Fluoroquinolones
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Fluoroquinolones
- 1. Dr. Sahil Kumar Department of Pharmacology Maulana Azad Medical College FLUOROQUINOLON ES
- 2. Parent drug: Nalidixic acid
- 3. NALIDIXIC ACID (Quinolone) •Available for the management of UTI. •Limited therapeutic ability. •A/E – GI upset, rashes, neurological toxicity, hemolysis. •Bacterial resistance.
- 4. Structure Carboxylic acid moiety at position 3 Many new FQs have Fluorine at position 6 Piperazine moiety at position 7
- 5. Mechanism of Action DNA GYRASE: Gram negative bacteria (negative super coiling) TOPOISOMERASE 4: Gram positive bacteria (separation of daughter strands) TOPOISOMERASE 2: Eukaryotic cells
- 7. Mechanism of Resistance Unique MOA, so plasmid mediated resistance less. Resistance is d/t Chromosomal mutation producing DNA gyrase/ Topoisomerase 4 with reduced affinity for FQs. Reduced permeability/ increased efflux.
- 11. Pharmacokinetics Good oral BA : 85-95% Oral absorption decreased by divalent cations High tissue penetrability.
- 12. DRUG T ½ hr ORAL BA ORAL DOSE mg ROUTE OF EXCRETION CIPROFLOXACIN 3-5 70 500 RENAL GATIFLOXACIN 8 98 400 RENAL LEVOFLOXACIN 5-7 95 500 RENAL LOMEFLOXACIN 8 95 400 RENAL MOXIFLOXACIN 9-10 >85 400 NON RENAL NORFLOXACIN 3.5-5 80 400 RENAL OFLOXACIN 5-7 95 400 RENAL SPARFLOXACIN 18 92 50%RENAL, 50%FECAL TROVAFLOXACIN 11 88 200 NON RENAL
- 13. CIPROFLOXACIN Prototype of FQs. Most potent 1st gen FQ against broad range of bacteria. Aerobic gram –ve.
- 14. Microbiological Properties • Rapid bactericidal activity and high potency. • Relatively long post-antibiotic effect on Enterobacteriaceae, Pseudomonas and Staph. • Low frequency of mutational resistance. • Protective intestinal streptococci, anaerobes spared. • Active against many β-lact. & AG resistant bacteria. • Less active at acidic pH.
- 15. Adverse Drug Reactions GIT: Nausea, Vomiting, Anorexia. Diarrhea infrequent. HYPERSENSITIVITY: Rash CNS: Headache, Dizziness, Insomnia JOINTS, CARTILAGE: Reversible Arthropathy, Tendon Rupture, Tendinitis
- 18. Drug interactions Food and Antacids, Iron: Decrease absorption Theophylline, caffeine, warfarin: increase d/t Enzyme Inhibition. NSAIDs may increase CNS toxicity. (Seizures)
- 19. Therapeutic Uses UTI : Multi Drug Resistant Pseudomonas. Norflox 400mg bd Cipro 500 mg bd Oflox 400mg bd Bacterial dysentery: Shigella, Salmonella, E coli, Campylobacter. Typhoid: 500 mg bd X 10d ◦Quick defervescence ◦Early abetment of symptoms. ◦Prevention of carrier state.
- 20. STDs : Chlamydia (7d), Chancroid (3d), PID (14d) Bone & soft tissue infection: Cipro + Metro. Respiratory infection: both upper and lower RTI Tuberculosis: Resistant, atypical( MAC ) Septicemias Meningitis Neutropenic patients - prophylaxis. Conjunctivitis
- 22. NORFLOXACIN Less potent than Ciprofloxacin. Attains lower conc. in tissues. Used in UTI, dysentery.
- 23. PEFLOXACIN Methyl derivative of Norfloxacin. Passage in CSF greater than in other tissues. Longer t-half, so accumulates effective in systemic inf as well.
- 24. OFLOXACIN Less active than Ciprofloxacin against G-ve. Equally or more potent against G+ve/ anaerobes. Used in Chlamydial inf, TB, Leprosy. Comparable to Cipro in therapy of systemic and mixed infections.
