Quinolones and Fluoroquinolones TABLE OF CONTENTS Introduction and

Quinolones and Fluoroquinolones

TABLE OF CONTENTS

Introduction and Classification

Quinolones And Fluoroquinolones o The quinolones (Qs) and fluoroquinolones (FQs) are a family of broad-spectrum synthetic antimicrobial agents. o The parent of the group is nalidixic acid, which was acid introduced in 1962. o The fluoroquinolones have a fluoro group attached the central ring system.

Quinolones And Fluoroquinolones Classification GENERATIONS DRUGS INCLUDED 1 st generation Nalidixic acid Cinoxacin (removed from clinical use) 2 nd generation Ciprofloxacin Enoxacin Norfloxacin Ofloxacin 3 rd generation Levofloxacin Grepafloxacin Sparfloxacin 4 th generation Moxifloxacin Trovafloxacin

Quinolones And Fluoroquinolones ¡ ¡ Qs and FQs are bactericidal drugs. FQs enter into the host cells and therefore active against intracellular pathogens such as Legionella spp. , Mycoplasma spp. and Chlamydia spp.

MECHANISM OF ACTION

Quinolones And Fluoroquinolones Mechanism of action The fluoroquinolones work by inhibiting one or more of a group of enzymes called topoisomerase, enzymes needed for supercoiling, replication and separation of circular bacterial DNA. 1. DNA Gyrase is a topoisomerase II that catalyzes the negative supercoiling of the circular DNA found in bacteria. 2. Topoisomerase IV, on the other hand, is involved in the relaxation of the supercoiled circular DNA, enabling the separation of the interlinked daughter chromosomes at the end of bacterial DNA replication

Quinolones And Fluoroquinolones Mechanism of action

Quinolones And Fluoroquinolones Mechanism of action Gram-negative bacteria ¡ primary target is DNA gyrase. Gram-positive bacteria ¡ primary target is topoisomerase IV.

ANTIMICROBIAL SPECTRUM

Pharmacokinetics ¡ ¡ ¡ Well absorbed after oral administration. Abs ↓ with sucralfate , antacids containing Aluminium or Magnesium , or dietary supplements containing iron or Zinc. So FQ should be given 2 hrs before or 4 hrs after these preparations. Norfloxacin only 35 -70 % abs. Others have oral bioavailability of 80 -98%. Ciprofloxacin , Levofloxacin & Ofloxacin also available for I/V use. Distributed widely in body tissues & fluids.

¡ ¡ Concentration in prostate tissue , kidneys , neutrophils & macrophages & lung exceed serum conc. High levels in bone. Penetration into CSF is poor , except Ofloxacin— 90 % of serum t 1/2 Variable– 3 -10 hrs--- BD or OD dosing

Elimination mostly by kidneys via active tubular secretion , can be blocked by probenecid. ¡ Dosage adjustments in renal dysfunction except for Moxifloxacin eliminated Nonrenally –partly by hepatic metabolism & partly by biliary excretion. Gemifloxacin partly renal & partly non-renal– Important in renal insufficiency. ¡

Antimicrobial spectrum of quinolones

Example Nalidixic acid Antibacterial Spectrum Gram-negative bacteria: E. coli, Proteus spp, Klebsiella spp, Shigells spp. Have no activity against P. aeruginosa Ciprofloxacin Gram-negative including P. aeruginosa Gram-positive: only Staphylococcus spp. Have no activity against Streptococcus pneumonia. Atypical bacteria: Legionella spp. Levofloxacin Gram-negative Gram-positive. Improved activity against Streptococcus pneumonia Atypical bacteria. Improved activity against Mycoplasma spp. , Chlamydia spp. Moxifloxacin Gram-negative Gram-positive including Streptococcus pneumonia Antianaerobic activity

CLINICALLY USEFUL FLUOROQUINOLONES

Nalidixic Acid ¡ Well absorbed from GIT. ¡ Partly metabolized in liver. ¡ Poor tissue penetration and low plasma levels. Cannot be used for the treatment of systemic infections. ¡ Excreted in urine. High urine concentration.

Nalidixic Acid. Clinical Use ¡ Norflxacin is effectives against gram –ve and gram +ve organisms in treating complicated and uncomplicated urinary tract infections and prostitis. ¡ Bacterial gastrointeritis caused by E. coli, Proteus spp, Klebsiella spp, Shigella spp.

