Antibiotics in ophthalmology

use of antibiotics in ocular disorders ,

1. ANTIBIOTICS IN OPHTHALMOLOGY Dr.M.Sudheer kumar

2. The term “antibiotic” is refer to drugs,,, natural or synthetic, used to treat bacterial infections. Selective toxicity of anti microbial agent ,which is harmful only to bacteria, and not to host is because of the presence of a specific receptor in the bacteria or different metabolic pathway that is not present in host.

3. Depending on mode of action , they divided into 5 groups. 1)Anti biotics acting by inhibition of cell wall synthesis.. eg ; penicillins cephalosporins bacitracin vancomycin 2)Alteration in the permeability of cell membrane eg ; amphotericin b colistin nystatin polymixin

4. 3)Inhibition of protein synthesis eg ; chlormphenicol erythromycin tetracyclin streptomycin 4)Inhibition of nucleic acid synthesis.. eg ; rifampicin pyrimrthamine novobiocin nalidixic acid

5. 5)interference with bacterial metabolism…. eg ; sulfonamide trimethoprim aminosalicylic acid

6. Based on antibacterial activity…. Bactericidal Bacteriostatic Penicillins Chloramphenicol Cephalosporin Erythromycin Vancomycin Clindamycin Gentamicin Sulfonamides Based on spectrum of activity - broad spectrum - narrow spectrum

7. BETA LACTAM ANTIBIOTICS The first beta lactam antibiotic, penicillin, was discovered by Sir Alexander Fleming in 1928. Bactericidal in nature. Resistance ,mechanism is associated with enzymatic hydrolysis of the beta lactam ring by the bacterial enzymes, beta lactamases or penicillinases

8. This mechanism of beta lactam resistance is very common in Gram-negative bacteria such as E. coli , Klebsiella species, Proteus species, Pseudomonas aeruginosa . These are having beta lactam ring. Eg ; penicillins cephalosporins carbapenem monobactam

9. penicillins

10. Antibacterial Activity Natural Penicillins The natural penicillins are narrow spectrum antibiotics primarily effective against Grampositive and a few Gram-negative bacteria. The spectrum of antibacterial activity of penicillin includes: ƒƒ - Gram-positive cocci ( Staphylococcus species and Streptococcus species)

11. ƒ -ƒ Gram-negative cocci Neisseria gonorrhoeae , Neisseria meningitidis -ƒƒ Gram-positive bacilli Bacillus anthracis , Corynebacterium diphtheriae , Clostridium tetani ƒƒ Listeria species ƒƒ Spirochetes Treponema pallidum , Leptospira

12. Majority of Gram-negative bacilli are insensitive to natural penicillins . most strains of S. aureus and N. gonorrhoeae are resistant to penicilli Penicillins penetrate well into all parts of the ocular tissue such as the lid margins, conjunctival sacs, corneae and lacrimal sacs but not the ocular muscles.

13. Aminopenicillins .. They have enhanced ability to penetrate Gramnegative organisms thus they have greater activity against, -ƒƒ Enterobacteriaceae (E. coli, Shigella species , Salmonella spp., Proteus mirabilis) ƒƒ- Haemophilus influenzae ƒƒ- Helicobacter pylor . Antipseudomonal Penicillins They active against Pseudomonas aeruginosa and other Gram-negative bacteria such as Enterobacter species , Klebsiella species , but they have no Gram-positive activity

14. Currentlymost strains of Pseudomonas aeruginosa produce different types of beta lactamase . As such antipseudomonal penicillins are generally used in combination with beta lactamase inhibitors for the treatment of pseudomonal infections . Beta Lactamase Inhibitors … clavulanic acid, sulbactam tazobactam . -These drugs are not antibiotics.

