Quinolone

From Wikipedia, the free encyclopedia
  (Redirected from Quinolones)
Jump to: navigation, search
Not to be confused with quinoline.
Essential structure of all quinolone antibiotics: the blue drawn remainder of R is usually piperazine; if the connection contains fluorine (red), it is a fluoroquinolone.

The quinolones are a family of synthetic broad-spectrum antibacterial drugs.[1][2][3]

The first generation of quinolones began with the introduction of nalidixic acid in 1962 for treatment of urinary tract infections in humans.[4] Nalidixic acid was discovered by George Lesher and coworkers in a distillate during an attempt at chloroquine synthesis.[5] Quinolones exert their antibacterial effect by preventing bacterial DNA from unwinding and duplicating.[6] The majority of quinolones in clinical use belong to the subset fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-7 position.

Medical uses[edit]

Fluoroquinolones are broad-spectrum antibiotics (effective for both gram-negative and gram-positive bacteria) that play an important role in treatment of serious bacterial infections, especially hospital-acquired infections and others in which resistance to older antibacterial classes is suspected. Because the use of broad-spectrum antibiotics encourages the spread of multidrug-resistant strains and the development of Clostridium difficile infections, treatment guidelines from the Infectious Disease Society of America, the American Thoracic Society, and other professional organizations recommend minimizing the use of fluoroquinolones and other broad-spectrum antibiotics in less severe infections and in those in which risk factors for multidrug resistance are not present.[medical citation needed]

Fluoroquinolones are featured prominently in The American Thoracic Society guidelines for the treatment of hospital-acquired pneumonia.[7] The Society recommends fluoroquinolones not be used as a first-line agent for community-acquired pneumonia,[8] instead recommending macrolide or doxycycline as first-line agents. The Drug-Resistant Streptococcus pneumoniae Working Group recommends fluoroquinolones be used for the ambulatory treatment of community-acquired pneumonia only after other antibiotic classes have been tried and failed, or in those with demonstrated drug-resistant Streptococcus pneumoniae.[9]

Fluoroquinolones are often used for genitourinary infections, and are widely used in the treatment of hospital-acquired infections associated with urinary catheters. In community-acquired infections, they are recommended only when risk factors for multidrug resistance are present or after other antibiotic regimens have failed. However, for serious acute cases of pyelonephritis or bacterial prostatitis where the patient may need to be hospitalised, fluoroquinolones are recommended as first-line therapy.[10]

Due to sickle-cell disease patients' being at increased risk for developing osteomyelitis from the Salmonella genus, fluoroquinolones are the "drugs of choice" due to their ability to enter bone tissue without chelating it, as tetracyclines are known to do.

Specific populations[edit]

Children[edit]

The use of fluoroquinolones to treat infections in children is controversial.

In most countries, fluoroquinolones are approved for use in children only under narrow circumstances, owing in part to the observation of high rates of musculoskeletal adverse events in fluoroquinolone treated juvenile animals. In the UK, the prescribing indications for fluoroquinolones for children is severely restricted. Only inhalant anthrax and pseudomonal infections in cystic fibrosis infections are licensed indications in the UK due to ongoing safety concerns. In a study comparing the safety and efficacy of levofloxacin to that of azithromycin or the ceftriaxone in 712 children with community-acquired pneumonia, serious adverse events were experienced by 6% of those treated with levofloxacin and 4% of those treated with comparator antibiotics. Most of these were considered by the treating physician to be unrelated or doubtfully related to the study drug. Two deaths were observed in the levofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the FDA Adverse Effects Reporting System at the time of the 20 September 2011 FDA Pediatric Drugs Advisory Committee include musculoskeletal events (39, including 5 cases of tendon rupture) and central nervous system events (19, including 5 cases of seizures) as the most common spontaneous reports between April 2005 and March 2008. An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients during that period.[11]

A number of recent meta analyses have concluded that fluoroquinolones pose little or no additional risk to children compared to other antibiotic classes.[12][13][14]

Current recommendations by the American Academy of Pediatrics state that the use of fluoroquinolines in children may be appropriate when the infection is caused by multidrug-resistant bacteria, or when alternative treatment options require parenteral administration and oral therapy is preferred.[15]

Adverse effects[edit]

In general, fluoroquinolones are well tolerated, with most side-effects being mild to moderate.[16] On occasion, serious adverse effects occur.[17] Common side-effects include gastrointestinal effects such as nausea, vomiting, and diarrhea, as well as headache and insomnia.