- 25. LEVOFLOXACIN Active levo-isomer of Ofloxacin. 100% oral BA. Used in CAP, Chronic Bronchitis Exacerbation (90% cure rate)
- 26. LOMEFLOXACIN 2nd generation. Equal in activity to Ciprofloxacin. Single daily administration. High incidence of Phototoxicity and QT prolongation.
- 27. MOXIFLOXACIN 2nd generation. Activity against Str. pneumoniae, G+ve including Beta-lactam and Macrolide resistant ones, anaerobes. Pneumonias, bronchitis, sinusitis, otitis media.
- 28. GEMIFLOXACIN 2nd generation. Another broad spectrum FQ. CAP, Chronic Bronchitis Exacerbation.
- 29. PRULIFLOXACIN 2nd generation. Prodrug of Ulifloxacin. Broad spectrum. Chronic Bronchitis Exacerbation, UTI
- 30. Banned/ Withdrawn from market Gatifloxacin : QT prolongation, Hypoglycemia Sparfloxacin : Fatal arrhythmias, phototoxicity Temafloxacin : Immune hemolytic anemia Trovafloxacin : Hepatotoxicity Grepafloxacin : Cardiotoxicity Clinafloxacin : Phototoxicity
- 31. Which of the following fluoroquinolones does not require dose adjustment in a patient with Cr. CL of < 50 mL/min? (a) Ciprofloxacin (b) Trovafloxacin (c) Lomefloxacin (d) Sparfloxacin A contraindication to the use of Ciprofloxacin is a history of: (a) Epilepsy (b) Deep vein thrombosis (c) Gout (d) G-6 PD deficiency
- 32. Which of the following statements about fluoroquinolones is FALSE? (a) Gonococcal resistance to fluoroquinolones may involve changes in DNA gyrase. (b) Modification of fluoroquinolones dosage is required in patients if creatinine clearance is less than 50 mL/min. (c) A fluoroquinolone is the drug of choice for treatment of an uncomplicated UTI in a 7 year-old girl. (d) Fluoroquinolones inhibit relaxation of positively supercoiled DNA.
- 33. THANK YOU!
Editor's Notes
- These are synthetic antimicrobials having a quinolone structure that are active primarily against gram negative bacteria, though the newer fluorinated compounds also inhibit gram- positive ones.
- All the antibiotics in the quinolone class are derived from the parent drug nalidixic acid
- The first member Nalidixic Acid introduced in mid 1960s had usefulness limited to urinary (urinary antiseptic) and GI tract infections (active against esp coliformsbut not pseudomonas) because of low potency, limited spectrum, high frequency of resistance. Acts by inhibiting DNA gyrase and is bactericidal. 1. Nalidixic acid is primarily used as a urinary antiseptic, generally as a second line drug in recurrent cases or on the basis of sensitivity reports. Nitrofurantoin should not be given concurrently-antagonism occurs. 2. It has also been employed in diarrhoea caused by Proteus, E. coli, Shigella or Salmonella but Norflox/Ciplox more commonly used now. A breakthrough was achieved in the early 1980s by fluorination of the quinolone structure resulting in Fluoroquinolones with high potency, expanded spectrum, slow development of resistance, better tissue penetration and good tolerability.
- The FQs inhibit the enzyme bacterial DNA gyrase (primarily in G-ve bacteria), which nicks double-stranded DNA, introduces negative supercoils and then reseals the nicked ends. This is necessary to prevent excessive positive supercoiling of the strands when they separate to permit replication or transcription. The DNA gyrase consists of two A and two B subunits: The A subunit carries out nicking of DNA, B subunit introduces negative supercoils and then A subunit reseals the strands. FQs bind to A subunit with high affinity and interfere with its strand cutting and resealing function. In gram-positive bacteria the major target of FQ action is a similar enzyme topoisomerase IV which nicks and separates daughter DNA strands after DNA replication (separation of replicated chromosomal DNA into daughter cells during cell division). Greater affinity for topoisomerase 4 may confer higher potency against gram-positive bacteria. Bactericidal action probably results from digestion of DNA by exonucleases whose production is signalled by the damaged DNA. In place of DNA gyrase or topoisomerase IV, the mammalian cells possess an enzyme topoisomerase II (that also removes positive supercoils) which has very low affinity for FQs hence the low toxicity to host cells. (Anticancer agents like Doxorubicin/ Adriamycin, Daunorubicin used for AML/ALL and Breast Ca, HL & NHL, soft tissue sarcoma, Ovarian Ca, Lung Ca, Wilm’s tumor & Neuroblastoma act as Topoisomerase 2 inh.)
