophthalmol 24:105, 1979

19. Osato MS, Jensen HG, Trousdale MD et al: The comparative in vitro activity of ofloxacin and selected ophthalmic antimicrobial agents against ocular bacterial isolates. Am J Ophthalmol 108:380, 1989

20. Bower KS, Kowalski RP, Gordon YJ: Fluoroquinolones in the treatment of bacterial keratitis. Am J Ophthalmol 121:712, 1996

21. Leibowitz HM: Clinical evaluation of ciprofloxacin 0.3% ophthalmic solution for the treatment of bacterial keratitis. Am J Ophthalmol 112:345, 1991

22. Parks DJ, Abrams DA, Sarfarazin FA: Comparison of topical ciprofloxacin to conventional antibiotic therapy in the treatment of ulcerative keratitis. Am J Ophthalmol 115:471, 1993

23. O'Brien TP, Maguire MG, Fink NE et al: Efficacy of ofloxacin vs cefazolin and tobramycin in the therapy of bacterial keratitis. Arch Ophthalmol 113:1257, 1995

24. Kowal VO, Meade MD: Community acquired corneal ulcers: The impact of cultures on management. Invest Ophthalmol Vis Sci 33:1210, 1992

25. McLeod SD, Kolahdouz-Isfahani A, Rostamian K et al: The role of smears, cultures and antibiotic sensitivity testing in the management of suspected infectious keratitis. Ophthalmology 103:23, 1996

26. McDonnell PJ: Empirical or culture-guided therapy for microbial keratitis?: A plea for data. Arch Ophthalmol 114:84, 1996

27. Baum JL: Therapy for ocular bacterial infection. Trans Ophthalmol Soc UK 105:69, 1986

28. Barza M: Antibacterial agents in the treatment of ocular infections. Infect Dis Clin N Am 3:533, 1989

29. Glasser DB, Baum J: Medical management in bacterial keratitis. In Stenson S (ed): Surgical Management of External Diseases of the Eye, p 107. New York, Igagu-Shoin Medical Publishers, 1995

30. Barza M, Baum J: Ocular pharmacology of antibiotics. In Duane TD, Jaeger EA (eds): Biomedical Foundations of Ophthalmology, Vol 2, Chap 61. Philadelphia, Harper & Row, 1987

31. Barza M, Ernst C, Baum J, Weinstein L: Effect of lidocaine on the antibacterial activity of 7 antibiotics. Arch Ophthalmol 92:514, 1974

32. Jones DB: A plan for the antimicrobial therapy in bacterial keratitis. Trans Am Acad Ophthalmol Otolaryngol 79:95, 1973

33. Osborn E, Baum JL, Ernst C, Koch P: The stability of 10 antibiotics in artificial tears. Am J Ophthalmol 82:775, 1976

34. Jones DB, Robinson NM: Anaerobic ocular infections. Trans Am Acad Ophthalmol Otolaryngol 83:309, 1977

35. Forster RK: Endophthalmitis: Diagnostic cultures and visual results. Arch Ophthalmol 92:387, 1974

36. Forster RK, Abbott RL, Gelender H: Management of infectious endophthalmitis. Ophthalmology 87:313, 1980

37. Driebe WT, Mandelbaum S, Forster RK et al: Pseudophakic endophthalmitis: Diagnosis and management. Ophthalmology 93:442, 1986

38. Baum JL: Antibiotic administration in the treatment of bacterial endophthalmitis. Surv Ophthalmol 21:332, 1977

39. Peyman GA: Antibiotic administration in the treatment of bacterial endophthalmitis: II. Intravitreal injections. Surv Ophthalmol 21:332, 1977

40. Paven PR, Brinser JH: Exogenous bacterial endophthalmitis without systemic antibiotic. Am J Ophthalmol 104:121, 1987

41. Endophthalmitis Vitrectomy Study Group: Results of the Endophthalmitis Vitrectomy Study: A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol 113:1479, 1995

42. Han DP, Wisniewski SR, Wilson LA et al: Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol 122:1, 1996

43. Campochiaro PA, Lim JI: The Aminoglycoside Toxicity Study Group: Aminoglycoside toxicity in the treatment of endophthalmitis. Arch Opthalmol 112:48, 1994

44. D'Amico DJ, Caspers-Velu L, Libert J et al: Comparative toxicity of intravitreal aminoglycoside antibiotics. Am J Ophthalmol 100:264, 1985

45. Lim JI, Anderson CT, Hutchinson A et al: The role of gravity in gentamicin-induced toxic effects in a rabbit model. Arch Ophthalmol 112:1363, 1994