The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes.[18][19][20][21] A U.S. Centers for Disease Control study found patients treated with fluoroquinolones experienced adverse events severe enough to lead to an emergency department visit more frequently than those treated with cephalosporins or macrolides, but less frequently than those treated with penicillins, clindamycin, sulfonamides, or vancomycin.[22]

Post-marketing surveillance has revealed a variety of relatively rare but serious adverse effects that are associated with all members of the fluoroquinolone antibacterial class. Among these, tendon problems and exacerbation of the symptoms of the neurological disorder myasthenia gravis are the subject of "black box" warnings in the United States. Quinolones are associated with an increase risk of tendinitis and tendon rupture in all age groups. This side effect is most common but not limited to the Achilles tendon. Fluoroquinolone-associated tendinopathy symptoms have occurred as early as 2 hours after the initial fluoroquinolone exposure and as late as 6 months after the medication was discontinued.[23] The most severe form of tendonopathy associated with fluoroquinolone administration is tendon rupture, which in the great majority of cases involves the Achilles tendon. Younger people typically experience good recovery, but permanent disability is possible, and is more likely in older patients.[24] The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin is has been estimated at 17 per 100,000 treatments (three times the rate in people without fluoroquinolone exposure).[25][26] Risk is substantially elevated in the elderly and in those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture.[27] Other risk factors include patients with kidney, heart and lung transplants,strenuous physical activity during or immediately after treatment, renal failure or previous tendon disorders like rheumatoid arthritis. Some experts have advised avoidance of fluoroquinolones in athletes.[23]

Fluoroquinolones (FQs) prolong the heart's QT interval by blocking voltage-gated potassium channels.[28] Prolongation of the QT interval can lead to torsades de pointes, a life-threatening arrhythmia, but in practice this appears relatively uncommon in part because the most widely prescribed fluoroquinolones (ciprofloxacin and levofloxacin) only minimally prolong the QT interval.[29]

Clostridium difficile-associated diarrhea may occur in connection with the use of any antibacterial drug, especially those with a broad spectrum of activity such as clindamycin, cephalosporins, and fluoroquinolones. Fluoroquinoline treatment is associated with risk that is simlar to[30] or less [31][32] than that associated with broad spectrum cephalosporins. Fluoroquinoline administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridium strain.[33]

The U.S. prescribing information contains a warning regarding uncommon cases of peripheral neuropathy, which can be permanent.[34] Other nervous system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis[35] Other rare and serious adverse events have been observed with varying degrees of evidence for causation.[36][37][38][39]

Events that may occur in acute overdose are rare, and include renal failure and seizure.[40] Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.[16][41][42]

Contraindications[edit]

Quinolones are contraindicated if a patient has epilepsy, QT prolongation, pre-existing CNS lesions, or CNS inflammation, or the patient has suffered a stroke.[17] They are best avoided in the athlete population.[43] There are safety concerns of fluoroquinolone use during pregnancy and, as a result, are contraindicated except for when no other safe alternative antibiotic exists.[44] However, one meta-analysis looking at the outcome of pregnancies involving Quinolone use in the first trimester found no increased risk of malformations.[45] They are also contraindicated in children due to the risks of damage to the musculoskeletal system.[46] Their use in children is not absolutely contraindicated, however. For certain severe infections where other antibiotics are not an option, their use can be justified.[47] Quinolones should also not be given to people with a known hypersensitivity to the drug.[48][49]

Pharmacology[edit]

The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon the quinoline ring system.[50] The addition of the fluorine atom at C6 distinguishes the successive-generation fluoroquinolones from the first-generation quinolones. The addition of the C6 fluorine atom has since been demonstrated to not be required for the antibacterial activity of this class (circa 1997).[51]

Mechanism of action[edit]

Structure of bacterial DNA gyrase complexed with DNA and two ciprofloxacin molecules (green)

First and second generation fluoroquinolones selectively inhibit the topoisomerase II ligase domain, leaving the two nuclease domains intact. This modification, coupled with the constant action of the topoisomerase II in the bacterial cell, leads to DNA fragmentation via the nucleasic activity of the intact enzyme domains. Third and fourth generation fluoroquinolones are more selective for topoisomerase IV ligase domain, and thus have enhanced gram positive coverage.