15.  The combination of clavulanic acid and ticarcillin is known as timentin . Given parenterally . The combination increases the spectrum of activity of ticarcillin to include,, Gramnegative aerobic organisms, Staphylococcus aureus Bacteroides  Clavulanic acid is also combined with amoxicillin, and the combination is known as augmentin . given orally

16. Effectively treats infection by beta lactamase producing organisms that include Haemophilus influenzae Staphylococcus species Escherichia coli Neisseria gonorrhea . Administration … Besides oral and parenteral routes, penicillins can be administered by -topical, - subconjunctival - intravitreal routes for the treatment of ophthalmic infections

17. Therapeutic Uses Penicillins are useful in the treatment of many acute ophthalmic bacterial infections and are suited for surface application in the form of drops. can be used for subconjunctival injections as well intravenous or intramuscular injections. Organisms commonly found in ocular infections, which are susceptible to the action of penicillin are Staphylococcus pyogenes , the hemolytic Streptococcus , the Gonococcus and the Pneumococcus .

18. Types of Ocular Infection Suitable for Treatment by Penicillins ….. Acute conjunctivitis, blepharitis and canaliculitis .  Penicillin G potassium ophthalmic solution has been used, however, currently not a favored choice in clinical practice due to its narrow spectrum and instability. Chronic blepharitis due to S. aureus .  Oxacillin subconjunctival injections Keratitis and corneal ulcers caused by S. aureus .  Oxacillin subconjunctival injections

19. Canaliculitis … blepharitis

20. Treatment of blepharitis Lid hygiene can be carried out once or twice daily initially by… - A warm compress should frst be applied for several minutes to soften crusts at the bases of the lashes. - Lid cleaning is subsequently performed to mechanically remove crusts and other debris, scrubbing the lid margins with a cotton bud or clean facecloth dipped in a warm dilute solution of baby shampoo or sodium bicarbonate.

21. Antibiotics ○ Topical sodium fusidic acid, erythromycin, bacitracin , azithromycin or chloramphenicol is used to treat active folliculitis . Oral antibiotic regimens include doxycycline (50–100 mg twice daily for 1 week and then daily for 6–24 weeks) .

22. Gonococcal conjunctivitis and gonococcal corneal ulcer Ocular syphilis. Acquired syphilis with ocular involvement should be treated as neurosyphilis with intravenous penicillinG . The dose is 18–24 million units (MU) daily for 10 to 14 days, followed by procaine penicillin, intramuscular, 2.4 MU weekly for three weeks

23. Adverse Effects Penicillins are among the least toxic drugs known. The most common side-effect of penicillins is diarrhea . Nausea, vomiting, and epigastric discomfort are also common. Penicillins can cause immediate and delayed allergic reactions - specifcally , skin rashes, fever, and anaphylactic shock.

24. CEPHALOSPORINS The cephalosporins are beta lactam antibiotics cephalosporins more resistant to penicillinase compared to penicillins These drugs were frst obtained from Cephalosporium acremonium , a fungus. The cephalosporins structures have now been modified to include various substitutions of their side chains (R1 and R2) and have proliferated to four “generations ”.

25. In general Gram positive activity decreases from frst generation to the fourth and Gram negative activity increases in a reverse order. Stability to beta lactamase also increases from the frst to fourth generations. Pharmacokinetics Besides oral and pareteral administration, cephalosporins can be administered by topical, subconjunctival and intravitreal route for the treatment of ophthalmic infections. The formulations of cefazolin sodium, ceftazidime and ceftriaxone available for ophthalmic use. These drugs are widely distributed to most body tissues fluids including aqueous humor .

26. Overall, cephalosporins do not undergo metabolism and are excreted unchanged by glomerular filtration and tubular secretion in urine Cefoperazone and ceftriaxone undergo billiary secretion, which makes them both, the choice in patients with renal impairment.

27. Therapeutic Uses Types of Ocular Infection Suitable for Treatment by Cephalosporins Acute conjunctivitis and blepharitis caused by Gram-positive flora ( S. aureus , Streptococcus species): Topical frst generation cephalosporins ( cefazolin ) Gonococcal conjunctivitis and gonococcal corneal ulceration: Basic third generation cephalosporins ( ceftriaxone , cefotaxime ) intramuscularly or intravenously.

