1. The use of antibiotics for treatment of ocular infections should be initiated whenever a patient has an infection which is microbial in nature and the organism is susceptible to the antibiotic prescribed
2. The patient’s history and eye examination should be consistent with the diagnosis of microbial infection
3. Ocular specimens for stain, cultures, or molecular diagnosis (e.g., PCR) should be obtained before the initiation of therapy and sent immediately to the laboratory. The etiologic organism causing the infection should be identified
4. In serious infections, treatment may be started empirically before laboratory results are obtained
5. The selection of the antibiotic should be based on the susceptibility of the organisms, adverse effects, penetration into the affected tissue, and cost
6. Discrepancies between the results of the laboratory sensitivity tests and the patient clinical response should be carefully evaluated
7. Adverse effects from the use of the antibiotic (allergic or toxic) should be taken into account in the selection and administration of antibiotic agents’ autotoxicity, nephrotoxicity, or hepatotoxicity. The antibiotic should be discontinued if an allergic or serious adverse reaction occurs after its use
8. Blood level monitoring of systemic antibiotics should be assessed whenever indicated
9. Duration of therapy is dependent on the nature of the infection and site of the infection but should not be less than 1 week
10. The route of antibiotics should be given at a dosage level that will allow penetration of the antibiotic into the desirable infected site within the safe margin and for the shortest period of time to eradicate the offending agent
11. The possibility of a superinfection should always be kept in mind when antibiotics are used for a prolonged period of time
12. The use of antibiotic combinations should be avoided unless the organism has not been cultured and the findings are highly suggestive of infectious etiology
13. Antibiotic prophylaxis in surgery should be used very carefully; the antibiotic used should cover both Gram-negative and Gram-positive organisms and be started just before surgery and discontinued immediately following surgery
14. Long-term use of antibiotics should be avoided
The dramatic decrease in the incidence of classic infectious diseases is due largely to, first, mass vaccination, which has eradicated certain infectious disease such as smallpox; second, the implementation of rigorous public health measures by many countries; and, third, the introduction of newly discovered antimicrobial agents. In the first decade of the twenty-first century, infectious diseases continue to be a serious cause of visual loss, mortality, and morbidity. We should not rest on the laurels we have won for overcoming the classic infections, but we should, rather, prepare ourselves to confront the microorganisms emerging from the degradation of our ecosystem as well as those bacteria that are becoming increasingly antibiotic resistant. Several new infectious agents have been recently identified as a cause of disease in man (Table 2.2).
Table 2.2
Newly discovered microbial pathogens
Disease | Cause |
|---|---|
Cat scratch disease | Bartonella henselae |
Pneumonia | Hanta virus |
Kaposi’s sarcoma | Human herpes simplex virus type 6 |
Autoimmune deficiency syndrome (AIDS) | Human immunodeficiency virus type 1 and type 2 |
T cell lymphoma | Human T cell lymphoma virus |
Lyme disease | Borrelia burgdorferi |
Whipple’s disease | Treponema whippelii |
Severe acute respiratory syndrome (SARS) | Corona virus |
Middle East Respiratory Syndrome (MERS) | Corona virus |
Avian influenza | H5N1 virus |
Chemicals were used as early as the seventeenth century to treat infectious disease. Quinine was used for malaria, and emetine was used for amebiasis. Antibiotics, however, can cause harm as well as good. Erlich, in 1900 in Germany, introduced the concept of selective toxicity of chemicals, showing that it is possible to use an antibiotic that is toxic to the microorganism but does not harm the host. In 1929, Fleming recorded his observation that agar plates in his laboratory contaminated with Penicillium spp. were free of other bacteria such as staphylococci and went to discover penicillin. In 1935 in Germany, Domagk described sulfonamide, not only winning the Nobel Prize in 1939 but also launching a new era of antimicrobial agents. It was not until 1940, however, when Chain and Florey used penicillin in the treatment of Streptococcus pneumoniae infections, and that was the turning point in the management of infectious diseases.
Streptomycin was described in the late 1940s; tetracyclines were launched in the early 1950s, followed by chloramphenicol and later followed by lincomycin in the 1960s. Lincomycin was described from the systematic analysis of soil samples in Lincoln, Nebraska, in the United States and was named after the state’s capital city, Lincoln. It was produced by a strain of Streptomyces lincolnensis. After this discovery, extensive soil sampling was conducted worldwide to isolate and identify antibiotic-producing organisms.
There are so many different types and generations of antibiotics. It is important, therefore, to identify those which are useful in ophthalmology and those that are not. It is of paramount importance to select the right antibiotic to treat ocular infection; fundamental to this is the identification of the organism responsible for the infection.