Fluoroquinolones can enter cells easily via porins and, therefore, are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many gram-negative bacteria, DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. Some compounds in this class have been shown to inhibit the synthesis of mitochondrial DNA.[52][53][54][55][56][57][58]

Mechanism of toxicity[edit]

The mechanisms of the toxicity of fluoroquinolones has been attributed to their interactions with different receptor complexes, such as blockade of the GABAa receptor complex within the central nervous system, leading to excitotoxic type effects[17] and oxidative stress.[59]

Interactions[edit]

Products containing multivalent cations, such as aluminium- or magnesium-containing antacids and products containing calcium, iron, or zinc, invariably result in marked reduction of oral absorption of fluoroquinolones.[60] Other drugs that interact with fluoroquinolones include sucralfate, probenecid, cimetidine, theophylline, warfarin, antiviral agents, phenytoin, cyclosporine, rifampin, pyrazinamide, and cycloserine.[60]

Fluoroquinolones have varying specificity for Cytochrome P450, and so may have interactions with drugs cleared by those enzymes; the order from most P450-inhibitory to least, is: enoxacin > ciprofloxacin > norfloxacin > ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin.[60]

Antibiotic misuse and bacterial resistances[edit]

Resistance to quinolones can evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide.[61] Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.[62]

Though considered to be very important and necessary drugs required to treat severe and life-threatening bacterial infections, the associated antibiotic misuse remains unchecked, which has contributed to the problem of bacterial resistance. The overuse of antibiotics such as happens with children suffering from otitis media (ear infections) has given rise to a breed of super-bacteria that are resistant to antibiotics entirely.[63]

For example, the use of the fluoroquinolones had increased threefold in an emergency room environment in the United States between 1995 and 2002.[64][65] Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study supported in part by the Agency for Healthcare Research and Quality.[65][66] In addition, they are commonly prescribed for medical conditions, such as acute respiratory illness, that are usually caused by viral infections.[67]

Three mechanisms of resistance are known.[68] Some types of efflux pumps can act to decrease intracellular quinolone concentration.[69] In Gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drugs' effectiveness.

History[edit]

Nalidixic acid is considered to be the predecessor of all members of the quinolone family, including the second, third and fourth generations commonly known as fluoroquinolones. This first generation also included other quinolone drugs, such as pipemidic acid, oxolinic acid, and cinoxacin, which were introduced in the 1970s. They proved to be only marginal improvements over nalidixic acid.[70]

Since the introduction of nalidixic acid in 1962, more than 10,000 analogs have been synthesized, but only a handful have found their way into clinical practice.

Advocacy groups and regulation[edit]

Several advocacy groups have petitioned the FDA to increase the prominence of adverse effect warnings on the labels of fluroquinolone antibacterials, and to withdraw others from the market.[71][72][73][74][75][76][77]

Boxed warnings[edit]

In the US, the package insert for fluoroquinolone antibiotics includes a boxed warning of increased risk of developing tendonitis and tendon rupture in patients of all ages taking fluoroquinolones for systemic use. This risk is further increased in individuals over 60 years of age, taking corticosteroid drugs, and have received kidney, heart, or lung transplants. Another boxed warning says fluoroquinolones, due to their neuromuscular blocking activity, may exacerbate muscle weakness in persons with myasthenia gravis. Serious adverse events, including deaths and requirement for ventilatory support, have been reported in this group of patients. Avoidance of fluoroquinolones in patients with known history of myasthenia gravis is advised.[78]

Partly as a result of the efforts of Public Citizen, the FDA ordered boxed warnings on all fluoroquinolones, advising consumers of an enhanced risk of tendon damage.[79]

Generations[edit]

Researchers divide the quinolones into generations based on their antibacterial spectrum.[80][81] The earlier-generation agents are, in general, more narrow-spectrum than the later ones, but no standard is employed to determine which drug belongs to which generation. The only universal standard applied is the grouping of the nonfluorinated drugs found within this class (quinolones) within the 'first-generation' heading. As such, a wide variation exists within the literature dependent upon the methods employed by the authors.

The first generation is rarely used today. Nalidixic acid was added to the OEHHA Prop 65 list as a carcinogen on 15 May 1998.[82] A number of the second-, third-, and fourth-generation drugs have been removed from clinical practice due to severe toxicity issues or discontinued by their manufacturers. The drugs most frequently prescribed today consist of Avelox (moxifloxacin), Cipro (ciprofloxacin), Levaquin (levofloxacin), and, to some extent, their generic equivalents.