28. Bacterial keratitis and corneal ulceration due to Gram-positive flora : First generation cephalosporins ( cefazolin ) by subconjunctival injections Pseudomonal keratitis and corneal ulceration: Third and fourth generation cephalosporins with antipseudomonal activity ( ceftazidime , cefipime ), subconjunctival injections or systemic injection in case of corneal perforation . Pesudomonal keratitis

29. Dacryocystitis and dacryoadenitis : Second and third generation cephalosporins intravenously . Bacterial endophthalmitis : Usually combination therapy of ceftazidime and vancomycin intravitreal . Pre-operative prophylaxis of post-operative endophthalmitis : Second generation cephalosporins ( cefuroxime ) intracameral injection.

30. Treatment of endophthalmitis Intravitreal antibiotics are the key to management because levels above the minimum inhibitory concentration of most pathogens are achieved, and are maintained for days. Antibiotics commonly used in combination are ceftazidime , which will kill most Gram-negative organisms (including Pseudomonas aeruginosa ) and vancomycin to address Gram-positive cocci (including methicillin -resistant Staphylococcus aureus ) . ceftazidime 2 mg in 0.1 ml vancomycin 2 mg in 0.1 ml;

31. CARBAPENEMS This class of beta lactam antibiotics include,,, imipinem / cilastatin , meropenem , etarpenem , doripenem , panipenem , biapenem , razupenem are derived from thienamycin , naturally obtained from Streptomyces cattleya .

32. The antibacterial activity of the carbepenems includes both, Gram-positive and Gram-negative organisms such as Streptococcus, Staphylococcus, Listeria , Pseudomonas andAcinetobacter . They are also effective against anaerobes, including Clostridium diffcile and Bacteroides fragillis Pharmacokinetics … - Carbapenems are administered intravenously and are not absorbed orally - They penetrate well into aqueous humor and vitreous

33. Adverse Effects Imipenem causes thrombophlebitis on intravenous administration. It can also cause nausea and vomiting. Some metabolites of imipenem are neurotoxic with effects such as tremor, seizure and confusional state,

34. Therapeutic Uses Carbapenems are administred intravenously and are used in the treatment of severe ocular infections such as bacterial endophthalmitis . They are also may be used as pre-operative prophylaxis of post-operative endophthalmitis and in the treatment of orbital cellulitis .

35. Treatment of orbital cellulitis Hospital admission is mandatory, with urgent otolaryngological assessment and frequent ophthalmic review. Antibiotics are given intravenously, with the specifc drug depending on local sensitivities; - ceftazidime is a typical choice, supplemented by oral metronidazole to cover anaerobes. Intravenous antibiotics should be continued until the patient has been apyrexial for 4 days,followed by 1–3 weeks of oral treatment.

36. MONOBACTAMS Mechanism of action is similar to other beta lactams . It is beta lactamase resistant and is highly effective against most Gram-negative aerobes, including Pseudomonas aeruginosa , Escherichia coli, Klebsiella , and Enterobacter . The clinical uses of aztreonam include severe ocular infections such as bacterial endophthalmitis caused by Gram- nagative bacteria including Pseudomonas aeruginosa resistant to other beta lactam antibiotics .

37. NON BETA LACTAM ANTIBIOTICS Chloramphenicol …. Chloramphenicol’s spectrum of activity covers the majority of ocular pathogens. In a study of 738 patients with acute bacterial infections of the external eye, there was an overall resistance rate of only 6% to chloramphenicol , compared to 9% with tetracycline and around 20% to the aminoglycosides tested .

38. Mechanism of Action … Chloramphenicol is a bacteriostatic antibiotic. It inhibits bacterial protein synthesis. It binds to the 50S ribosomal subunit and inhibits the activity of the enzyme, peptidyl transferase . Antibacterial Spectrum … Chloramphenicol exerts bacteriostatic effect on a wide range of Gram-positive and Gram-negative organisms and is active against Rickettsia species , Chlamydia species and Mycoplasma species. It is particularly effective against H. influenzae , S. pneumoniae , S. typhi , Neisseria meningitidis , Neisseria gonorrhoeae , Brucella species and Bordetella pertussis .

39. Pharmacokinetics penetrates well into the aqueous humor after topical application Chloramphenicol is approximately 60% protein bound. It is widely distributed in the body. An important aspect of chloramphenicol’s distribution is that it is able to penetrate blood ocular barrier. The drug crosses the placenta and is distributed into the breast milk.

