Quinolone

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.

Nalidixic acid

Ciprofloxacin

Levofloxacin

Trovafloxacin

The quinolones are a family of synthetic broad-spectrum antibiotics. The parent of the group is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluoro group attached the central ring system, typically at the 6-position.

Mechanism

Quinolones and fluoroquinolones are bactericidal drugs, actively killing bacteria. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones 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. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV.

Adverse effects

In the fall of 2004, the Food and Drug Administration upgraded the warnings found within the package inserts for quinolones regarding potentially serious adverse reactions. It is important to note that pharmaceutical companies claim that the incidence of the following is quite rare, with occurrences at less than one per ten thousand person-years. However, many people that have been adversely effected dispute that the adverse reactions are rare, and contend that they may, in fact, be much more widespread than previously thought. ^[1]

Side-effects from fluoroquinolones can be mild and short-lived or they can be severe and long-lasting after therapy has been discontinued. If side-effects affecting the central nervous system, peripheral nervous system, or muscular system occur, the patient should discontinue therapy and consult with his/her doctor. The side-effects from fluoroquinolones include tingling, anxiety, numbness, twitching, joint pain, muscle pain, tendinitis, fear, blurred vision, memory loss, diarrhea, severe panic attacks, insomnia, tear of achilles tendon, confusion, impaired concentration, burning pain, carpal tunnel syndrome, nightmares, confusion, tachycardia, nausea, palpitations, hyperesthesia, fatigue, depersonalisation, pins and needles sensation, muscular spasms, tremors, headaches, agitation, hallucinations, psychosis, tinnitus, skin rash, hair loss, abdominal pain, visual disturbances.^[2]

• Peripheral neuropathy (nerve damage): "Rare cases of sensory or sensor motor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoaesthesias, dysesthesias, and weakness have been reported in patients taking quinolones. Therapy should be discontinued if the patient experiences symptoms of neuropathy, including pain, burning, tingling, numbness and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength, in order to prevent the development of an irreversible condition."^[3]

• Tendon damage: "Ruptures of the shoulder, hand, Achilles tendon, or other tendons that require surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Fluoroquinolone therapy should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until diagnosis of tendinitis or tendon rupture had been excluded. Tendon rupture can occur during or after therapy with quinolones." On July 8, 2008, the FDA requested manufacturers to include a black box warning for tendon damage.^[4]

• Kidney stones due to loss of Oxalobacter formigenes^[5]

Interactions

Caffeine, nonsteroidal antiinflamatory drugs, Theophylline, and corticosteroids enhance the toxicity of fluoroquinolones.^[6][2][7]

Other drugs that interact with fluoroquinolones include Antacids, Sucralfate, Probenecid, Cimetidine, Probenecid, Warfarin, Antiviral agents, phenytoin, cyclosporine, rifampin, pyrazinamide, and cycloserine.^[8]

Resistance

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.^[9] Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.

There are three known mechanisms of resistance.^[10] Some types of efflux pumps can act to decrease intracellular quinolone concentration. 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 drug's effectiveness.

Generations

The quinolones are divided into generations based on their antibacterial spectrum.^[11][12] The earlier generation agents are, in general, more narrow spectrum than the later ones.

1st generation

• cinoxacin (Cinobac)^[13]
• flumequine (Flubactin) (Veterinary use)
• nalidixic acid (NegGam, Wintomylon)^[13]
• oxolinic acid (Uroxin)
• piromidic acid (Panacid)
• pipemidic acid (Dolcol)
• rosoxacin (Eradacil)

2nd generation

• ciprofloxacin (Ciprobay, Cipro, Ciproxin)^[13][14]
• enoxacin (Enroxil, Penetrex)^[13]
• fleroxacin (Megalone, Roquinol) (withdrawn)
• lomefloxacin (Maxaquin)^[13]
• nadifloxacin (Acuatim, Nadoxin, Nadixa)
• norfloxacin (Lexinor, Noroxin, Quinabic, Janacin)^[13]
• ofloxacin (Floxin, Oxaldin, Tarivid)^[13]
• pefloxacin (Peflacine)
• rufloxacin (Uroflox)

3rd generation

• balofloxacin (Baloxin)
• gatifloxacin (Tequin (withdrawn), Zymar) ^[13] Sometimes reported as fourth generation.^[15][14]
• grepafloxacin (Raxar) (withdrawn)^[14]
• levofloxacin (Cravit, Levaquin)^[13][14]
• moxifloxacin (Avelox,Vigamox)^[13] Sometimes reported as fourth generation.^[16][14]
• pazufloxacin (Pasil, Pazucross)
• sparfloxacin (Zagam)^[13]
• temafloxacin (Omniflox) (withdrawn)^[17]
• tosufloxacin (Ozex, Tosacin)

4th generation

• clinafloxacin ^[14]
• garenoxacin (Geninax)
• gemifloxacin (Factive)
• sitafloxacin (Gracevit)
• trovafloxacin (Trovan) (withdrawn)^[13][14]
• prulifloxacin (Quisnon)

In development

• ecinofloxacin^[18]

Veterinary use

The quinolones have been widely used in agriculture and several agents exist which have veterinary but not human use.

• danofloxacin (Advocin, Advocid) (for veterinary use)
• difloxacin (Dicural, Vetequinon) (for veterinary use)
• enrofloxacin (Baytril) (for veterinary use)
• ibafloxacin (Ibaflin) (for veterinary use)
• marbofloxacin (Marbocyl, Zenequin) (for veterinary use)
• orbifloxacin (Orbax, Victas) (for veterinary use)
• sarafloxacin (Floxasol, Saraflox, Sarafin) (for veterinary use)

External links

• Fact Sheet: Quinolones
• Information to healthcare professionals on fluoroquinolone safety from the U.S. Food and Drug Administration
• Research on Adverse Effects of Fluoroquinolones
• Fluoroquinolone-Induced Tendinopathy: What do we know? Richard M. Harrell, MD.
• Fluoroquinolones "Family Practice Notebook" entry page for Fluoroquinolones
• Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD

References