IMPORTANCE OF FLUOROQUINOLONES IN HUMAN HEALTHCARE: A COMPREHENSIVE REVIEW

IMPORTANCE OF FLUOROQUINOLONES IN HUMAN HEALTHCARE: A COMPREHENSIVE REVIEW

Girish M. Bhopale

Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Tathawade, Pune, 411033, Maharashtra, India

ABSTRACT:Fluoroquinoloes are a very important group of antibacterial agents that are widely prescribed for the treatment of infectious diseases in humans. These agents have excellent bioavailability and good tissue penetration with antimicrobial   activity against pathogens especially resistance to other class of antimicrobial drugs. This article gives a comprehensive review on different aspects of fluoroquinolones such as discovery, structural modifications, pharmacokinetic properties, antibacterial activity, present status of important drugs in which pharmacists and medical microbiologists should be interested.

Fluoroquinolones, Antibacterial agents, Emerging resistance, Ocular infections

INTRODUCTION: Fluoroquinolones gained wide spread use as antibacterial drugs for the human healthcare after the development of norfloxacin and ciprofloxacin in 1980’s. Thereafter more fluoroquinolones have been developed ^{1 - 2}. The usefulness of newer fluroquinolones has been greatly expanded due to their improved properties as compared to older members. Simultaneously fluoroquinolones resistance strains have also developed as a consequence of their heavy uses ³.

In view of this, the present article gives a comprehensive review on different aspects of fluoroquinolones especially present status of their clinical uses and development of resistance against bacteria.

 Background information:

The first quinolone discovered was nalidixic acid in 1962 as a byproduct of antimalarial research.  Further structure modifications to the quinolone nucleus have resulted in the production of number of fluoroquinolones ^{1- 2, 4}.  The selected important fluoroquinolones for human uses are present in Table 1 ^{4 - 6}.

These structural modifications Figure 1 have altered mainly to improve the pharmacokinetic and antimicrobial activity of the fluoroqunolones Table 2 ^{5, 7- 8}.

FIGURE 1: CHEMICAL STRUCTURE OF CLINICALLY IMPORTANT FLUOROQUINOLONES AVAILABLE IN MARKET FOR HUMAN USE

TABLE 1: SELECTED CLINICALLY IMPORTANT FLUOROQUINOLOES

 TABLE 2: STRUCTURAL MODIFICATIONS OF FLUOROQUINOLONES WITH SUPERIOR PROPERTIES.

Fluoroquinolones have favorable pharmacokinetic properties that have encouraged their widespread clinical usages Table 3 ^{6, 9-10}. They are well absorbed and have good tissue penetration but absorption is inhibited by coadministration with antacids containing divalent metals such as magnesium, calcium and iron which they form insoluble chelates. Most fluoroquinolones are eliminated via the kidney. Moxifloxacin which is eliminated via the hepatic route is lacking antimicrobial activity against genitourinary infections.

The currently marketed fluroquinolones have safety profiles similar to that of other antimicrobial classes. Some of the serious effects occur with fluroquinolones includes CNS and tendon toxicity ¹¹.

Fluoroquinolones have broad spectrum activity against many clinically important bacteria which are mainly responsible for the bacterial infections of urinary tract, gastrointestinal, respiratory tract and skin Table 4 ^12-17. Fluoroquinolones exhibit concentration dependent antibacterial activity and inhibit the two bacterial enzyme, DNA gyrase [target for gram negative bacteria] and topoisomerase IV [target for gram positive bacteria].

 TABLE 3. PHARMACOKINETICS OF CLINICALLY IMPORTANT FLUOROQUINOLONES.

 TABLE 4: ANTIBACTERIAL ACTIVITY OF SELECTED IMPORTANT FLUOROQUNOLONES.

* Gram Negative bacteria, ** Gram positive bacteria *** Other bacteria

 Present status:  

General clinical use: Nalidixic acid, the first generation agent has moderate gram negative activity and minimal systemic distribution and today less often used ¹.