First-generation[edit]

Second-generation[edit]

The second-generation class is sometimes subdivided into "Class 1" and "Class 2".[84]

Third-generation[edit]

Unlike the first- and second-generations, the third-generation is active against streptococci.[84]

Fourth-generation[edit]

Fourth-generation fluoroquinolones act at DNA gyrase and topoisomerase IV.[88] This dual action slows development of resistance.

In development[edit]

Veterinary use[edit]

The quinolones have been widely used in agriculture, and several agents have veterinary, but not human, applications.

However, the agricultural use of fluoroquinolones in the U.S. has been restricted since 1997, due to concerns over the development of antibiotic resistance.[90]

References[edit]

  1. ^ Andriole, VT The Quinolones. Academic Press, 1989.
  2. ^ Andersson, MI, MacGowan, AP. Development of the quinolones. J. Antimicrob. Chemother. (2003) 51, Suppl. S1, 1–11 doi:10.1093/jac/dkg212
  3. ^ Ivanov DV, Budanov SV (2006). "[Ciprofloxacin and antibacterial therapy of respiratory tract infections]". Antibiot. Khimioter. (in Russian) 51 (5): 29–37. PMID 17310788. 
  4. ^ sanofi-aventis U.S. LLC (September 2008). "NegGram Caplets (nalidixic acid, USP)" (PDF). US: FDA. 
  5. ^ Wentland MP: In memoriam: George Y. Lesher, Ph.D., in Hooper DC, Wolfson JS (eds): Quinolone antimicrobial agents, ed 2., Washington DC, American Society for Microbiology : XIII - XIV, 1993.
  6. ^ Hooper, DC. (Mar–Apr 2001). "Emerging mechanisms of fluoroquinolone resistance". Emerg Infect Dis 7 (2): 337–41. doi:10.3201/eid0702.010239. PMC 2631735. PMID 11294736. 
  7. ^ "Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia". Am. J. Respir. Crit. Care Med. 171 (4): 388–416. February 2005. doi:10.1164/rccm.200405-644ST. PMID 15699079. 
  8. ^ Mandell LA, Wunderink RG, Anzueto A, et al. (March 2007). "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults". Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159. PMID 17278083. 
  9. ^ MacDougall C, Guglielmo BJ, Maselli J, Gonzales R (March 2005). "Antimicrobial drug prescribing for pneumonia in ambulatory care". Emerging Infect. Dis. 11 (3): 380–4. doi:10.3201/eid1103.040819. PMC 3298265. PMID 15757551. 
  10. ^ Liu, H.; Mulholland, SG. (July 2005). "Appropriate antibiotic treatment of genitourinary infections in hospitalized patients". Am J Med. 118 Suppl 7A (7): 14S–20S. doi:10.1016/j.amjmed.2005.05.009. PMID 15993673. 
  11. ^ "www.fda.gov". 
  12. ^ Sung L, Manji A, Beyene J, et al. (May 2012). "Fluoroquinolones in children with fever and neutropenia: a systematic review of prospective trials". Pediatr. Infect. Dis. J. 31 (5): 431–5. doi:10.1097/INF.0b013e318245ab48. PMID 22189521. 
  13. ^ Rosanova MT, Lede R, Capurro H, Petrungaro V, Copertari P (December 2010). "[Assessing fluoroquinolones as risk factor for musculoskeletal disorders in children: a systematic review and meta-analysis]". Arch Argent Pediatr (in Spanish; Castilian) 108 (6): 524–31. doi:10.1590/S0325-00752010000600008. PMID 21132249. 
  14. ^ Forsythe CT, Ernst ME (November 2007). "Do fluoroquinolones commonly cause arthropathy in children?". CJEM 9 (6): 459–62. PMID 18072993. 
  15. ^ "The Use of Systemic and Topical Fluoroquinolones". 
  16. ^ a b Owens RC, Ambrose PG (July 2005). "Antimicrobial safety: focus on fluoroquinolones". Clin. Infect. Dis. 41 Suppl 2: S144–57. doi:10.1086/428055. PMID 15942881. 
  17. ^ a b c De Sarro A, De Sarro G (March 2001). "Adverse reactions to fluoroquinolones. an overview on mechanistic aspects". Curr. Med. Chem. 8 (4): 371–84. doi:10.2174/0929867013373435. PMID 11172695. 