46. Campochiaro PA, Green WR: Toxicity of intravitreous ceftazidime in primate retina. Arch Ophthalmol 110:1625, 1992

47. Irvine WD, Flynn HW Jr, Miller D, Pflugfelder SC: Endophthalmitis caused by gram-negative organisms. Arch Ophthalmol 110:1450, 1992

48. Jay WM, Fishman P, Aziz M et al: Intravitreal ceftazidime in a rabbit model: Dose and time-dependent toxicity and pharmacokinetic analysis. J Ocul Pharmacol 1:257, 1987

49. Lim JI, Campochiaro PA: Successful treatment of gram-negative endophthalmitis with intravitreous ceftazidime. Arch Ophthalmol 110:1686, 1992

50. Aaberg TM Jr, Flynn HW Jr, Murray TG: Intraocular ceftazidime as an alternative to the aminoglycosides in the treatment of endophthalmitis. Arch Ophthalmol 112:18, 1994

51. Smith MA, Sorenson JA, Lowy FD et al: Treatment of experimental methicillin-resistant Staphylococcal epidermidis endophthalmitis with intravitreal vancomycin. Ophthalmology 93:1328, 1986

52. Pflugfelder SC, Hernandez E, Fliesler SJ et al: Intravitreal vancomycin: Retinal toxicity, clearance and interaction with gentamicin. Arch Ophthalmol 105:831, 1987

53. Davis JL, Koidou-Tsiligianni A, Pflugfelder SC et al: Coagulase-negative staphylococcal endophthalmitis: Increase in antimicrobial resistance. Ophthalmology 95:1404, 1988

54. Flynn HW Jr, Pulido JS, Pflugfelder SC et al: Endophthalmitis therapy: Changing antibiotic sensitivity patterns and current therapeutic recommendations. Arch Ophthalmol 109:175, 1991

55. Meisler DM, Palestine AG, Vastine DW et al: Chronic Propionibacterium endophthalmitis of the extracapsular cataract extraction and intraocular lens implantation. Am J Ophthalmol 102:733, 1986

56. Zambrano W, Flynn HW Jr, Pflugfelder R et al: Management options for Propionibacterium acnes endophthalmitis. Ophthalmology 96:1100, 1989

57. Oum BS, D'Amico DJ, Wong KW: Intravitreal antibiotic therapy with vancomycin and aminoglycoside: An experimental study of combination and repetitive infections. Arch Ophthalmol 107:1055, 1989

58. Stern GA: Factors affecting the efficacy of antibiotics in the treatment of experimental postoperative endophthalmitis. Trans Am Ophthalmol Soc 91:775, 1993

59. Baum JL: The treatment of bacterial endophthalmitis. Ophthalmology 85:350, 1978

60. Mandelbaum S, Forster RK: Exogenous endophthalmitis. In Pepose JS, Holland GN, Wilhelmus (eds): Ocular Infection and Immunity. St. Louis, Mosby, 1996

61. Maurice D: Iontophoresis of fluorescein into the posterior segment. Ophthalmology 93:128, 1986

62. Barza M, Peckman C, Baum J: Transscleral iontophoresis of cefazolin, ticarcillin and gentamicin in the rabbit. Ophthalmology 93:133, 1986

63. Goodner E, Okumoto M: Intraocular listeriosis. Am J Ophthalmol 64:682, 1967

64. Neu HC: New Antibacterial Strategies. New York, Churchill Livingstone, 1993

65. Handbook of antibacterial therapy. Med Lett, 1994

66. Greenwood D: Antimicrobial Chemotherapy, 3rd ed. Philadelphia, WB Saunders, 1995

67. Mann J: Bacteria and Antibacterial Agents. New York, WH Freeman, 1995

68. Williams RAD: Antimicrobial Drug Action. Herndon, VA, BIOS Scientific, 1996

69. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996

70. Wolfson JS, Hooper DC: The fluoroquinolones: Pharmacology: Clinical uses and toxicity in humans. Antimicrob Agents Chemother 28:716, 1985

71. Starr MB, Lully JM: Antimicrobial prophylaxis for ophthalmic surgery. Surv Ophthalmol 39:485, 1995

72. Speaker MG, Milch FA, Shah MK et al: Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology 98:639, 1991

73. Allen HF, Mangiaracine AB: Bacterial endophthalmitis after cataract surgery: II. Incidence in 36,000 consecutive operations with special reference to preoperative topical antibiotics. Arch Ophthalmol 91:3, 1974

74. Apt L, Isenberg S, Yoshimuri R, Paez JH: Chemical preparation of the eye in ophthalmic surgery: III. Effects of povidone-iodine on conjunctiva. Arch Ophthalmol 102:728, 1984

75. Isenberg SJ, Apt L, Yoshimuri R, Kwarg S: Chemical preparation of the eye in ophthalmic surgery: IV. Comparison of povidone-iodine on the conjunctiva with prophylactic antibiotics. Arch Ophthalmol 103:1340, 1985

