Fluoroquinolones in Ophthalmology - Dr Ravin N Das - Jabalpur Divisional Ophthalmic Society



	Fluoroquinolones in Ophthalmology Dr. Ravin N. Das (MS) This JDOS CME was held on October 23, 2005 in Hotel Krishna at 4 PM. The Program was sponsored by Milmet division of Sun Pharma. High tea sponsored by Milmet followed the CME. Introduction This class of drugs represents a particularly important therapeutic advance, since they have; A broad antimicrobial activity Are bactericidal Relatively few side effects Resistance does not develop rapidly Development The first quinolone (Nalidixic Acid) was developed in 1962 as a by-product of Chloroquine synthesis. Cinoxacin, Pipemedic acid and Oxolinic Acid soon followed (II generation). However their use was mainly restricted to the treatment of Urinary Tract Infections (UTI), due to their poor plasma concentration and excellent concentration in the Urinary System. It was also observed that resistance developed rapidly, and that these were not effective against Pseudomonas Aeruginosa. The Fluoroquinolones Also called the fluorinated 4-quinolones (III and IV generation quinolones). They contain a corboxylic acid moiety at the III position of the ring structure and a fluorine substituent at the VI position, Piperazine moiety at VII position. Introduced in the 1980's and gained popularity in the 1990's. Chemical characteristics Piperazinyl group (at C7) Increases activity against Pseudomonas spp. Fluorine atom (at C6) Increases activity against some gram(+) bacteria Carboxyl moiety (at C3) DNA binding Gatifloxacin Moxifloxacin Drawbacks Incompatibilities Large inocula (concentration dependent antibiotics as against time-dependent) Bivalent cations (e.g., Mg++) and other antacids -- chelation reduce bioavailability Alkaline pH decreases solubility (problem in urine if pH>7 with crystalluria) Classification Divided into 4 generations Generation 1 = Nalidixic acid Generation 2 = Oxolinic acid, Pipemidic acid, Cinoxacin Generation 3 = Norfloxacin, Ciprofloxacin, Ofloxacin, Lomefloxacin, Pefloxacin, Fleroxacin, Amifloxacin, Sparfloxacin and Levofloxacin. Generation 4 = Gatifloxacin and Moxifloxacin (developed in 1999 - introduced in 2003). Mechanism of action Generation 1-3 inhibit the DNA gyrase (topoisomerase II) in bacteria which causes failure in replication and cell death. This action occurs at concentrations of 0.1 to 10 micro-grams/ml. Why are human cells not affected? No DNA gyrase, but a similar type II topoisomerase which is inhibited at higher concentrations (100 to 1000 micro-grams/ml). Generation 4 also inhibit topoisomerase IV. The Advantage of Gen-IV The most apparent advantage of the IV generation lies in the fact that the drugs act by inhibiting both topoisomerases II and IV in both +ve & -ve. (Whereas the III generation were active against topo IV in gm +ve and topo II in gm -ve) It would therefore appear that resistance to these drugs may not occur as a spontaneous mutation at two levels at once. A possible mechanism of drug resistance development to this generation has been postulated - resistance at the bacterial cell wall by increased eflux (remains to be seen). Bacterial resistance The Moxifloxacin Advantage Moxifloxacin has a unique advantage over Gatifloxacin in having a bi-cyclic C-7 side chain; Which reduces the ability of the bacterial cells eflux pump to flush out the antibiotic, This increased drug stay in the bacterial cell allows for; Enhanced activity Expanded spectrum of activity Additional defense against resistance. Moxifloxacin is "KING"! The pH value is close to tears (6.8) Does not need a preservative Topical dosage need not be increased beyond thrice a day due to increased drug stay in the bacterial cell. Systemic administration - Has the lowest phototoxic and CNS adverse event potential among the currently available fluoroquinolones. Spectrum of Action Whereas the earlier quinolones had limitations in treating only the common Gm -ve infections (and had no action against Pseudomonas sp.), the newer generations have a broad spectrum. Most of the common Gm +ve organisms Gm -ve organisms (including Pseudomonas sp) Chlamydia, Mycoplasma, Legionella, Brucella and Mycobacteria (including tuberculosis). Most anaerobes are resistant with the exception to Sparfloxacin. Susceptible Gm +ve Corynebacterium sp. Micrococcus luteus Staphylococcus (aureus, epidermidis, haemolyticus, hominis, warneri, pneumoniae) Streptococcus viridans group. MAINLY - CIPROFLOXACIN, OFLOXACIN, PEFLOXACIN, SPARFOXACIN, GATIFLOXACIN AND MOXIFLOXACIN. Susceptible Gm -ve Acinetobacter Haemophilus influenzae and parainfluenzae Pseudomonas, enterococci, pneumococci and E coli (CIPROFOXACIN AND NORFLOXACIN) Other susceptible organisms Chlamydia trachomatis (OFLOXACIN given for a few days - Azithromycin 500 mg stat (single dose) more effective and the drug of choice) Mycobacteria and Atypical Mycobacteria (CIPROFOXACIN OR OFLOXACIN with other drugs especially in cases of HIV related tuberculosis) Adverse Effects (Systemic) Generally well tolerated 2-12% report nausea, abdominal discomfort, headache and dizziness. 