40. Types of Ocular Infections Suitable for Treatment by Chloramphenicol 1. Acute bacterial conjunctivitis and blepharitis . 2. Gonococcal conjunctivitis and gonococcal corneal ulcer. Chloramphenicol is used as an alternate for the treatment of gonococcal infection when the cephalosporins or penicillin are not suitable. 3. Bacterial keratitis and corneal ulceration. 4. Dacryocystitis and dacryoadenitis . risk of aplastic anemia due to topical application of chloramphenicol is not well founded, it is very important to monitor the blood count during the chloramphenicol treatment.

41. Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly discontinued Fever, macular and vesicular rashes, angioedema and urticaria may occur, especially after topical use.

42. Contraindications As chloramphenicol readily crosses the placenta, it should be used with caution in pregnant women although birth defects in humans have not been documented. However, it should not be used in pregnancy at term or during labor because of potential toxicity in premature or full-term infants, including gray baby syndrome

43. QUINOLONES AND FLUOROQUINOLONES They are derivatives of quinolones which have a fluorine atom attached to the central ring, Classification Quinolones and fluoroquinolones are divided into four generations.

44. First Generation… the oldest and least often used quinolones . they are more susceptible to the development of bacterial resistanc Second Generation… increased Gram-negative activity, as well as some Gram-positive and atypical pathogen coverage. Ciprofloxacin is the most potent fluoroquinolone against P. aeruginosa .

45.  Ciprofloxacin and ofloxacin are the most widely used second generation quinolones because of their availability in oral, intravenous and topical formulations Third Generation … They have expanded activity against Gram-positive organisms, particularly penicillin-sensitive and penicillin-resistant S. pneumoniae , and atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae . Less active than ciprofloxacin against Pseudomonas species.

46. Fourth Generation… signifcant antimicrobial activity against anaerobes while maintaining the Gram-positive and Gramnegative activity of the third generation drugs. They also retain activity against Pseudomonas species.

47. Mechanism of Action Fluoroquinolones are the only class of antimicrobial agents in clinical use that are direct inhibitors of bacterial DNA synthesis. Fluoroquinolones inhibit two bacterial enzymes, DNA gyrase ( topoisomerase II) and topoisomerase IV . fluoroquinolones are bactericidal agents Pharmacokinetics…  Fluoroquinolones penetrate well into the aqueous humour after topical application.  Moxifloxacin 0.5% has better corneal penetration compared to gatifloxacin 0.3% .

48. So Moxifloxacin 0.5 % achieves highest level in aqueous humor . Levofloxacin 0.5% has better ocular penetration.

49. Types of Ocular Infection Suitable for Treatment by Fluoroquinolones Second generation fluoroquinolones are very effective in the treatment of acute bacterial conjunctivitis and blepharitis Power et al. investigated the effcacy of ciprofloxacin and chloramphenicol in 57 culture-positive patients and reported that the difference between the groups was not significant Both antibiotics were highly effective and signifcantly superior to placebo .

50. Treatment of acute bacterial conjunctivitis About 60% resolve within 5 days without treatment. Topical antibiotics , usually four times daily for up to a week ,but sometimes more intensively, are frequently administered to speed recovery and prevent re-infection and transmission. There is no evidence that any particular antibiotic is more effective. Ointments and gels provide a higher concentration for longer periods than drops but daytime use is limited because of blurred vision.

51. Some practitioners, particularly in the United States, believe that chloramphenicol should not be used for routine treatment because of a possible link with aplastic anaemia. Topical steroids may reduce scarring in membranous and pseudomembranous conjunctivitis, although evidence for their use is unclear. A broad-spectrum antibiotic with good Gram-positive coverage such as a third- or fourthgeneration fluoroquinolone , 10% sodium sulfacetamide , or trimethoprim-polymyxin may be used for 7–10 days

52. Irrigation to remove excessive discharge may be useful in hyperpurulent cases. Contact lens wear should be discontinued until at least 48 hours after complete resolution of symptoms Risk of transmission should be reduced by hand-washing and the avoidance of towel sharing

53. Gonococcal conjunctivitis and gonococcal corneal ulcer. Second generation fluoroquinolones ( ciprofloxacin ) are used topically and parenterally in the treatment of gonococcal conjunctivitis and keratitis

54. Bacterial keratitis and corneal ulceration. The common pathogens causing bacterial keratitis are Pseudomonas aeruginosa , Pneumococcus , Moraxella species, and Staphylococci. Fluoroquinolones such as levofloxacin 0.5%, ofloxacin 0.3%, norfloxacin 0.3%, or ciprofloxacin 0.3% are commonly used as frstline agents to treat this condition as long as local prevalence of resistant organisms is low.