- To create a visual image of the MOA.
- I contrast to nalidixic acid which selects single step resistant mutants at high frequency, FQ-resistant mutants are not easily selected. Therefore, resistance to FQs has been slow to develop. However, increasing resistance has been reported among Salmonella, Pseudomonas, staphylococci, gonococci and pneumococci.
- Coming to FQs - These are quinolone antimicrobials having one or more fluorine substitutions. The &apos;first generation&apos; fluoroquinolones (FQs) introduced in 1980s have one fluoro substitution. In the 1990s, compounds with additional fluoro and other substitutions have been developed-further extending antimicrobial actvity to gram-positive cocci and anaerobes, and/or confering metabolic stability (longer t-half). These are referred to as &apos;second generation&apos; FQs.
- Just to show that Fluorination is at various sites of the Nalidixic Acid or Quinolone ring.
- Rapidly absorbed orally, but food delays absorption, and first pass metabolism occurs. High tissue penetrability: concentration in lung, sputum, muscle, bone, prostate and phagocytes exceeds that in plasma, but CSF and aqueous levels are lower. It is excreted primarily in urine, both by glomerular filtration and tubular secretion. Urinary and biliary concentrations are 10-50 fold higher than plasma.
- Distributed widely in fluids and tissues Half life : 3 hrs- 22hrs Levo, Lome – have high oral BA Excretion : mostly renal Trova, moxi : non renal c/i hepatic failure
- Notable resistant bacteria are: Bacteroides, Clostridia, anaerobic cocci.
- The remarkable microbiological features of ciprofloxacin and also other FQs are: Low propensity to select plasmid type resistant mutants.
- Because gut anaerobes are not affected-diarrhoea is infrequent. Skin/hypersensitivity: rash, pruritus, photosensitivity, urticaria, swelling of lips, etc. Serious cutaneous reactions are rare CNS: dizziness, headache, restlessness, anxiety, insomnia, impairment of concentration and dexterity (caution while driving), tremor. Seizures are rare, occur only at high doses or when predisposing factors are present: possibly reflect GABA antagonistic action of FQs. JOINTS, CARTILAGE: Risk of tendon damage is higher in patients above 60 yrs and in those receiving Corticosteroids. FQs should be stopped at the first sign of tendinitis.
- Pregnancy Category C - FDA Image of a child with some arthropathy due to FQs. Ciprofloxacin and other FQs are contraindicated during pregnancy. On the basis of the finding that administered to immature pups ciprofloxacin (and other FQs) caused cartilage damage in weight bearing joints, the FQs have been contraindicated in children. However, under pressing situations like Pseudomonas pneumonia in cystic fibrosis and multi-resistant typhoid, ciprofloxacin has been administered to millions of children in India and elsewhere. Though a few cases of joint pain and swelling have been reported, cartilage damage has not occurred. Caution may seem prudent while using FQs in children.
- Rash and urticarial.
- What are other enzyme inhibitors?
- Should not be used for minor cases or where gram-positive organisms and/or anaerobes are primarily causative. 1. Urinary tract infections: High cure rates, even in complicated cases or those with indwelling catheters prostatitis, have been achieved. Chronic Pseudomonas infections respond less completely. 4. Bacterial gastroenteritis: Severe cases due to EPEC, Shigella, Salmonella and Campy. Jejuni respond quickly. 5. Typhoid: Ciprofloxacin is the first choice drug in typhoid fever since chloramphenicol, ampicillin and cotrimoxazole have become unreliable due to development of resistance. In India and elsewhere up to 95% S. typhi isolates are sensitive to ciprofloxacin. However, increasing number of nonresponsive cases are being reported. A dose of 500-750 mg BD for 10 days is recommended. Patients unable to take the drug orally may be treated with 200 mg. i.v. 12 hourly in the beginning. Being bactericidal the advantages of ciprofloxacin are: • Quick defervescence: On an average fever subsides in 4-5 days. • Early abetment of symptoms; low incidence of complications and relapse. • Prevention of carrier state due to cidal action, good penetration into infected cells, high biliary and intestinal mucosal concentration.
