International journal of advance research and innovation
Volume 2, Issue 2 (2014) 373-378 ISSN 2347 - 3258 International Journal of Advance Research and Innovation Fluoroquinolones-A New Definition of AntibioticsNishant Verma *, a, K. K. Jha a, Rajesh Sharma a, Niraj K. Singh a, Ajai Kumar Singh b,
Sachin Tyagi c, Umesh kumar d
a Department of Pharmacy, T. M. College of Pharmacy, TMU, Moradabad, Uttar Pradesh, India
b Department of Pharmaceutics, Gandhi College of Pharmacy, Karnal, Haryana, India
c School of Pharmacy, Bharat Institute of Technology, Meerut, Uttar Pradesh, India
d Translam Institute of Pharmaceutical Education & Research, Meerut, Uttar Pradesh, India
Abstract
Article Info
Fluoroquinolones have been regarded as the latest class of antibacterials Article history: derived from the synthetic origins possessing broader spectrum of bactericidal Received 2 March 2014 activity. They were first discovered in early 1960s but introduced as Received in revised form antibacterials in 1986. These drugs fall in to four generations. Chemically they are modified quinolones. The first generation quinolones were widely used, Accepted 20 May 2014 pertaining to their suitability in oral application, for the treatment of serious Available online 15 June 2014 infections caused by gram (-) ve organisms including pseudomonas. The Keywords
current fourth generations, fluoroquinolones have got splendid areas of chemical chemotherapy against varieties of afflictions etiologically induced by gram (+) ve and gram (-) ve bacteria, aerobic and anaerobic microorganisms even significantly in community acquired pneumonia, intra abdominal infections as well.
1. Introduction
2. Classification
The evolution of quinolones actually originated from the discovery of nalidixic acid in 1962 as a by-product of Classifications are of the following types: Table 1 and 2. antimalarial research it is the first representative of the 3. Mechanism of Action
The bactericidal effects of fluoroquinolones like earlier microbes.1 Nalidixic acid became the lead compound for quinolones are mediated through their ability to block medicinal chemists for structural modifications to get many activity of bacterial DNA gyrase enzyme system. The newer fluoroquinolones in order to getrid of its three major function of this enzyme is to enable the long bacterial DNA shortcomings are narrow spectrum covering Gram (-ve) to fit into the cell through supercoiling. In linear as well as organisms, achieves inadequate tissue levels for systematic circular DNA, the two strands of polynucleotides are coiled infections and bacterial resistance development.2 around each other so as to form a double helix.7 There are This opened the flood gate for synthesizing newer and approximately 10 base pairs per turn of helix. Every time more interesting fluoroquinolones.3 Out of more than 8000 one of the strands of DNA winds with each other and makes analogues of fluoroquinolones synthesized bearing variety a link. Thus a circular DNA containing several base pairs is of ring systems, a few dozens have been established in the expected to contain about 500 links. When such a number in market, and more are in the horizon to be introduced.4 Such a molecule is less than 500, the molecule becomes strained. an explosive growth of this group of compounds occurred To relieve the strain it supercoils and results in further mainly due to three factors; firstly, an unprecedented mode coiling making a supercoiled structure.8 The supercoiled of action depending on inhibition ability of susceptible DNA occupies less space than the relaxed DNA. In cells micro-organisms to shape their DNA for storage or and in microorganisms enzymes topoisomerases control replication; secondly, their potency and antimicrobial super coiling e.g. Gyrase. The inactivation of gyrase kills spectrum being equally comparative to the desired the bacterial cell by distrupting the DNA supercoiling so fermentation-based semi-synthetic antibiotics; and finally, that DNA can no longer be contained within the cell and it their chemical structure being simple, a large number of bursts. The DNA gyrase is composed of two subunits A & analogues could be prepared following simple synthetic B. A is coded with gyrase A gene and has the molecular size sequences in a cheaper way from readily available of 9700 daltons.9 The sub unit B has a molecular size of 89,835 daltons