Ciprofloxacin ¡ The most potent of the fluoroquinolones for P. aeruginosa. ¡ Long post-antibiotic effect. ¡ Well absorbed from GIT. ¡ Administration: orally, IV. ¡ Excreted in urine. Potent CYP 450 inhibitor

Ciprofloxacin. Clinical Uses ¡ ¡ ¡ ¡ ¡ UTIs Intra-abdominal infections (peritonitis) Bacterial gastrointeritis Sepsis Skin/soft tissue infections Typhoid (ciprofloxacin is the first choice in typhoid fever) Tuberculosis Gonorrhea Conjunctivitis

Ciprofloxacin. Clinical Uses

Levofloxacin ¡ An isomer of Ofloxacin and has largely replaced it clinically. ¡ Very well absorbed from GIT. ¡ Administration: orally, iv. ¡ Excreted unchanged ¡ Long post-antibiotic effects. ¡ Long-acting (single daily dose) .

Levofloxacin. Clinical Uses ¡ ¡ Mostly used for the treatment respiratory tract infections due to S. pneumonia (pneumonia, COPD exacerbation). Used in the treatment of prostitis due to E. coli and of sexually transmitted diseases, with the exception of syphilis. Used as an alternative in patients with gonorrhea. Additionally due to its broad spectrum activity, levofloxacin is utilized in wide range of infections, including skin infections, acute sinusitis, nosocomal pneumonia.

Moxifloxacin ¡ Long-acting (single daily dose). ¡ Long post-antibiotic effect. ¡ Mostly used for the treatment respiratory tract infections (pneumonia, COPD exacerbation). ¡ Used for the treatment severe bacterial infections including sepsis, peritonitis. ¡ The most potent fluoroquinolones against M. tuberculosis. ¡ Poor activity against P. aeruginosa.

RESISTNACE OF FLUOROQUINOLONES

ADVERSE DRUG REACTIONS

Quinolones And Fluoroquinolones Adverse Effects ¡ Abnormalities of bone and cartilage formation. (Cause cartilage damage in weight bearing joints in animal studies) Qs and FQs are contraindicated in children under 18 and pregnant women!!!

Quinolones And Fluoroquinolones Adverse Effects ¡ Photosensitivity (photodermatitis) Avoid sun and U. V. radiation exposure during therapy!!!

Quinolones And Fluoroquinolones Adverse Effects ¡ ¡ ¡ Tendonitis/tendon rupture. A few cases of ruptures of the shoulder, hand Achilles tendon have been reported. CNS: confusion, insomnia, fatigue, depression, somnolence, seizures. CVS: QT-prolongation.

DRUG INTERACTIONS

DRUG INTERACTIONS ¡ Ciprofloxacin is a potent CYP 450 inhibitor. Increases plasma levels and toxic effects of anticoagulants, digoxin, theophylline

DRUG INTERACTIONS ¡ ¡ ¡ FQs in combination with class IA and class III antiarrhythmics prolong QT and may cause arrhythmias. Qs and FQs have no sinergistic effects with other antibiotic classes. A synergistic inhibitory effect of fluoroquinolones has been observed on the binding of the neurotransmitter GABA.

DRUG INTERACTIONS ¡ ¡ The conocmitant oral administeration of magnesium or Aluminium containing Antacids has been found to result in six to ten fold decreases in the absorption of oral quinolones. Studies have documented substantial reductions in quinolones bioavailability when coadministered with sucralfate.

CONTRAINDICATIONS

Contraindications ¡ Fluoroquinolones are contraindicated in patients with known hypersensitivity reactions with any member of fluoroquinolones class of antimicrobial agents.

Contraindications Fluoroquinolones generally should not be administered to patients younger than 18 years of age. ¡ Fluoroquinolones should not be administerd to pregnant or lactating women. ¡ Should not be given to arrythmic patient. ¡

COMPLICATIONS

Complications Ophthalmia Venerea": A dreadful complication of fluoroquinolone-resistant Neisseria gonorrhoeae. ¡ Fluoroquinolone antibiotics are associated with a wide spectrum of musculoskeletal complications that involve not only tendon but also cartilage, bone, and muscle. ¡

References 1. Hooper, D. C. Mode of action of fluoroquinolones. Drugs 1999; 58 Suppl. 2; 610. 2. J. Antimicrob. Chemother. (1990)26 (suppl D): 7 -29. doi: 10. 1093/jac/26. suppl_D. 7 3. Drug Interactions in Infectious Diseases By Stephen C Piscitelli, Keith A. Rodvold, Manjunath P. Pai 4. Pharmacotherapeutics For Advanced Practice: A Practical Approach, Page 536 By Virginia Poole Arcangelo, Andrew M. Peterson

References 5. http: //www. ncbi. nlm. nih. gov/pubmed/2042 9088 6. Musculoskeletal complications of 6. fluoroquinolones: guidelines and precautions for usage in the athletic population. Mederic M Hall, Jonathan T Finnoff, Jay Smith Department of Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Mayo Clinic Sports Medicine Center, Rochester, MN 55905, USA.

References 7. lippincott’s illustrated Reviews Pharmacology 4 th edition.