0.2% hallucinations, delirium, and seizures (especially when given in conjuction with theophylline, NSAID's) (CIPRO AND ENOXACIN). Very rare - rashes and photosensitivity (accentuated by biotin deficiency), Leukopenia. Arthralgias and joint swelling in prepubertal age. Acute hepatitis and failure Trovafloxacin Photosensitivity Sparfloxacin Lomefloxacin Pefloxacin Levofloxacin, Gatifloxacin, Moxifloxacin and Ofloxacin have the least phototoxic potential. QT prolongation & arrhythmia Grepafoxacin Moxifloxacin Levofloxacin Sparfloxacin Gatifloxacin Blood sugar levels Gatifloxacin & Moxifloxacin - Associated with hyperglycemia in DM Hypoglycemia in patients taking anti-diabetic drugs (insulin and glyburide) Drug interactions NSAID, theophylline, warfarin (hepatic biotransformation) May be given after food, but not with chelating agents - upto 8 hours after taking antacids & 1-2 hours before taking antacids. Antacids (aluminum, calcium,or magnesium-containing) Laxatives (magnesium-containing, or sucralfate or Zinc) Ferrous sulfate and Bismuth salicylate Precautions History of hypersensitivity to the quinolones (Steven Johnson's type syndrome may occur). For systemic administration - hepatic and renal impairment needs to be considered. Achilles tendinitis and tendon rupture reported 2-42 days after systemic administration. Contraindicated in pts. with history of convulsions. Pregnancy category C - NOT to be given to pregnant mothers, lactating mothers (Adequate animal studies, inadequate human studies). Ocular Adverse Reactions 1-6% of the patients report some of the following: conjunctival chemosis and inflammation reduced visual acuity (cause not known) dry eye, keratitis, ocular discomfort ocular pain, pruritis subconjunctival hemorrhage and tearing. Crystaline corneal deposits (Ciprofoxacin, Sparfloxacin, Norfloxacin, Ofloxacin and Gatifloxacin). Ofloxacin in Cornea (from the www) Sparfloxacin in Cornea (from IJO, Dr Nikhil Gokhale) Corneal deposits implications Deposits occur at the superficial to mid-stromal level Usually occur whenever there is a break in the epithelium Cause delayed re-epithelization, therefore delayed wound healing Permanent. Indications Acute susceptible bacterial infections with or without breach in the epithelium. Chronic susceptible bacterial infections - Chlamydia trachomatis Prophylaxis - pre-surgical - administered topically 2-3 times before surgery (pre-surgical povidone iodine irrigation of the conjuctiva, cul-de-sacs, and painting of the lid margins is a must). (OFLOXACIN, GATIFLOXACIN AND MOXIFLOXACIN). Gatifloxacin Vs Moxifloxacin pH Moxifloxacin 0.5% has a pH of 6.8 Gatifloxacin 0.3% has a pH of 6.0 Inference: Moxifloxacin being closer to neutral pH has a negligible chance of precipitation Also, Moxifloxacin has a higher solubility than Gatifloxacin at neutral pH Penetration into the Aqueous Moxifloxacin achieves a concentration of 1.86 µg/ml Gatifloxacin achieves a concentration of 0.94 µg/ml Due to the above fact - the Cmax is 10x the MIC, therefore the chances of mutation and resistance reduce significantly No other anti-bacterial a Cmax that is 10x the MIC. Why the better penetration? Moxifloxacin is more soluble at neutral pH than Gatifloxacin Moxifloxacin has a concentration of 0.5% as compared to 0.3% of Gatifloxacin Moxifloxacin has a bi-phasic characteristic in penetration. Preservatives Moxifloxacin is preservative-free Gatifloxacin has BAC (0.005%) Advantage Moxifloxacin maintains health and integrity of the corneal surface and thus has no effect on ulcer or wound healing Disadvantage The likelyhood of drug contamination with yeasts and amoeba increases (bottle tip handling) Dosage Moxifloxacin is recommended 3 times a day for 4 days in Acute Bacterial Conjunctivitis Gatifloxacin is recommended 2 hourly initially and then 4 times a day (Patient compliance?) Adverse reactions The chances of conjunctival erythema are more with Moxifloxacin (p = .0005) Reduction in pupil size with moxifloxacin (p = .001) (prostaglandin release) 5-10% cases on Gatifoxacin may develop keratitis and papillary conjunctivitis All other systemic and topical adverse effects are similar One case of Fatal Anaphylaxis has been reported with intra-venous Gatifloxacin