55. Treatment of bacterial keratitis fluoroquinolone is the usual choice for empirical monotherapy and appears to be about as effective as duotherapy . Ciprofloxacin instillation is associated with white corneal precipitates that may delay epithelial healing.

56. Antibiotic duotherapy may be preferred as frst -line empirical treatment in aggressive disease. Empirical duotherapy usually involves a combination of two fortifed antibiotics, typically a cephalosporin and an aminoglycoside , in order to cover common Grampositive and Gram-negative pathogens. Mydriatics are used to prevent the formation of posterior synechiae and to reduce pain. Steroids reduce host inflammation , improve comfort, and minimize corneal scarring.

57. - Epithelialization may be retarded by steroids and they should be avoided if there is signifcant thinning or delayed epithelial healing . Many people do not commence topical steroids until evidence of clinical improvement is seen with antibiotics alone, typically 24–48 hours after starting treatment .

58. If the pathogen identifed is Mycobacteria , the fourth-generation fluoroquinolones ( moxifloxacin 0.5% and gatifloxacin 0.3%) are indicated Bacterial endophthalmitis Fluoroquinolones are the drug of choice in the prophylaxis of postoperative endophthalmiti

59. Adverse Effects Local adverse effects following ocular administration of fluoroquinolones include pain or discomfort in the eye, swelling, foreign body sensation, itching, conjunctival hyperemia and transient burning . white crystalline precipitate, commonly located in the superfcial portion of the corneal defect i.e. the area of inflammation .

60. Phototoxicity …..The degree of phototoxic potential of fluoroquinolones is as follows: lomefloxacin > sparfloxacin > ciprofloxacin > norfloxacin = ofloxacin = levofloxacin = gatifloxacin = moxifloxacin nausea, vomiting, diarrhea , constipation, and abdominal pain, which occur in 1 to 5% of patients. Contraindications … previous allergic reaction to ciprofloxacin or other quinolones .

61. certain disorders that predispose to arrhythmias such as QT-interval prolongation, uncorrected hypokalemia or hypomagnesemia . Fluoroquinolones are approved for use only in people older than 18 years of age. They are contraindicated in children and in pregnant women because they may cause cartilage lesions if growth plates are open potential to cause teratogenic orembryocidal effects . also excreted in breast milk and should be avoided during breast-feeding

62. TETRACYCLINES Tetracycline is a group of broad spectrum antibiotics that inhibit bacterial protein synthesis and are bacteriostatic . Gram-positive cocci ( Staphylococcus species and Streptococcus species) ƒƒGram-negative cocci ( Neisseria gonorrhoeae ) Gram-positive bacilli ( Bacilus anthracis

63. Gram-negative bacilli ( Haemophilus influenzae , Helicobacter pylori) Atypical bacteria ( Chlamydia species Mycoplasm species , Legionella species , Ureaplasma ) Spirochetes ( Treponema pallidum , Borrelia recurrentis , Borrelia burgdorferi ) Rickettsiae , Listeria , Vibrio choler ƒƒ,Anaerobes Tetracyclines penetrate into most body tissues and fluids and tetracycline particularly penetrates well into the ocular tissue Tetracycline is available as eyedrop and ointment

64. Therapeutic Uses … 1. Acute conjunctivitis and blepharitis . 2. Ophthalmia neonatorum . Tetracycline ointment 1% is used in prevention and treatment of gonococcal and chlamydial ophthalmia neonatorum (neonatal conjunctivitis). 3 . Trachoma . Doxycycline and tetracycline are the frst line drugs in the treatment of trachoma. 4. Bacterial keratitis and corneal ulceration due to Gram-positive flora ( Staphylococcus species). trachoma

65. 5. Dacryocystitis and dacryoadenitis . Tetracyclin is used as alternative to other antibiotics. 6. Bacterial endophthalmitis Adverse Effects… burning sensation of the stomach, diarrhea , sore mouth or tongue. Tetracyclines should not be used in children under the age of 8 years, and specifcally during periods of tooth development. Tetracyclines are classed as pregnancy categoryD Minocycline commonly causes vestibular dysfunction.