Second generation fluoroquinolones such as ciprofloxacin, ofloxacin and levofloxacin have expanded gram negative activity but limited gram positive activity. Norfloxacin is primarily used to treat gastrointestinal or genitourinary infections ¹². It is good for bacterial diarrhea because high concentrations are present in the gut and anaerobic flora is not disturbed ⁹. Ciprofloxacin is the one of the most potent fluoroquinolone active against a broad range of bacteria and used worldwide. It is used for the treatment of urinary tract infections, respiratory tract infections, skin, bone, joint and gastrointestinal infections caused by gram negative and gram positive bacteria ^13. Ofloxacin has intermediate antibacterial activity between ciprofloxacin and norfloxacin against gram negative bacteria but more potent than ciprofloxacin for gram positive organisms ⁹.

It is generally used for respiratory tract infections and urinary tract infections ¹⁴. Ofloxacin is available worldwide. Levofloxacin [levoisomer of ofloxacin] having improved activity against Strep. pneumoniae and some other gram positive and gram negative bacteria ^9. The antibacterial spectrum of enoxacin, lomefloxacin and pefloxacin is similar to that of norfloxacin and use of these fluoroqunolones is now limited due to availability of newer highly active fluoroqunolones ¹⁸.

Third generation fluoroquinolones retain expanded gram negative and atypical intracellular activity but have improved gram positive coverage.  The main advantages of sparfloxacin over older fluoroquinolone are its improved activity against gram positive pathogens (especially Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus spp,), Bacteroides fragilis and Mycobacteria ⁹.

Sparfloxacin was withdrawn from USA market due to severe photosensitivity but remains available in Japan, India and some parts of Europe. Gatifloxacin has good activity against many gram positive and negative respiratory pathogens, atypical organism and some anaerobes ¹⁹. However, gatifloxacin is associated with the risk of hypoglycemia and hyperglycemia ²⁰. Grepafloxacin and temafloxacin had a broad range of activity against gram positive as well as gram negative pathogens with some advantages but due to a high rate of reported adverse reactions including several death these were discontinued ²¹.

Tosufloxacin is used for the treatment of respiratory and gastrointestinal tract infections as well as genitourinary, hepatobiliary and orthopedic infections ²². It has a controversial safety profile and associated with severe thrombocytopenia and nephritis, and hepatotoxicity ²³. It is available in Japan and some Asian countries.

Fourth generation agents improve gram positive coverage maintaining gram negative coverage and gram anaerobic coverage. Trovafloxacin had better positive bacterial coverage and less gram negative coverage than previous fluoroquinolones ²².

However it was withdrawn from the market due to the risk of hepatotoxicity ²⁴. Moxifloxacin has a broad spectrum activity and is used for the treatment of respiratory, skin and gastrointestinal infections ^{25, 26, 27}.  Other clinical conditions in which moxifloxacin may be considered for use includes diabetic foot infections, intra-abdominal sepsis, pelvic inflammatory diseases and TB ²⁸.

Gemifloxacin is used for the treatment of acute bacterial exacerbations of chronic bronchitis and commonly occurred pneumonia of mild to moderate severity ²⁹. Sitafloxacin was recently approved in Japan for the treatment of respiratory and urinary tract infections and especially very effective against methicillin resistant Staphylococci, Streptococcus pneumonia ³⁰. Prulifloxacin has been used in Italy and Japan for the treatment of urinary tract infection and also in several European countries for the treatment of urinary tract infections and exacerbations of chronic bronchitis ³¹.

Newer fluoroquinolones such as delafloxacin ³², zalbofloxacin ³³ and finafloxacin ³⁴ are undergoing different phases of clinical trials. Delafloxacin has an anionic character which results in a 10 fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH. This property is believed to confer to delafloxacin an advantage for the eradication of Straphylococcus aureus in acidic environments including intracellular infections ³².