The initial selection of antibiotics for the treatment of ocular infections is based on the most frequently encountered organism, pharmacokinetics of the antibiotic, dosage, and cost.
The great stumbling blocks to safe and effective antibiotic therapy are resistance and toxicity, two factors which must always be taken into account when choosing an antibiotic. Cost is another factor and one that is often overlooked. It is important to be aware of the fact that some antibiotics are expensive. There have been instances of patients receiving very expensive therapy when in fact the organism responsible for their infection was sensitive to much cheaper antibiotics. The combination of antibiotic agents may be used simultaneously in the following conditions:
(a)
In a severe devastating vision-threatening ocular infection of unknown etiology and after lab tests have been initiated to determine a specific etiologic agent
(b)
If an infection is caused by more than one organism
(c)
The emergence of resistant strains of bacteria during the treatment
(d)
In case of infections caused by organisms that are known to respond better to simultaneous use of more than one antibiotic such as Toxoplasma and Acanthamoeba
(e)
Organisms not cultured and the clinical findings are highly suggestive of infectious etiology
2.2 Mechanism of Action
Although antibiotics can be described as being either bacteriostatic or bactericidal, this is a less useful classification than the one which is based on the drug mechanism of action, namely, how and where they affect the target organism. Under this system of classification, the first group of antibiotics inhibits synthesis of the cell wall, the second group inhibits the cell membrane, the third group affects ribosomal function and protein synthesis, and the fourth group affects nucleic acid synthesis.
Topical antimicrobial agents used in ocular infections are listed in Table 2.3. The antimicrobial agents that can be compounded for the treatment of ocular infections for topical, subconjunctival, intravitreal, and intravenous are summarized in Table 2.4. Antibiotics that are used for bacterial (Table 2.5), fungal (Table 2.6), viral infections (Table 2.7) are also listed.
Table 2.3
Commercially available topical ophthalmic antibacterial agents
Generic name | Trade name | Concentration | |
|---|---|---|---|
Ophthalmic solution | Ophthalmic ointment | ||
Individual agents | |||
Bacitrin | Not available | 500 units/g | |
Besifloxacin | Besivance | 0.6 % | Not available |
Ciprofloxacin hydrochloride | Ciloxan | 0.3 % | 0.3 % |
Erythromycin | Not available | 0.5 % | |
Gatifloxacin | Zymar, Tymer | 0.3 % | Not available |
Gentamicin sulfate | Genoptic, Garamycin | 0.3 % | 0.3 % |
Lomefloxacin | Okacin | ||
Levofloxacin | Iquix | 1.5 % | Not available |
Quixin | 0.5 % | Not available | |
Moxifloxacin | Vigamox | 0.5 % | Not available |
Ofloxacin | Oflox, Optiflox | 0.3 % | Not available |
Sulfacetamide | Bleph-10 | 10 % | Not available |
Sulf-10 (15 mL) or preservative-free | 10 % | Not available | |
Generic | 10 % | 10 % | |
Tobramycin sulfate | Tobrex | 0.3 % | 0.3 % |
Generic | 0.3 % | Not available | |
Tosufloxacin | Ozex | 0.3 % | Not available |
Mixtures | |||
Chloramphenicol eyedrops and ointment | Generic | 0.5 % | |
Polymyxin B/bacitracin zinc | AK-Poly-Bac | Not available | 10,000 units – 500 units/g |
Polysporin | |||
Polycin-B | |||
Generic | |||
Polymyxin B/neomycin/bacitracin | Neosporin | Not available | 10,000 units – 3.5 mg – 400 units/g |
Generic | |||
Polymyxin B/neomycin/gramicidin | Neosporin | 10,000 units – 1.75 mg – 0.025 mg/mL | Not available |
Generic | |||
Polymyxin B/trimethoprim | Polytrim | 10,000 units – 1 mg/mL | Not available |
Generic | |||
Table 2.4
Compounding of major antibiotics for the treatment of ocular infections
Route of administration | ||||
|---|---|---|---|---|
Drug namea | Topical | Subconjunctival | Intravitreal | Intravenousb |
Amikacin sulfate | 10 mg/mL | 25 mg | 400 μgm | 15 mg/kg daily in 2–3 doses |