66. MACROLIDES Macrolides are usually administered orally. Erythromycin is also available as ophthalmic ointment . After systemic administration, macrolides enetrate well into all tissues including ocular tissues. Therapeutic Uses… Bacterial conjunctivitis and blephritis adult inclusion conjunctivitis (AIC) and neonatal inclusion conjunctivitis (NIC) Trachoma

67. Adverse Effects nausea, vomiting, abdominal pain, diarrhea and anorexia. ( Azithromycin and clarithromycin have fewer gastrointestinal side-effects than erythromycin ) pseudomembranous colitis QT prolongation and ventricular arrhythmias,

68. AMINOGLYCOSIDES Bactericidal action 1 st gen are effective against M. tuberculosis . streptomycin is still the first line drug in the treatment of tuberculosis. second generation… Tobramycin is more active than gentamicin against Pseudomonas aeruginosa , whereas gentamicin is usually more active against Serratia . Pharmacokinetic… Topically applied aminoglycosides are primarily absorbed through conjunctiva due to their hydrophilic nature After parenteral administration, aminoglycosides are primarily distributed within the extracellular fluid . They do not penetrate well into the aqueous humor and vitreous fluid of the eye.

69. The commercially available topical ocular aminoglycosides include gentamicin , neomycin, framycetin and tobramycin . Gentamicin is also administered subconjunctivally and intravitreally Therapeutic Uses Gentamicin and tobramycin (in fortifed form) has been a “go to” agent for the treatment of Gram-negative ocular infections, especially Pseudomonas aeruginosa . 1. Conjunctivitis, blepharitis and blepharoconjunctivitis . 2. Bacterial keratitis and corneal ulceration.

70. 3. Dacryocystitis and dacryoadenitis . 4 . Bacterial endophthalmitis Adverse Effects… Nephrotoxicity , which is usually reversible. Ototoxicity is irreversible,

71. SULFONAMIDES sulfonamides inhibit the biosynthesis of folic acid, which is essential for the synthesis of purine nucleotides for DNA and RNA. Trimethoprim is a potent inhibitor of the bacterial enzyme dihydrofolate reductase and interferes competitively with the conversion of dihydrofolic acid to tetrahydrofolic acid . Cotrimoxazole is a combination of a sulfonamide ( sulfamethoxazole ) and trimethoprim . Combined administration of both exerts synergistic antimicrobial activity leading to bactericidal effect .

72. Sulfonamides generally are used in the oral form, though parenteral preparations are also available Commercially available 30% ophthalmic solutions of sulfacetamide sodium are present. Use..Treatment of conjunctivitis, corneal ulcers, and other superfcial infections of the eye caused by susceptible Staphylococcus aureus , Streptococcus pneumoniae , Streptococcs viridans , Haemophilus influenzae . S/E; irritation, stinging, and burning. Conjunctivitis, conjunctival hyperemia

73. BACITRACIN Derived from the cultures of Bacillus subtilis , Bacitracin has a narrow antibacterial spectrum. Gram-positive bacteria such as Staphylococcus species and Streptococcus species are susceptible. Therapeutic Uses - Bacitracin is never used as a systemic agent because it causes serious nephrotoxicity . -It is usually used in combination with polymixin B and neomycin, to treat superfcial infections of conjunctiva, eyelids and cornea.

74. POLYMYXIN B Not used systemically as it causes neurotoxicity and nephrotoxicity . Topically, it is used in combined preparations with other anti- infectives such as bacitracin . Trimethoprim / polymixin B ophthalmic preparation is available as ointment and solution. Polymixin B is also available for subconjunctival injections USES; 1. Conjunctivitis, blepharitis and blepharoconjunctivitis due to Gram-negative infection. 2. Keratitis and corneal ulcers .

75. Thank you