  18. ^ "www.fda.gov". 
  19. ^ Skalsky K, Yahav D, Lador A, Eliakim-Raz N, Leibovici L, Paul M (April 2013). "Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials". Clin. Microbiol. Infect. 19 (4): 370–8. doi:10.1111/j.1469-0691.2012.03838.x. PMID 22489673. 
  20. ^ Falagas ME, Matthaiou DK, Vardakas KZ (December 2006). "Fluoroquinolones vs beta-lactams for empirical treatment of immunocompetent patients with skin and soft tissue infections: a meta-analysis of randomized controlled trials". Mayo Clin. Proc. 81 (12): 1553–66. doi:10.4065/81.12.1553. PMID 17165634. 
  21. ^ Van Bambeke F, Tulkens PM (2009). "Safety profile of the respiratory fluoroquinolone moxifloxacin: comparison with other fluoroquinolones and other antibacterial classes". Drug Saf 32 (5): 359–78. doi:10.2165/00002018-200932050-00001. PMID 19419232. 
  22. ^ Shehab N, Patel PR, Srinivasan A, Budnitz DS (September 2008). "Emergency department visits for antibiotic-associated adverse events". Clin. Infect. Dis. 47 (6): 735–43. doi:10.1086/591126. PMID 18694344. 
  23. ^ a b Hall MM, Finnoff JT, Smith J (February 2011). "Musculoskeletal complications of fluoroquinolones: guidelines and precautions for usage in the athletic population". PM R 3 (2): 132–42. doi:10.1016/j.pmrj.2010.10.003. PMID 21333952. 
  24. ^ Kim GK (April 2010). "The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture: What Does The Clinician Need To Know?". J Clin Aesthet Dermatol 3 (4): 49–54. PMC 2921747. PMID 20725547. 
  25. ^ Sode J, Obel N, Hallas J, Lassen A (May 2007). "Use of fluroquinolone and risk of Achilles tendon rupture: a population-based cohort study". Eur. J. Clin. Pharmacol. 63 (5): 499–503. doi:10.1007/s00228-007-0265-9. PMID 17334751. 
  26. ^ Owens RC, Ambrose PG (July 2005). "Antimicrobial safety: focus on fluoroquinolones". Clin. Infect. Dis. 41 Suppl 2: S144–57. doi:10.1086/428055. PMID 15942881. 
  27. ^ Khaliq Y, Zhanel GG (October 2005). "Musculoskeletal injury associated with fluoroquinolone antibiotics". Clin Plast Surg 32 (4): 495–502, vi. doi:10.1016/j.cps.2005.05.004. PMID 16139623. 
  28. ^ Heidelbaugh JJ, Holmstrom H (April 2013). "The perils of prescribing fluoroquinolones". J Fam Pract 62 (4): 191–7. PMID 23570031. 
  29. ^ Rubinstein E, Camm J (April 2002). "Cardiotoxicity of fluoroquinolones". J. Antimicrob. Chemother. 49 (4): 593–6. doi:10.1093/jac/49.4.593. PMID 11909831. 
  30. ^ Deshpande A, Pasupuleti V, Thota P, et al. (September 2013). "Community-associated Clostridium difficile infection and antibiotics: a meta-analysis". J. Antimicrob. Chemother. 68 (9): 1951–61. doi:10.1093/jac/dkt129. PMID 23620467. 
  31. ^ Slimings C, Riley TV (December 2013). "Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis". J. Antimicrob. Chemother. doi:10.1093/jac/dkt477. PMID 24324224. 
  32. ^ "Data Mining Analysis of Multiple Antibiotics in AERS". 
  33. ^ Vardakas KZ, Konstantelias AA, Loizidis G, Rafailidis PI, Falagas ME (November 2012). "Risk factors for development of Clostridium difficile infection due to BI/NAP1/027 strain: a meta-analysis". Int. J. Infect. Dis. 16 (11): e768–73. doi:10.1016/j.ijid.2012.07.010. PMID 22921930. 
  34. ^ "FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection". 
  35. ^ Galatti L, Giustini SE, Sessa A, et al. (March 2005). "Neuropsychiatric reactions to drugs: an analysis of spontaneous reports from general practitioners in Italy". Pharmacol. Res. 51 (3): 211–6. doi:10.1016/j.phrs.2004.08.003. PMID 15661570. 