Further, rapid progress has been made towards and is coded by the gyr B gene. The effect of quinolones on broadening their spectrum of activity based on structure- DNA replicative enzymes in mammalian cells and activity relationship (SAR) to treat various systemic molecular mechanism of inhibition of DNA gyrase by such infections other than that of urinary tract infections (UTI) 5, agents have been investigated extensively.10 Quinolones improving their pharmacokinetic properties 6 and to reduce bind co-operatively to DNA gyrase-induced specific sites on adverse reactions, especially central nervous system (CNS) relaxed DNA. These investigations revealed that quinolones side effects; which is common among these group of do not bind to DNA gyrase at their inhibitory concentrations rather conjugate preferentially to single-stranded DNA.11 Corresponding Author,
This showed that quinolones bind poorly to relaxed double E-mail address: [email protected]
stranded DNA but specifically to a saturable site on All rights reserved: http://www.ijari.org
supercoiled DNA in a highly co-operative manner and such Volume 2, Issue 2 (2014) 373-378 ISSN 2347 - 3258 International Journal of Advance Research and Innovation Table: 1. On the basis of chemical composition of fluoroquinolones
Miloxacin Abufloxacin Droxacin Ofloxacin EN 272 Rufloxacin Levofloxacin QA 241 Purfloxacin Merbofloxacin Pyrido [2-3] pyrimidine Pipedemic Acid Acroxacin Premidic Acid WIN 35439 Nalidixic Acid 6- Fluorinated
Norfloxacin
Pirlofloxacin Y2504 Volume 2, Issue 2 (2014) 373-378 ISSN 2347 - 3258 International Journal of Advance Research and Innovation Table: 2. On the basis of Biological properties of fluoroquinolones
Limited spectrum (Enterobacterinceae) Nalidixic acid Pipemidic acid Pipromidic acid Cinoxacin Miloxacin Ofloxacin Lomefloxacin Volume 2, Issue 2 (2014) 373-378 ISSN 2347 - 3258 International Journal of Advance Research and Innovation binding to relaxed double stranded DNA is enhanced by resistant bacteria, eg, pseudomonas.18 These agents are also DNA gyrase. They are bactericidal at concentrations above effective for bacterial diarrhea caused by shigella, MIC. The bactericidal action of older quinolones such as nalidixic acid was inhibited by the simultaneous addition of Fluoroquinolones (except norfloxacin, which does not rifampin suggesting that protein synthesis was a achieve adequate systemic concentrations) have been used requirement for bactericidal action for E. coli even in in infections of soft tissues, bones, and joints and in intra- presence of rifampin or chloramphenicol.12 It was also abdominal and respiratory tract infections, including those concluded that these compounds were bactericidal for non- multidrug-resistant dividing cells also. New quinolones such as ciprofloxacin is pseudomonas and enterobacter.19 Ciprofloxacin is a drug of less active against Gr (+ve) than against Gr (– ve) bacteria choice for prophylaxis and treatment of anthrax, although suggesting the bactericidal mechanism of ciprofloxacin the newer fluoroquinolones are active in vitro and very against Gram (+ve) and Gr (-ve) bacterial cell is different. likely in vivo as well.20 This difference in mechanisms may be the attributed to Ciprofloxacin and levofloxacin are effective for inability of ciprofloxacin to achieve bactericidal cure in gonococcal infection, including disseminated disease and Staphylococcal infections.13 Therefore, it appears that some of the newer levofloxacin, or moxifloxacin is occasionally used for fluoroquinolones treatment of tuberculosis and atypical mycobacterial lomefloxacin etc. also damage the bacterial cell memberane infections.22 They may be suitable for eradication of which leads to loss of cell contents. This unique mode of meningococci from carriers or for prophylaxis of infection action of newer fluoroquinolones is mainly responsible for in neutropenic patients.23 infrequent occurrence of bacterial resistance to this drugs.14 Currently it is established that the mode of action of moxifloxacin are called respiratory fluoroquinolones, with quinolones involves interaction with both DNA gyrase, (the their enhanced gram-positive activity against atypical originally recognised drug target) and topoisomerase IV (a pneumonia agents (eg, chlamydia, mycoplasma, and related type II topoisomerase). In a bacterial cell, these two legionella), are effective and used increasingly for treatment enzymes often differ in their relative sensitivities to many of upper and lower respiratory tract infections.24 quinolones and commonly DNA gyrase is more sensitive to 5. Pharmacokinetic