Ampicillin sodium | 50 mg/mL | 50–150 mg | 5 mg | 4–12 g daily in 4 doses |
Bacitracin zinc | 10,000 units/mL | 5,000 units | – | – |
Cefazolin sodium | 50 mg/mL | 100 mg | 2,250 μgm | 2–4 g daily in 3–4 doses |
Ceftazidime | 50 mg/mL | 100 mg | 2,000 μgm | 1 g daily in 2–3 doses |
Ceftriaxone | 50 mg/mL | – | – | 1–4 g daily in 1–2 doses |
Clindamycin | 50 mg/mL | 15–50 mg | 1,000 μgm | 900–1,800 mg daily in 2–3 doses |
Colistimethate sodium | 10 mg/mL | 15–25 mg | 100 μgm | 2.5–5 mg/kg daily in 2–4 doses |
Erythromycin | 50 mg/ml | 100 mg | 500 μgm | – |
Gentamicin sulfate | 8–15 mg/ml | 10–20 mg | 100–200 μgm | 3–5 mg/kg daily in 2–3 doses |
Imipenem/cilastatin sodium | 5 mg/ml | – | – | 2 g daily in 3–4 doses |
Kanamycin sulfate | 30–50 mg/ml | 30 mg | 500 mg | – |
Neomycin sulfate | 5–8 mg/ml | 125–250 mg | – | – |
Penicillin G | 100,000 units/mL | 0.5–1.0 million units | 300 units | 12–24 million units daily in 4–6 doses |
Piperacillin | 12.5 mg/mL | 100 mg | – | – |
Polymyxin B sulfate | 10,000 units/mL | 100,000 units | – | – |
Ticarcillin disodium | 6 mg/mL | 100 mg | – | 200–300 mg/kg daily 3 × in 4–6 doses |
Tobramycin sulfate | 8–15 mg/mL | 10–20 mg | 100–200 μgm | 3–5 mg/kg daily in 2–3 doses |
Vancomycin hydrochloridec | 20–25 mg/mL | 25 mg | 1,000 μgm | 15–30 mg/kg daily in 1–2 doses |
Table 2.5
Bacterial keratitis therapy (initial therapy for bacterial keratitis)
Organism | Antibiotic | Topical dose | Subconjunctival dose |
|---|---|---|---|
Gram(+) cocci | Cefazolin | 50 mg/mL | 100 mg in 0.5 mL |
Vancomycina | 50 mg/mL | 25 mg in 0.5 ML | |
Gram(−) rods | Tobramycin | 9–14 mg/mL | 20 mg in 0.5 mL |
Ceftazidime | 50 mg/mL | 100 mg in 0.5 mL | |
Fluoroquinolones | 3 mg/mL | Not available | |
No organism or multiple types of organisms | Cefazolin | 50 mg/mL | 100 mg in 0.5 mL |
with | |||
Tobramycin | 9–14 mg/mL | 20 mg in 0.5 mL | |
or | |||
Fluoroquinolones | 3 mg/mL | Not available | |
Gram(−) cocci | Ceftriaxone | 50 mg/mL | 100 mg in 0.5 mL |
Ceftazidime | 50 mg/mL | ||
Mycobacteria | Amikacin | 20 mg/mL | 20 mg in 0.5 mL |
Azithromycin | 1.5 mg/ml (0.15 %) |
Table 2.6
Antimicrobial agents for fungal keratitis
Generic (trade) name | Route | Dosage |
|---|---|---|
Amphotericin B (Fungizone) | Topical | 0.1–0.5 % solution (most commonly 0.15 %); dilute with water for injection or dextrose 5 % in water |
Subconj. | 0.8–1.0 mg | |
Intravitreal | 5 mcg | |
Intravenous | * | |
Liposomal amphotericin B | ||
Fluconazole (Diflucan) | Oral | 200 mg on day 1, then 100 mg daily in divided doses |
400 mg on day 1, then 200 mg daily in divided doses | ||
Intravenous | 200–400 mg IV daily* | |
Flucytosine (Ancobon) | Oral | 50–150 mg/kg daily 4 divided doses* |
Itraconazole (Sporanox) | Oral | 200–400 mg/kg daily* |
Intravenous | 200 mg IV twice a day for 4 doses, then 200 mg IV daily for 14 days* | |
Ketoconazole (Nizoral) | Oral | 200–400 mg daily* |
Natamycin (Natacyn) | Topical | 5 % suspension |
Voriconazole (Vfend) | Oral | 200 mg twice a day |
Intravenous | 3–6 mg/kg every 12 h* | |
Intracorneal | 25 μgm | |
Topical | 1 % eyedrops | |
Table 2.7
Antimicrobial agents for viral ocular infections
Generic (trade) name | Topical conc. | Intravit. dose | Systemic dosage |
|---|---|---|---|
Trifluridine (Viroptic®) | 1.0 % | – | – |
Acyclovir sodium | – | 24,000 μgm | Oral – herpes simplex keratitis: 200 mg 5 times daily for 7–10 days |
Oral – herpes zoster ophthalmicus: 600–800 mg 5 times daily for 10 days; IV therapy | |||
Cidofovir (Vistide®) | – | – | IV – induction: 5 mg/kg constant infusion over 1 h administered once weekly for 2 consecutive weeks |
Maintenance: 5 mg/kg constant infusion over 1 h administered once every 2 weeks | |||
Famciclovir (Famvir®) | – | – | Oral – herpes zoster ophthalmicus 500 mg 3 times daily for 7 days |
Fomivirsen (Vitravene®) | – | 330 μgm | Every other week for 4 doses, then every 4 weeks. Contains 6.6 mg/mL, in a 0.25-ml vial |
Foscarnet sodium (Foscavir®) | – | 1 mg | IV – by controlled infusion only, either by central vein or by peripheral vein induction: 60 mg/kg (adjusted for renal function) given over 1 h every 8 h for 14–21 days |