  36. ^ Babar, S. (October 2013). "SIADH Associated With Ciprofloxacin.". The Annals of Pharmacotherapy (Sage Publishing) 47 (10): 1359–1363. doi:10.1177/1060028013502457. ISSN 1060-0280. PMID 24259701. Retrieved November 139,2013.  Check date values in: |accessdate= (help)
  37. ^ Rouveix, B. (Nov–Dec 2006). "[Clinically significant toxicity and tolerance of the main antibiotics used in lower respiratory tract infections]". Med Mal Infect 36 (11–12): 697–705. doi:10.1016/j.medmal.2006.05.012. PMID 16876974. 
  38. ^ Mehlhorn AJ, Brown DA (November 2007). "Safety concerns with fluoroquinolones". Annals of Pharmacotherapy 41 (11): 1859–66. doi:10.1345/aph.1K347. PMID 17911203. 
  39. ^ Jones SF, Smith RH (March 1997). "Quinolones may induce hepatitis". BMJ 314 (7084): 869. doi:10.1136/bmj.314.7084.869. PMC 2126221. PMID 9093098. 
  40. ^ Nelson, Lewis H.; Flomenbaum, Neal; Goldfrank, Lewis R.; Hoffman, Robert Louis; Howland, Mary Deems; Neal A. Lewin (2006). Goldfrank's toxicologic emergencies. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-143763-0. 
  41. ^ Iannini PB (June 2007). "The safety profile of moxifloxacin and other fluoroquinolones in special patient populations". Curr Med Res Opin 23 (6): 1403–13. doi:10.1185/030079907X188099. PMID 17559736. 
  42. ^ Farinas, Evelyn R; PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH (1 March 2005). "Consult: One-Year Post Pediatric Exclusivity Postmarketing Adverse Events Review" (PDF). US: FDA. Retrieved 31 August 2009. 
  43. ^ http://www.levaquinadversesideeffect.com/wp-content/uploads/Documents/Hall-2011.pdf
  44. ^ Nardiello, S.; Pizzella, T.; Ariviello, R. (March 2002). "[Risks of antibacterial agents in pregnancy]". Infez Med 10 (1): 8–15. PMID 12700435. 
  45. ^ Eur J Obstet Gynecol Reprod Biol. 2009 Apr;143(2):75-8. Epub 2009 Jan 31. The safety of quinolones--a meta-analysis of pregnancy outcomes. Bar-Oz B, Moretti ME, Boskovic R, O'Brien L, Koren G.
  46. ^ Noel, GJ.; Bradley, JS.; Kauffman, RE.; Duffy, CM.; Gerbino, PG.; Arguedas, A.; Bagchi, P.; Balis, DA.; Blumer, JL. (October 2007). "Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders". Pediatr Infect Dis J 26 (10): 879–91. doi:10.1097/INF.0b013e3180cbd382. PMID 17901792. 
  47. ^ Leibovitz, E.; Dror, Yigal (February 2006). "The use of fluoroquinolones in children". Current Opinion in Pediatrics 18 (1): 64–70. doi:10.1097/01.mop.0000192520.48411.fa. PMID 16470165. 
  48. ^ Janssen Pharmaceutica (September 2008). "HIGHLIGHTS OF PRESCRIBING INFORMATION" (PDF). US: FDA. 
  49. ^ Scherer, K.; Bircher, AJ. (January 2005). "Hypersensitivity reactions to fluoroquinolones". Curr Allergy Asthma Rep 5 (1): 15–21. doi:10.1007/s11882-005-0049-1. PMID 15659258. 
  50. ^ Schaumann, R.; Rodloff, A. C. (January 2007). "Activities of Quinolones Against Obligately Anaerobic Bacteria" (PDF). Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) (Bentham Science Publishers) 6 (1): 49–56. doi:10.2174/187152107779314179. 
  51. ^ Chang Y.H.; Se H.K.; Young K.K (22 July 1997). "Novel 5-amino-6-methylquinolone antibacterials: A new class of non-6-fluoroquinolones". Bioorganic & Medicinal Chemistry Letters (Elsevier) 7 (14): 1875–1878. doi:10.1016/S0960-894X(97)00324-7. 
  52. ^ Bergan T.; Bayer (1988). "Pharmacokinetics of fluorinated quinolones". Academic Press: 119–154. 
  53. ^ Bergan T; Dalhoff A; Thorsteinsson SB (1985). "A review of the pharmacokinetics and tissue penetration of ciprofloxacin". pp. 23–36. 