Properties
Gram (-ve) bacteria while topoisomerase IV is more sensitive in Gram (+ve) bacteria.15 Usually the more sensitive enzyme represents the primary drug target After oral administration, the fluoroquinolones are well determined by genetic tests with poorly understood absorbed (bioavailability of 80–95%) and distributed widely exceptions. X-ray crystallographic studies of a fragment of in body fluids and tissues (Table 1). Serum half-lives range the gyrase A subunit as well as of yeast topoisomerase IV from 3 to 10 hours. The relatively long half-lives of have revealed domains that likely include DNA and levofloxacin, gemifloxacin gatifloxacin, and moxifloxacin permit once-daily dosing. Oral absorption is impaired by The inhibition of DNA synthesis by quinolones divalent cations, including those in antacids. Serum requires the targeted topoisomerase to have DNA cleavage concentrations of intravenously administered drug are capability and collisions of replication forks with reversible similar to those of orally administered drug. Most quinolone DNA topoisomerase complexes convert them to fluoroquinolones are eliminated by renal mechanisms, either irreversible forms. However the molecular factors tubular secretion or glomerular filtration (Table 1). Dose subsequently generating DNA doublestrand breaks from adjustment is required for patients with creatinine irreversible complexes and that probably initiate cell death. clearances less than 50 ml/min, the exact adjustment depending on the degree of renal impairment and the 4. Clinically Uses of Fluoroquinolones
specific fluoroquinolone being used. Dose adjustment for Fluoroquinolones (other than moxifloxacin, which renal failure is not necessary for moxifloxacin. Nonrenally achieves relatively low urinary levels) are effective in cleared fluoroquinolones are relatively contraindicated in urinary tract infections even when caused by multidrug- patients with hepatic failure.25 Oral Bioavailability
Peak Serum
Oral Dose
Primary Route of
Life (Hr.)
Conc. (G/Ml
Excretion
Renal & nonrenal 6. Resistance
staphylococci, pseudomonas, and serratia.26 Resistance is During fluoroquinolone therapy, resistant organisms due to one or more point mutations in the quinolone binding emerge about once in 107–109, especially among region of the target enzyme or to a change in the Volume 2, Issue 2 (2014) 373-378 ISSN 2347 - 3258 International Journal of Advance Research and Innovation permeability of the organism. Resistance to one class of antimicrobial agents is being increasingly used fluoroquinolone, particularly if it is of high level, generally empirically as resistance has developed to the more confers cross-resistance to all other members of this class.27 traditional antimicrobial agents. Evidence is mounting that 7. Adverse Effects
suggests a link between inappropriate fluoroquinolone use, development of antimicrobial resistance against the entire Fluoroquinolones are extremely well tolerated. The fluoroquinolone class, and clinical failure. To maintain the most common effects are nausea, vomiting, and diarrhea. activity of the fluoroquinolone class, clinicians need to Occasionally, headache, dizziness, insomnia, skin rash, or implement an evidence-based approach to antimicrobial abnormal liver function tests develop.28 Photosensitivity has selection, particularly a strategy in which the most been reported with lomefloxacin and pefloxacin. QTc pharmacodynamically potent fluoroquinolone is matched, prolongation may occur with gatifloxacin, levofloxacin, on an empiric basis when required, to anticipated bacterial gemifloxacin, and moxifloxacin.29 Ideally, these agents should be avoided or used with caution in patients with Traditional reporting of susceptibility data may be misleading and may not readily identify initial changes in hypokalemia; in those receiving class IA (eg, quinidine or resistance patterns or differences between agents of the procainamide) or class III antiarrhythmic agents (sotalol, same class. To preserve fluoroquinolone activity, the ibutilide, amiodarone); and in patients receiving other activity of these agents must be continually assessed, and agents known to increase