- Gonorrhoea: Initially a single 500 mg dose was nearly 100% curative in non-PPNG as well as PPNG infections, but cure rate has declined in the recent years due to emergence of resistance. Chancroid: 500 mg BDfor3 days is an excellent alternative to ceftriaxone/erythromycin. Bone, soft tissue : caused by resistant Staph. and g-negative bacteria: high cure rates have been obtained but prolonged treatment with high dose is required in osteomyelitis and joint inf. Used along with clindamycin/ metronidazole cover anaerobes) it is a good drug for diabetic foot. 7. Respiratory infections: Ciprofloxacin should not be used as the primary drug because Streptococci and pneumococci have low and variable susceptibility. However, it can treat Mycoplasma, Legionella, H. influenzae. US-FDA has approved use of Cipro for post exposure treatment of inhalational anthrax which may occur due to bioterrorism. 8. Tuberculosis It is second line component of combination chemo against multidrug resistant TB. FQ-resistant TB (extensively XDR) have arisen recently. 9. Gram-negative septicaemias: Parenteral ciplofloxacin maybe combined with 3rd gen cephalosporin or an aminoglycoside 10. Meningitis: Though penetration not very good, ciplox for g- bacterial meningitis (esp in immune compromised) 11)Prophylaxis – of inf in neutropenic cancer 12)Conjunctivitis – by G- topical therapy effective.
- Norfloxacin is primarily used for urinary and genital tract infections. lt is also good for bacterial diarrhoeas, because high concentrations are present in the gut and anaerobic flora is not disturbed. Norfloxacin is not recommended for respiratory and other systemic infections, particularly where gram-positive cocci are involved.
- Preferred for meningeal inf
- alternative drug for nonspecific urethritis, cervicitis and atypical pneumonia. It also inhibits M. tuberculosis; can be used in place of ciprofloxacin. It is highly active against M. leprae: is being used in alternative multidrug therapy regimens.
- improved activity against Strep. pneumoniae and some other gram-positive and gramnegative bacteria. Anaerobes are moderately susceptible. PK advantages – 100% BA, Theophylline, warfarin, cyclosporine and zidovudine pharmacokinetics has been found to remain unchanged during levofloxacin treatment.
- Single dose as long t-half and persistence in tissues. Still available in India but infrequently used.
- It is the most potent FQ against M. tuberculosis. Bacterial topoisomerase IV is the major target of action. Should not be given to patients predisposed to seizures and to those receiving proarrhythmic drugs, because it can prolong Q-Tc interval. Phototoxicity occurs only rarely
- CAP, Chr Bronchitis – similar to Levofloxacin Rash, QT prolongation, Rise in Liver enzymes.
- S/E – Similar to Ciprofloxacin.
- Which other antimicrobials cause phototoxicity, QT prolongation?
- Ans. (b) Trovafloxacin (Goodman & Gilman 11/e p1121) (100-150 ml/min) Fluoroquinolones safe in renal failure are: • P – Pefloxacin • M – Moxifloxacin • T – Trovafloxacin (a) Epilepsy
- (c) A fluoroquinolone is the drug of choice for treatment of an uncomplicated urinary tract infection in a 7 year old child (Ref: KDT 6/e p689) • Fluoroquinolones are contra-indicated in children (due to risk of cartilage damage) and pregnant female. • Most common mode of resistance to fluoroquinolones is mutation in DNA gyrase. • Dose of fluoroquinolones should be adjusted in renal failure (except moxifloxacin and trovafloxacin). • These drugs act by inhibiting DNA gyrase.