Fluoroquinolones Lecture Notes PDF

DNA SYNTHESIS INHIBITORS QUINOLONES & FLUOROQUINOLONES Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Quinolones in market Ciprofloxacin* (Cipro, Proquin P#.) Ofloxacin * (Floxin, P#) Norfloxacin (Noroxin) Levofloxacin * (Levaquin, Respo Quixin P#) G...

DNA SYNTHESIS INHIBITORS QUINOLONES & FLUOROQUINOLONES Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Quinolones in market Ciprofloxacin* (Cipro, Proquin P#.) Ofloxacin * (Floxin, P#) Norfloxacin (Noroxin) Levofloxacin * (Levaquin, Respo Quixin P#) Gemifloxacin (Factive) Moxifloxacin * (Avelox, Vigamox) OPH, ORAL I.V. Lomefloxacin (Maxaquin) Seeonggen Delafloxacin * (Baxdela) ASSSI drug Besifloxacin (Ophthalmic, conjunctivitis) Nalidixic acid (Original Quinolone, seldom used) *MRSA drugs ASSSI: acute skin and skin structure infections JETman  Drugs that were removed Sparfloxacin (Zagam) not in the US due to QT prolongation & torsade de pointes Grepafloxacin (Raxar not in US anymore due to torsade de pointes-a VT) Trovafloxacin-Alatrofloxacin (Trovan, a fluoro- naphthyridone related to flouroquinolones) not in the US due to hepatic damage Gatifloxacin (Tequin) not in US due to commercial reasons, Ophthalmic available  Mechanism of action The two strands of double-helical DNA must be separated to permit DNA replication and transcription. The topoisomerase II enzyme (in prokaryotes topoisomerase is called DNA gyrase) is responsible for the introduction of “negative supercoils” in to DNA to stop “positive supercoiling” in the process of “unwinding.” This process is an ATP dependent reaction requiring bacterial DNA to be cut and resealed (nicking and closing). The DNA gyrase enzyme of E. coli is a large enzyme with one A subunit (105kD) and two B subunits (95kD each). The A subunit that carries out the strand cutting function of the DNA gyrase is the site of action of the quinolones. The drug inhibits gyrase mediated DNA supercoiling at concentrations 0.1 to 10 ug/ml. Quinolones also inhibit topoisomerase IV in bacteria. Eukaryotes do not contain DNA gyrase but mechanistically similar topoisomerase II, removes positive supercoils from eukaryotic DNA. Quinolones inhibit eukaryotic topoisomerase II only at much higher concentrations (100 to 1000 ug/ml). Fluoroquinolones are bactericidal in action.  Mechanism of resistance The point mutations of the gene that encode GyrA, a subunit of the DNA gyrase enzyme is the mechanism of resistance to these drugs.  Pharmacokinetics and classification They have good oral bioavailability and they penetrate most body tissues except the CNS. Peak serum levels reach after 3 hours of administration. Food does not impair oral absorption, Delays the time to peak the serum concentration. Serum half-lives vary with from 3-11 hours. Route of elimination differ among quinolones. Specifically, Ofloxacin, Lomefloxacin, and Cinoxacin are eliminated renally. Pefloxacin and nalidixic acid are eliminated non-renally. Pefloxacin and nalidixic acid do not require dose adjustments. Gemifloxacin is excreted renally. Moxifloxacin has elimination via renal and biliary routes Levofloxacin is mainly eliminated renally Dosage adjustment is needed in case of renal dysfunction in cases of Cinoxacin, Norfloxacin, Ciprofloxacin, Ofloxacin, Enoxacin, and Lomefloxacin.  Antimicrobial Spectrum The fluoroquinolones5594 are bactericidal and more potent against E. coli, Salmonella, Shigella, Enterobacter, Campylobacter (diarrhea, dysentery, periodontitis) and Neisseria. MIC for 90% of these strains is less than 0.2ug/ml. Ciprofloxacin is more active than norfloxacin for Pseudomonas aeruginosa, enterococci and pneumococci. Ciprofloxacin, Ofloxacin, Pefloxacin, Moxifloxacin and Levofloxacin have good activity against Staphylococci, including MRSA (?) Resistance to these drugs may develop during therapy. Fluoroquinolones are effective against gram-negative organisms such as Pseudomonas, Haemophilus influenzae, Moraxella catarrhalis, Legionella, Brucella, Mycoplasma, Chlamydia and Mycobacteria. For mycobacteria, Ciprofloxacin, Ofloxacin, have MIC90 0.5 to 3 ug/ml They are effective in the treatment of gonorrhea, but not syphilis. They are used prophylactically in transurethral surgeries to lower post surgical UTI.  Indications.. Respiratory tract infections: They have poor in-vitro activity against Strep. pneumoniae and anaerobic bacteria. Therefore, beta lactams are preferred over quinolones against these organisms. Levofloxacin & Moxifloxacin have good invitro activity against Strep. Pneumonia and anaerobic bacteria while retaining its activity against other respiratory pathogens. Levofloxacin is known as a “respiratory” fluoroquinolone given orally and intravenously. Levofloxacin is very effective in treating community- acquired, nosocomial and ventilator-associated pneumonias. Ciprofloxacin is used in combination with vancomycin as empiric therapy of methicillin resistant Staph aureus (MRSA) and Pseudomonas aeruginosa infections Fluoroquinolones have good in-vitro activity against the rest of the respiratory pathogens such as H. influenzae, Moraxella catarrhalis, Staph. aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae and legionella pneumophilia. In patients with cystic fibrosis, P. aeruginosa infections has been well managed with oral fluoroquinolones. Moxi onlyResp UTI Ciproor Leved  INDICATIONS UTI: Fluoroquinolones are well used. Norfloxacin (Noroxin) is approved in the US only for UTI. Norfloxacin, Cipro, Levofloxacin and Ofloxacin and TMP-SMX are equally efficacious in treating UTIs. Moxifloxacin does not reach adequate therapeutic levels in the urinary tract and therefore not indicated for the treatment of urinary tract infections (UTIs). Prostatitis: Norfloxacin, Cipro, Levo and Ofloxacin are all equally efficacious. In TMP- SMX non-responders, 4 to 6 weeks of fluoroquinolones appear to be effective. STDs: Fluoroquinolones have no activity against Treponema pallidum. shypa.is It is important to remember that fluoroquinolones are contraindicated in pregnancy. For Chlamydia urethritis, a 7-day course of ofloxacin is given. Ofloxacin and ciprofloxacin are effective against gonorrhea, as an alternative to IM ceftriaxone (Rocephin) or oral cefixime (Suprax), but resistant strains are emerging and use is not recommended. Chancroid (soft sore, an STD caused by Hemophilus ducreyi resulting in enlargement and ulceration of lymph nodes in the groin) can be treated  INDICATIONS GI and Abdominal infections: Ecoli For traveler’s diarrhea and shigellosis (Norfloxacin, Ciprofloxacin or Ofloxacin). Norfloxacin is superior to TMP-SMX in decreasing diarrhea in cholera. Cipro and Ofloxacin cure most patients with S. typhi enteric fever.  Delafloxacin is used in ASSSIs (acute skin and skin structure infections) and Community acquired pneumonia (CAP), oral and parenteral formulations are available.  INDICATIONS Bone Joint and Soft Tissue infections: The chronic osteomyelitis requires prolonged treatment of weeks to months, against Staph aureus. Fluoroquinolones due to its oral availability and spectra are appropriate drugs. In diabetic foot infections with commonly caused by anaerobes, gram-negative rods, Streptococci and Staphylococci, the fluoroquinolones are given along with a drug for anaerobic coverage. Multidrug TB regimen: In multiple drug regimens for multi-drug resistant tuberculosis and for atypical mycobacterial infections as well as M. avium complex (MAC) in AIDS patients (Cipro is given with clarithromycin and Amikacin in 3-drug regimen or along with rifampin, ethambutol and Clofazimine in 4 drug regimen for MAC in HIV patients).  Fluoroquinolones comparison (Katzung 15th edition) Oral Peak Serum Primary Route Drug Half-Life (h) Bioavailability Concentration Oral Dose (mg) of Excretion (%) (mcg/mL) Ciprofloxacin 3–5 70 2.4 500 twice daily Renal Delafloxacin 4–8 59 7.5 450 twice daily Renal and nonrenal Gemifloxacin 8 70 1.6 320 once daily Renal and nonrenal Levofloxacin 5–7 95 5.7 500 once daily Renal Moxifloxacin 9–10 >85 3.1 400 once daily Nonrenal useinRenalcompromisedpatients Norfloxacin 3.5–5 80 1.5 400 twice daily Renal Ofloxacin 5–7 95 2.9 400 twice daily Renal  Other indications Used in neutropenic cancer patients with fever. In neutropenic patients, gram-negative bacteremias have been decreased with the use of quinolone prophylactically. Ciprofloxacin and Ofloxacin are occasionally used in the treatment of tuberculosis and atypical mycobacteria. Ciprofloxacin and Ofloxacin also treat meningococci in carriers. Resistance to the drug is mainly by point mutations on the sites on the enzymes where fluoroquinolones bind. Renal elimination: ofloxacin, lomefloxacin, cinoxacin, norfloxacin, ciprofloxacin, enoxacin. Non renal: Nalidixic acid, Pefloxacin  Toxicity of fluoroquinolones GI disturbances (diarrhea, nausea vomiting), Skin rashes, Headache, Dizziness, Insomnia, and Abnormal liver functions. Not recommended in young patients and in pregnancy (due to cartilage erosion). Arthralgia, Joint swelling, tendonitis and tendon rupture have been reported with fluoroquinolones. Fluoroquinolones are not recommended for use in people aged under 18 years as they are associated with arthropathy and damage to immature cartilage of weight-bearing joints.  Urinary antibiotics Nitrofurantoin (1953) Active in acidic urine. Inhibits acetyl CoA thus carbohydrate metabolism. Used UTI (E. coli) infections. Very similar in properties to Nalidixic acid. Adverse effects acute pneumonitis and neuropathies. In glucose-6-phosphate dehydrogenase (glucose oxidation) deficient patients, it may cause hemolysis. Due to hemolytic anemia, contraindicated in neonates and pregnant women. Methenamine (1939) Methenamine decomposes at acidic pH in the urine to produce formaldehyde. Methenamine mandelate (mandelate lowers pH) and methenamine hippurate combine to result in urinary acidification and release of formaldehyde. Proteus strains increases pH of the urine, therefore these drugs are inactive against these strains. Bacterial resistance do not develop against formaldehyde. Sulfonamides form insoluble complexes, so should not be used concurrently. In renal insufficient patients, mandelate precipitates. Used in chronic suppressive therapy. Contraindicated in hepatic insufficient patients (due to NH3 production).