It is under phase III clinical trials for the study of acute bacterial skin infections ³⁵. Zabofloxacin is undergoing phase II clinical trials for the treatment of community acquired pneumonia. Finafloxacin is with the unique property of increasing antibacterial activity at pH values lower than neutral. It is undergoing safety profile studies in human.

Ophthalmic uses:

Topical fluoroquinolones are used as antibacterial for the treatment of ocular infectious diseases such as conjunctivitis, keratitis and endophthalmitis. Ciprofloxacin (0.3% solution), ciprofloxacin (3mg/g ointment), ofloxacin (0.3% solution), gatifloxacin (0.3% solution), levofloxacin (0.5% and 1.5 % solution) and moxifloxacin (0.5%solution) are most commonly used ^{36- 37}.

A comparative study indicated that levofloxacin was highly active against streptococcal pneumonia and streptococcus viridians [isolated from keratitis and endophthalmitis patients] than ofloxacin and ciprofloxacin ³⁸. Further another study indicated that gatifloxacin and moxifloxacin were more potent than ciprofloxacin, ofloxacin and levofloxacin for gram positive bacteria and equally potent against gram negative bacteria. Duggirala and her colleagues ⁴⁰ reported that levofloxacin, gatifloxacin and moxifloxacin were more effective against gram positive bacteria and ciprofloxacin was most effective fluoroquinolone against gram negative bacteria.

 Emerging resistance:                     

With increasing utilization of fluoroquinolones in human health, emerging resistance for these agents has also increased. Various studies indicated that bacterial resistance to the fluoroqunolones is an emerging problem especially in Asia, America and other countries. ^{3 - 4}. Major resistance is developed due to three reasons ⁴¹. The first involves mutation of any one or both the enzymes, DNA gyrase and topoisomerase IV. The second reason involves the differential expression of efflux mechanism and third is due to the presence of a plasmid generally found in gram negative organisms that can be horizontally transferred.

As fluoroquinolone resistance increase worldwide, enormous challenge will be placed on physicians and industry.  Efforts to promote their judicious clinical use are therefore essential.

Research efforts are required for further modifications in the quinolone nucleus that may produce newer compounds which may have greater potency, better penetration into the CNS and cerebrospinal fluid, better patient tolerability with lower incidence of adverse reactions and serious toxicity. Further resistance can be overcome by synthesizing drugs that act equally on both the enzymes [DNA gyrase and topoisomerase IV]. This would require a concomitant mutation in both the enzymes to confer high level of resistance and this has less probability to occur than sequential mutations. Newer fluoroquinolone derivatives developed with the consideration of factors like hydrophobicity and structural features could avoid being pumped out by the efflux mechanisms.

 CONCLUSION: From all the information collected from various sources, it is observed that the fluoroquinolones have many favorable properties including broad spectrum activity. As a result they are widely used clinically and their uses as constantly growing. Misuse of these drugs has resulted in one of the problem of bacterial resistance that we face today. it is advised to use these drugs judiciously for specific condition.

In Australia ⁴² the use of fluroqiunolones in human and animals has been restricted through its national pharmaceutical subsidy scheme and through regulation. As a consequence resistance to fluoroquinolones in the country has been slow in emergence and has remained at low levels in key pathogens therefore appropriate use of fluoroquinolones will preserve its choice as an antibacterial drug for longer clinical uses.

 ACKNOWLEDGEMENTS: I wish to thank Dr. M. Khetmalas, Director, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Tathawade, Pune for the encouragement.