76. Speaker MG, Menikoff JA: Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology 98:1769, 1991

77. Ariyasu RG, Nakamura J, Trousdale MD, Smith RE: Intraoperative bacterial contamination of the aqueous humor. Ophthalmic Surg 24:367, 1993

78. Hodge WG, Bui DP, Cevallos V et al: Frequency of recovery of ciprofloxacin-resistant ocular isolates following topical ciprofloxacin therapy. Invest Ophthalmol Vis Sci 36(suppl): S155, 1995

79. Bompart F: Rhoªne-Poulenc Rorer, Personal communication, 1996

80. Pankuch GA, Lichtenberger C, Jacobs MR, Appelbaum PC: Antipneumococcal activities of RP 59500 (quinipristin-dalfopristin), penicillin G, erythromycin and sparflofloxacin determined by MIC and rapid time-kill methodologies. Antimicrob Agents Chemother 40:1653, 1996

81. Ford CW, Hamel JC, Wilson DM et al: In vitro activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections. Antimicrob Agents Chemother 40:1508, 1996

82. Eliopoulis GM, Wennersten CB, Gold HS, Moellering RC: In vitro activities of new oxazolidinone antimicrobial agents against enterococci. Antimicrob Agents Chemother 40:1745, 1996

83. Nicas TI, Mullen DL, Flokoiwitch JE et al: Semisynthetic glycopeptide antibiotics derived from LY264826 active against vancomycin-resistant enterococci. Antimicrob Agents Chemother 40:2194, 1996

84. Schwalbe RS, McIntosh AC, Qaiyumi S et al: In vitro activity of LY333328, an investigational glycopeptide antibiotic, against enterococci and staphylococci. Antimicrob Agents Chemother 40:2416, 1996

85. Mishima S, Gasset A, Klyce SD Jr, Baum J: Determination of tear volume and tear flow. Invest Ophthalmol 5:264, 1966

86. Mishima S: Pharmacology of ophthalmic solutions. Contact Intraocular Lens Med J 4:22, 1978

87. Baum JL, Barza M, Shushan D, Weinstein L: Concentration of gentamicin in experimental corneal ulcers. Arch Ophthalmol 92:315, 1974

88. Davis SD, Sarff LD, Hyndiuk RA: Antibiotic therapy of experimental Pseudomonas keratitis in guinea pigs. Arch Ophthalmol 95:1638, 1977

89. Adler CA, Maurice DM, Paterson ME: The effect of viscosity of the vehicle on the penetration of fluorescein into the human eye. Exp Eye Res 11:34, 1971

90. Swan KD, White NG: Corneal permeability: I. Factors affecting penetration of drugs into the cornea. Am J Ophthalmol 25:1043, 1942

91. Langham M: Factors affecting the penetration of antibiotics into the aqueous humor. Br J Ophthalmol 35:614, 1951

92. Norn MS: Role of vehicle in local treatment of the eye. Acta Ophthalmol (Copenh) 42:727, 1964

93. Waltman SR, Buerk K, Foster CS: Effects of ophthalmic ointments on intraocular penetration of topical fluorescein in rabbits and man. Am J Ophthalmol 78:2162, 1974

94. Waltman SR, Kaufman HE: Use of hydrophilic contact lenses to increase ocular penetration of topical drugs. Invest Ophthalmol 9:250, 1970

95. Praus R, Krejci L: Release from hydrophilic gel contact lens and intraocular penetration. Ophthalmol Res 9:213, 1977

96. Abel R Jr, Boyle GL, Furman M, Leopold IH: Intraocular penetration of cefazolin sodium in rabbits. Am J Ophthalmol 78:779, 1974

97. Barza M, Baum J: Penetration of ocular compartments by penicillin: Analysis of factors affecting concentration and half life. Surv Ophthalmol 18:71, 1973

98. Litwack KD, Pettet T, Johnson BL Jr, Penetration of gentamicin administered intramuscularly and subconjunctivally into aqueous humor. Arch Ophthalmol 82:687, 1969

99. Barza M, Kane A, Baum JL: Intraocular penetration of gentamicin after subconjunctival and retrobulbar injection. Am J Ophthalmol 85:541, 1978

100. Barza M, Baum JL, Kane A: Regional differences in ocular concentration of gentamicin after subconjunctival and retrobulbar injection in the rabbit. Am J Ophthalmol 83:407, 1977

101. Barza M, Kane A, Baum JL: The excretion of gentamicin in tears of rabbits after subconjunctival injection. Am J Ophthalmol 85:118, 1978