Maintenance: 90–120 mg/kg given over 2 h once daily | |||
Ganciclovir (gel) (Zirgan®, Virgan) | 0.15 % | ||
Ganciclovir sodium (Cytovene®) | – | 0.2 mg | IV – induction: 5 mg/kg every 12 h for 14–21 days |
Maintenance: 5 mg/kg daily for 7 days or 6 mg once daily for 5 days/week | |||
Oral – after IV induction: 1,000 mg 3 times daily with food or 500 mg 6 times daily every 3 h | |||
Ganciclovir sodium (Vitrasert®)a | – | 4.5 mg | |
Valacyclovir (Valtrex®) | – | – | Oral – herpes zoster ophthalmicus: 1 g 3 times daily for 7 days |
Herpes simplex virus (types 1 & II): 1 g 2 times daily |
2.3 Antibiotics That Inhibit Cell Wall Synthesis
Several antibiotics affect the cell wall of organisms including penicillins, cephalosporins, gramicidin, and bacitracin [6–17]. Bacterial survival can be compromised without a cell wall. The cell wall protects bacteria from the environmental noxious agents and maintains the intracellular milieu. The thickness of bacterial cell walls varies: Gram-positive bacteria have thick cell walls, and Gram-negative bacteria have thin cell walls. The internal osmotic pressure of Gram-positive organisms is higher than that in Gram-negative organisms. A Gram-positive organism, in particular, is under considerable risk of death when the cell wall is compromised.
Bacterial cell wall contains peptidoglycans and ligands of alternating pyranoside residues of two amino sugars, N-acetylglucosamine and N-acetylmuramic acid (the latter is not found in mammalian cells), and is cross-linked by pentapeptide chains. Pentapeptide cross-linking gives the cell wall its rigidity; consequently, the introduction of antimicrobial agents or antibiotics that interfere with cross-linking causes the cell wall to weaken and the organism to die.
Unlike bacteria, mammalian cells do not have cell walls a selective target and an example of selective toxicity.
2.3.1 Penicillins
Penicillins are beta-lactam antibiotics. There are four generations of penicillins. The first three are important in the treatment of ocular infections. The first-generation penicillins are penicillin G and penicillinase-resistant penicillins, of which there are two types, methicillin and nafcillin. Methicillin was used to treat beta-lactamase-producing organisms. Methicillin can cause interstitial nephritis and is no longer used in most centers. The penicillins are used specifically to treat ocular infections caused by Streptococcus, Neisseria, Clostridium spp., syphilis, and Actinomyces.
The second-generation penicillins include ampicillin and amoxicillin. These antibiotics have a slightly broader spectrum than those of the first generation. The second-generation penicillins are used to treat ocular infections caused by Haemophilus species and enterococci.
The third-generation penicillins are carbenicillin and ticarcillin. Ticarcillin has been combined with clavulanic acid as a suicide inhibitor of beta-lactamase. These antibiotics occupy receptor sites on Gram-negative bacteria making them more active against Gram-negative bacteria. Until recently, carbenicillin was used to treat Pseudomonas infections. Ticarcillin has replaced carbenicillin and may be used in combination with aminoglycosides. The fourth group of penicillins comprises of mezlocillin, piperacillin and azlocillin which are derivatives of ampicillin and are similar to carbenicillin and ticarcillin. These antibiotics are also effective against Gram-negative organisms because they have a greater affinity to cell wall receptor sites in Gram-negative organisms than in Gram-positive organisms. The fourth-generation penicillins have limited role in ophthalmology. New generations of antibiotics are not necessarily better or more effective than earlier generations. Each generation of antibiotics plays a specific role and has specific indication and advantages in the treatment of infections caused by susceptible organisms.
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