REFERENCES:

1. Emami S, Shafiee A and Foroumadi A: Quinolones: Recent structural and clinical developments. Iranian Journal of Pharmaceutical Research 2005; 3:123-136.
2. Sharma PC, Jain A and Jain S: Fluoroqunolone antibacterials: A review on chemistry, Microbiology and therapeutic prospects. Acta Poloniae Pharmaceutica – Drug Research 2009; 66: 587-604.
3. Dalhoff A: Global fluoroquinolone resistance epidemiology and implications for   clinical use. Interdisciplinary Perspectives on Infectious Diseases. 2012; 2012 Article ID 976273, 37 pages.
4. http:// Wikipedia.org/wiki/qunolone [Accessed on August 6, 2014]
5. Andriole VT: The quinolones: Past, Present, and future. Clinical Infectious Diseases.2005; 41: S113-119.
6. Bolon MK: The newer fluoroqunolones. Medical Clinics of North America. 2011; 95: 793-817
7. Sharma HL and Sharma KK: Quinolones and Treatment of urinary tract infection. Principles of Pharmacology, Paras Medical Publisher, Hyderabad & New Delhi: 728-735.
8. Somasundaram S and Manivannan K: An overview of fluoroquinolones. Annual Review & Research in Biology. 2013; 3:296- 313.
9. Tripathi KD: Sulfonamide, Cotrimoxazole and Quinolones, Essential of medical pharmacology, Jaypee Brothers Medical Publisher [Pvt]. Ltd., New Delhi, 2009; 682-693.
10. Stuat RL: Sitafloxacin, Kucers’ the use of Antibiotics. A clinical review of antibacterial antifungal, Antiparasite and Antiviral drugs. Vol. 1, Six Edition, CRC press, 2010; 1475.
11. Owens RC and Ambrose PG.: Antimicrobial safety: Focus on fluoroquinolones. Clinical Infectious Diseases. 2005: 41: S144-157.
12. http://www.drugs.com/monograph/norfloxacin html.[Accessed on August 28, 2013]
13. http:/www.drugs.com/pro/Ciprofloxacin.html  [Accessed on August 28, 2013]
14. http:/www.drugs.com/pro/ofloxacin,.html  [ Accessed on August 28, 2013]
15. http:/www.drugs.com/pro/Levofloxacin.html [ Accessed on August 28, 2013]
16. http:/www.drugs.com/pro/Avelox html [Accessed on August 28, 2013]
17. http:/en Wikipedia.org/wiki/gemifloxacin [Accessed on August 28, 2013]
18. Charles PGP: Enoxacin. Kucers’ the use of Antibiotics. A clinical review of antibacterial antifungal, Antiparasite and Antiviral drugs. , Vol. 1, Six Edition, CRC press, 2010, 1482.
19. Perry CM, Ormrod D, Hurst M and Onrust SV:  Gatifloxacin: a review of its use in the management of bacterial infections. Drugs 2002; 62: 1269-2007.
20. Park-Wyllie L, Jurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, Dresser L, Low DE and  Mamdani MM :Outpatient Galtifloxacin therapy and dysglycemia in older adults. New England Journal of medicine. 2006; 354: 1352-136.
21. Swaminathan A, Charles PGP and Gryson ML: Newer, discontinued fluoroquinolones: Temafloxacin, Trovafloxacin, Grepafloxacin and Clinafloxacin, Kucers’ the use of Antibiotics. A clinical review of antibacterial antifungal, Antiparasite and Antiviral drugs.  Vol. 1, Six Edition, CRC Press, 2010:1538.
22. Charles PGP: Tosufloxacin,   Kucers, The use of Antibiotics. A clinical review of antibacterial antifungal, Antiparasite and Antiviral drugs Vol. 1, Six Edition, CRC Press; 2010:1521.
23. http// en .Wikipedia .org/Wiki/Tosufloxacin. [Accessed on August 28, 2013]
24. http//en .Wikipedia .org/Wiki/Trovafloxacin [ Accessed on August 28, 2013]
25. http//en .Wikipedia .org/Wiki/Gemifloxacin [Accessed on August 28, 2013]