  54. ^ Castora, FJ.; Vissering, FF.; Simpson, MV. (September 1983). "The effect of bacterial DNA gyrase inhibitors on DNA synthesis in mammalian mitochondria". Biochim Biophys Acta 740 (4): 417–27. doi:10.1016/0167-4781(83)90090-8. PMID 6309236. 
  55. ^ Kaplowitz, Neil (2005). "Hepatology highlights". Hepatology 41 (2): 227. doi:10.1002/hep.20596. 
  56. ^ Enzmann, H.; Wiemann, C.; Ahr, HJ.; Schlüter, G. (April 1999). "Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver". Mutat Res 425 (2): 213–24. doi:10.1016/S0027-5107(99)00044-5. PMID 10216214. 
  57. ^ Holden, HE.; Barett, JF.; Huntington, CM.; Muehlbauer, PA.; Wahrenburg, MG. (1989). "Genetic profile of a nalidixic acid analog: a model for the mechanism of sister chromatid exchange induction". Environ Mol Mutagen 13 (3): 238–52. doi:10.1002/em.2850130308. PMID 2539998. 
  58. ^ Suto, MJ.; Domagala, JM.; Roland, GE.; Mailloux, GB.; Cohen, MA. (December 1992). "Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity". Journal of Medicinal Chemistry 35 (25): 4745–50. doi:10.1021/jm00103a013. PMID 1469702. 
  59. ^ Saint F, Salomon L, Cicco A, de la Taille A, Chopin D, Abbou CC (December 2001). "[Tendinopathy associated with fluoroquinolones: individuals at risk, incriminated physiopathologic mechanisms, therapeutic management]". Prog. Urol. (in French) 11 (6): 1331–4. PMID 11859676. 
  60. ^ a b c Fish DN. Fluoroquinolone Adverse Effects and Drug Interactions. Pharmacotherapy. 2001;21(10s) Published on Medscape. Accessed Aug 27, 2014
  61. ^ M Jacobs, Worldwide Overview of Antimicrobial Resistance. International Symposium on Antimicrobial Agents and Resistance 2005.
  62. ^ Nelson, JM.; Chiller, TM.; Powers, JH.; Angulo, FJ. (April 2007). "Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story" (PDF). Clin Infect Dis 44 (7): 977–80. doi:10.1086/512369. PMID 17342653. 
  63. ^ Froom J, Culpepper L, Jacobs M, et al. (July 1997). "Antimicrobials for acute otitis media? A review from the International Primary Care Network". BMJ 315 (7100): 98–102. doi:10.1136/bmj.315.7100.98. PMC 2127061. PMID 9240050. 
  64. ^ MacDougall C, Guglielmo BJ, Maselli J, Gonzales R (March 2005). "Antimicrobial drug prescribing for pneumonia in ambulatory care". Emerging Infect. Dis. 11 (3): 380–4. doi:10.3201/eid1103.040819. PMC 3298265. PMID 15757551. 
  65. ^ a b Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS (March 2005). "Fluoroquinolone prescribing in the United States: 1995 to 2002". The American Journal of Medicine 118 (3): 259–68. doi:10.1016/j.amjmed.2004.09.015. PMID 15745724. 
  66. ^ K08 HS14563 and HS11313
  67. ^ Neuhauser, MM; Weinstein, RA; Rydman, R; Danziger, LH; Karam, G; Quinn, JP (2003). "Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use". JAMA: the Journal of the American Medical Association 289 (7): 885–8. doi:10.1001/jama.289.7.885. PMID 12588273. "From 1995 to 2002, inappropriate antibiotic prescribing for acute respiratory infections, which are usually caused by viruses and thus are not responsive to antibiotics, declined from 61 to 49 percent. However, the use of broad-spectrum antibiotics such as the fluoroquinolones, jumped from 41 to 77 percent from 1995 to 2001. Overuse of these antibiotics will eventually render them useless for treating antibiotic-resistant infections, for which broad-spectrum antibiotics are supposed to be reserved." 
  68. ^ Robicsek A, Jacoby GA, Hooper DC (October 2006). "The worldwide emergence of plasmid-mediated quinolone resistance". Lancet Infect Dis 6 (10): 629–40. doi:10.1016/S1473-3099(06)70599-0. PMID 17008172. 