the QTc interval (eg, these agents must be used appropriately. The individual erythromycin, tricyclic antidepressants).30 Gatifloxacin has attributes of a given drug should be matched with the likely been associated with hyperglycemia in diabetic patients and pathogen at specific infective sites. Expecting a single with hypoglycemia in patients also receiving oral fluoroquinolone to be suitable for all infections is hypoglycemic agents. Because of these serious effects (including some fatalities), gatifloxacin was withdrawn fluoroquinolone for all indications will lead to resistance from sales in the USA in 2006; it may be available that will adversely affect the entire class. elsewhere.31, 32 Given the defined strategy of selecting the agent with Fluoroquinolones may damage growing cartilage and the best pharmacokinetic and pharmacodynamic profile cause an arthropathy.33 Thus, these drugs are not routinely against the known or suspected pathogen, an appropriate recommended for patients under 18 years of age.34 therapeutic choice for most serious infections, such as However, the arthropathy is reversible, and there is a nosocomial pneumonia in which P. aeruginosa is a known growing consensus that fluoroquinolones may be used in children in some cases (eg, for treatment of pseudomonal ciprofloxacin in combination with an antipseudomonal β- infections in patients with cystic fibrosis).35 Tendinitis, a lactam or an aminoglycoside antibiotic. Ciprofloxacin, rare complication that has been reported in adults, is levofloxacin, and gatifloxain all achieve high concentrations potentially more serious because of the risk of tendon in urine; thus, they would all be appropriate choices for rupture.36 They should be avoided during pregnancy in the treating urinary tract infections in the community. absence of specific data documenting their safety.37 Ciprofloxacin would be the most appropriate therapy in cases where P. aeruginosa is a known or suspected pathogen. For other gram-negative infections, levofloxacin Fluoroquinolones are the fastest growing antibacterial or gatifloxacin should be prescribed in appropriate doses to class in terms of global revenue. Fluoroquinolones surpass the mutant prevention concentrations at the development is based on structure activity relationship while pointing out to their mode of action. However, For infections in which S. pneumoniae is anticipated to increased indiscriminate prescribing has led to recent be the most likely pathogen (e.g., community-acquired occasional emergence of fluoroquinolone resistant bacteria. pneumonia), moxifloxacin, which currently has the best The new fluoroquinolones offer once daily dosing and a antipneumococcal pharmacodynamic activity and the lowest spectrum of activity different from that of existing mutant prevention concentrations against this organism. The fluoroquinolones. These differences should be placed in the targeted strategy proposed in this review is being context of local epidemiology, antibiotic resistance profiles implemented in a variety of institutions since the and patterns of antibiotics. Consideration of the newer introduction of the third-generation fluoroquinolones. Due fluoroquinolones for a hospital or provincial formulary to these reasons, fluoroquinolones have been increasingly should take into account the potential economic advantages used in the recent past. But care must be taken while with respect to dosing, acquisition cost and adverse effects prescribing the dose and the dosage regime so that the as well as potential for overuse of this class of agents. The new fluoroquinolones offer a useful addition to our current fluoroquinolones also. armamentarium of antibiotics for the institutional and community management of infections. The fluoroquinolone Reference
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Journal of Drug Issues 31(2), 325-394, 2001 Nicotine as an Addictive Substance: A Critical Examination of the Basic Concepts and EmpiricalEvidence Dale M. Atrens Dale Atrens received a B.A. from the University of Windsor, an A.M. from Hollins College, and a Ph.D. from Rutgers University. He has heldappointments at universities in North America, Europe, Asia, and Australia. He is currently a Reader in psychobiology at the University of Sydney.He is the author of several neuroscience textbooks and a number of popular books on diet and lifestyle.