26. Simoens S and Decramer M: A pharmacoeconomic review of the management of respiratory tract infections with moxifloxacin .Expert Opinion on Pharmacotherapy 2008; 9: 1735-1744.
27. Cheadle W, Lee JT, Napolitano LM and Nichols RL:  Clinical update on the use of moxifloxacin in the treatment of community acquired complicated intraabdominal infections. Surgical Infections (Larchmt) 2010; 11: 487-494.
28. Stuart RL. Moxifloxacin,Kucers’ The use of Antibiotics. A clinical review of antibacterial antifungal, Antiparasite and Antiviral drugs. Vol. 1, Six Edition, CRC Press, 2010:1412.
29. En .Wikipedia .org/Wiki/Gemifloxacin
30. Anderson DL: Sitafloxacin hydrate for the bacterial infections. Drugs Today, 2008; 44: 489-501.
31. Rafailidis PI, Polyzos KA, Sgoouros K and Falagas ME: Prulifloxacin: a review focusing on its use beyond respiratory and urinary tract infections. International Journal of Antimicrobial Agents. 2011; 37: 283-290.
32. http: en. Wikipedia. org/ w/index.php? title= Delafloxacin &oldid=555927900
33. Han H, Kim SE, Shin KH, Lim C, LimKS, Yu KS Cho JY: Comparison of pharmacokinetics between new qunolone antibiotics: the zabofloxacin hydrochloride capsule and the zabofloxacin asparttate tablet. Current Medical Research and Opinion; 2013, Aug 19 [ Epub ahead of print].
34. Patel H, Anderson A, Vente A. HeilmannHD, Stubbings W, Seiberling M. Lopez-Lazaro L, Pokorny R. Labischinski H. Human pharmacokinetics and safety profile of finafloxacin, a new fluoroqunolone antibiotic in healthy volunteers. Antimicrobial Agents Chemotherapy 2011; 55: 4386-4393.
35. www.rib-x.com/investors/press-release-2013.
36. Scoper SV: Review of third and fourth generation fluoroqunolones in ophthalmology: In vitro and in vivo efficacy. Advances in Therapy 2008; 25: 979-994.
37. Haas W, Pillar CM, Zurenko GE, Lee JC, Brunner LS and Morris TW:  Besifloxacin, a novel fluoroqunolone has broad spectrum in vitro activity against aerobic and anaerobic bacteria. Antimicrobial Agents Chemotherapy; 2009, 53: 3552-3560.
38. Miller D. and Alfonse EC   Comparative in vitro activity of levofloxacin, ofloxacin and ciprofloxacin against ocular streptococcal isolates. Cornea 2004; 23: 289-93.
39. Mather R, Karenchak LM, Romanowski EG and Kowalski RP:  Fourth generation fluoroqunolones: new weapons in the arsenal of opthalimmic antibiotics. American Journal of Ophthalmology; 2002; 133: 463-466.
40. Duggirala A, Josephh J, Sharma S, Nutheti R, Garg P. and Das T. Activity of newer fluoroqunolones against gram positive and gram negative bacteria isolated from ocular infections. An in vitro comparison. Indian Journal of Ophthalmology: 55: 15-19.
41. Guan X, Xue X, Liu Y, Wang J, Wang Y. Wan J, Wang K, Jiang H, ZhangL, Yang B, Wang N, and Pan L: Plasmid mediated qunolone resistance- current knowledge and future perspectives. Journal of International Medical Research 2013: 41: 20-30.
42. Cheng AC, Turnidge J, Collignon P, Looke  D, Barton M, Gottlieb T.: Control of Fluoroqunolone resistance through successful regulation, Australia  Emerging Infecious Diseases 2012, 18: 1-13.
    

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    How to cite this article:

    Bhopale GM: Importance of Fluoroquinolones in Human Healthcare: A Comprehensive Review. Int J Pharm Sci Res2014; 5(12): 5097-03.doi: 10.13040/IJPSR.0975-8232.5 (12).5097-03.

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