  69. ^ Morita Y, Kodama K, Shiota S, Mine T, Kataoka A, Mizushima T, Tsuchiya T (July 1998). "NorM, a Putative Multidrug Efflux Protein, of Vibrio parahaemolyticus and Its Homolog in Escherichia coli". Antimicrob. Agents Chemother. 42 (7): 1778–82. PMC 105682. PMID 9661020. 
  70. ^ Norris, S; Mandell, GL (1988). "The quinolones: history and overview". The quinolones: history and overview. San Diego: Academic Press Inc. pp. 1–22. 
  71. ^ "Petition to Require a Warning on All Fluoroquinolone Antibiotics (HRG Publication #1399)". Public Citizen. 1 August 1996. Retrieved 27 December 2008. 
  72. ^ "Public Citizen Petitions the FDA to Include a Black Box Warning on Fluoroquinolone Antibiotics (HRG Publication #1781)". Public Citizen. 29 August 2006. Retrieved 27 December 2008. 
  73. ^ Public Citizen; Michael T. Kickpatrick (3 January 2008). "In The United States District Court For The District Of Columbia" (PDF). US: Carey & Danis, LLC. 
  74. ^ Lisa Madigan (18 May 2005). "Office Of The Attorney General State Of Illinois, CITIZEN PETITION" (PDF). US: FDA. 
  75. ^ Joseph Baker; Sidney Wolfe; Peter Lurie (1 May 2006). "Petition to the FDA to Immediately Ban the Antibiotic Gatifloxacin (Tequin) (HRG Publication #1768)". US: Public Citizen. 
  76. ^ "Letter to the Food and Drug Administration to immediately ban the antibiotic trovafloxacin (Trovan) (HRG Publication #1485)". US: Public Citizen. 3 June 1999. 
  77. ^ Larry D. Sasich,; Sidney M. Wolfe; Allison Zieve; Patricia Christen; Ben Christen (9 June 1998). "Petition to the Food and Drug Administration to immediately stop the distribution of dangerous, misleading prescription drug information to the public. (HRG Publication #1442)". US: Public Citizen. 
  78. ^ Risk of fluoroquinolone-associated Myasthenia Gravis Exacerbation February 2011 Label Changes for Fluoroquinolones FDA, online access 16 March 2011
  79. ^ "FDA orders 'black box' label on some antibiotics". CNN. 8 July 2008. Retrieved 8 July 2008. 
  80. ^ Ball P (2000). "Quinolone generations: natural history or natural selection?". J. Antimicrob. Chemother. 46 Suppl T1 (Supplement 3): 17–24. doi:10.1093/oxfordjournals.jac.a020889. PMID 10997595. 
  81. ^ "New Classification and Update on the Quinolone Antibiotics - May 1, 2000 - American Academy of Family Physicians". Retrieved 18 March 2008. 
  82. ^ [Nalidixic Acid, case number 389-08-02, listing mechanism AB, NTP (1989b)]
  83. ^ a b c d e f g h i "Quinolones: A Comprehensive Review - February 1, 2002 - American Family Physician". 
  84. ^ a b Oliphant CM, Green GM (February 2002). "Quinolones: a comprehensive review". Am Fam Physician 65 (3): 455–64. PMID 11858629. 
  85. ^ a b c Paul G. Ambrose and Robert C. Owens, Jr (1 March 2000). "Clinical Usefulness Of Quinolones". Seminars in Respiratory and Critical Care Medicine (Medscape). 
  86. ^ The European Medicines Agency (24 July 2008). "EMEA Restricts Use of Oral Norfloxacin Drugs in UTIs". Doctor's Guide. 
  87. ^ Paul G. Ambrose and Robert C. Owens, Jr (1 March 2000). "New Antibiotics in Pulmonary and Critical Care Medicine: Classification Of Quinolones By Generation". US: Medscape. 
  88. ^ Gupta (2009). Clinical Ophthalmology: Contemporary Perspectives, 9/e. Elsevier India. pp. 112–. ISBN 978-81-312-1680-4. Retrieved 20 September 2010. 
  89. ^ Schmid, Randolph E. (1 May 2006). "Drug Company Taking Tequin Off Market". Associated Press. Archived from the original on 25 Nov 2007. Retrieved 1 May 2006. [dead link]
  90. ^ "FDA Order Prohibits Extralabel Use Of Fluoroquinolones And Glycopeptides". U.S. Food and Drug Administration. 2 June 1997. Retrieved 16 April 2013. 

External links[edit]