102. Oakley DE, Weeks RD, Ellis PP: Corneal distribution of subconjunctival antibiotics. Am J Ophthalmol 81:307, 1976

103. Barza M, Baum J, Birkley B, Weinstein L: Intraocular penetration of carbenicillin in the rabbit. Am J Ophthalmol 75:307, 1973

104. Golden B, Coppel SP: Ocular tissue absorption of gentamicin. Arch Ophthalmol 84:792, 1970

105. Jay WM, Shockley RK, Aziz et al: Ocular pharmacokinetics of ceftriaxone following subconjunctival injection on rabbits. Arch Ophthalmol 102:430, 1984

106. Rubenstein E, Trieatu G, Avin I: The intravitreal penetration of cefotaxime in man following systemic and subconjunctival administration. Ophthalmology 94:30, 1987

107. Barza M, Lynch E, Baum JL: Pharmacokinetics of newer cephalosporins after subconjunctival and intravitreal injections in rabbits. Arch Ophthalmol 111:121, 1993

108. Barza M, Kane A, Baum J: Pharmacokinetics of intravitreal carbenicillin, cefazolin, and gentamicin in Rhesus monkeys. Invest Ophthalmol Vis Sci 12:1602, 1983

109. Forbes M, Becker B: The transport of organic anions by the rabbit eye: II. In vivo transport of iodopyracet (Diodrast). Am J Ophthalmol 50:867, 1960

110. Leopold IA: Intravitreal penetration of penicillin and penicillin therapy of infections of the vitreous. Arch Ophthalmol 33:211, 1945

111. Axelrod JL, Newton JC, Sarakhun C et al: Ceftriaxone. Arch Ophthalmol 103:71

112. Meredith TA: Antimicrobial pharmacokinetics in endophthalmitis treatment: Studies of ceftazidime. Trans Am Ophthalmol Soc 91:653, 1993

113. Barza M: Treatment of bacterial infections of the eye. In Remington S, Swartz MN (eds): Current Clinical Topics in Infectious Diseases, pp 158–194. New York, McGraw Hill, 1980

114. Martin DF, Ficker LA, Aquilar HA et al: Vitreous cefazolin levels after intravenous injection: Effects of inflammation, repeated antibiotic doses and surgery. Arch Ophthalmol 108:411, 1990

115. Meredith TA, Mandell BA, Aquilar EA et al: Amikacin levels after intravitreal injection: Effects of inflammation and surgery. Invest Ophthalmol Vis Sci 33:747, 1992

116. English J, Gilbert DN, Kohlhepp S et al: Attenuation of experimental tobramycin nephrotoxicity by ticarcillin. Antimicrob Agents Chemother 27:897, 1985

117. Pickering LK, Rutherford I: Effective concentration and time upon inactivation of tobramycin, gentamicin, netilmicin, and amikacin, azlocillin or carbenicillin, mecillinam, mezlocillin and piperacillin. J Pharmacol Exp Ther 217:345, 1981

118. Jay W, Shockley RK, Aziz MA, Rissing JP: Ocular pharmacokinetics of ceftriaxone following subconjunctival injection in rabbits. Arch Ophthalmol 102:430, 1984

119. Maurice DM: Injections of drugs into the vitreous body. In Leopold IH, Burns RP (eds): Symposium on Ocular Therapy, Vol 9, Chap 6. New York, John Wiley & Sons, 1976

120. Hooton TM, Blair AD, Turck M, Counts GW: Synergism at clinically attainable concentrations of aminoglycoside and beta-lactam antibiotics. Antimicrob Agents Chemother 26:535, 1984

121. Adkinson NF Jr, A guide to skin testing for penicillin allergy. Med Times 104:164, 1976

122. Fraunfelder FT, Bagby GC Jr, Kelly DJ: Fatal aplastic anemia following topical administration of ophthalmic chloramphenicol. Am J Ophthalmol 93:356, 1982

123. Fraunfelder FT, Bagby GC Jr, Letter to the Editor: Ocular chloramphenicol and aplastic anemia. N Engl J Med 308:1536, 1983

124. Wolfson JS, Hooper DC: The fluoroquinolones: Structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother 28:581, 1985

125. Eliopoulos GM, Moellering AE, Reisner E, Moellering RC Jr, In vitro activities of the quinolone antimicrobial agents A-51669 and A-56620. Antimicrob Agents Chemother 28:514, 1985

126. Donnenfeld ED, Perry HD, Snyder RW et al: Intracorneal, aqueous and vitreous humor penetration of ofloxacin. Ocular Microbiology Immunology Group Program, October 29, 1994

127. Kowalski RP, Karenchak LM, Gordon YJ: Susceptibility of gram-positive bacteria to quinolone antibiotics using standards based on corneal tissue (abstr). Invest Ophthalmol Vis Sci 37:1424, 1996