Quinolone

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.

Nalidixic acid

Ciprofloxacin

Levofloxacin

Trovafloxacin

See also: 2- and 4-Quinolones

The quinolones are a family of synthetic broad-spectrum antibiotic drugs. Quinolones, and derivatives, have also been isolated from natural sources (such as plants, animals and bacteria) and can act as natural antimicrobials and/or signalling molecules.

Quinolones exert their antibacterial effect by preventing bacterial DNA from unwinding and duplicating. The majority of quinolones in clinical use are fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-7 position. Most of them are named with the -floxacin suffix.

Medical uses

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 Diseases 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.

Fluoroquinolones are featured prominently in The American Thoracic Society guidelines for the treatment of hospital-acquired pneumonia. The Society recommends fluoroquinolones not be used as a first-line agent for community-acquired pneumonia, 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 cases with demonstrated drug-resistant Streptococcus pneumoniae.

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.

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

Children

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

In most countries, fluoroquinolones are approved for use in children only under narrowly-defined 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 are 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 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 included 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.

A number of recent meta-analyses have concluded that fluoroquinolones pose little or no additional risk to children compared to other antibiotic classes.

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.

Adverse effects

In general, fluoroquinolones are tolerated, with side effects being mild to moderate. Common side effects include gastrointestinal effects such as nausea, vomiting, and diarrhea, as well as headache and insomnia. Postmarketing 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.

The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes. A U.S. Centers for Disease Control and Prevention 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.

Quinolones are associated with an increased risk of tendinitis and tendon rupture in all age groups. This side effect is most common in 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. 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. The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin has been estimated at 17 per 100,000 treatments (three times the rate in people without fluoroquinolone exposure). 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. 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.

Fluoroquinolones prolong the heart's QT interval by blocking voltage-gated potassium channels. 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.

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 similar to or less than that associated with broad spectrum cephalosporins. Fluoroquinoline administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridium strain.

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

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

On November 5, 2015, the FDA held a joint meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss risks and benefits of the systemic fluoroquinolone antibacterial drugs for the acute bacterial sinusitis, acute bacterial exacerbations of bronchitis in people with chronic obstructive pulmonary disease, and uncomplicated urinary tract infections. The Agency asked the committee to review reports of tendonitis and tendon ruputure, peripheral neuropathy, and cardiac arrhythmia associated with long-term disability to determine whether the benefits of fluoroquinolone therapy in these indications justifies the associated risk. The 21-member joint committee overwhelmingly recommended stronger label warnings on the containers because of rare but sometimes devastating side effects.

Contraindications

Quinolones are contraindicated if a patient has epilepsy, QT prolongation, pre-existing CNS lesions, or CNS inflammation, or the patient has suffered a stroke. They are best avoided in the athlete population. Safety concerns exist for fluoroquinolone use during pregnancy, so they are contraindicated unless no other safe alternative antibiotic exists. However, one meta-analysis looking at the outcome of pregnancies involving quinolone use in the first trimester found no increased risk of malformations. They are also contraindicated in children due to the risks of damage to the musculoskeletal system. 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. Quinolones should also not be given to people with a known hypersensitivity to the drug.

Pharmacology

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

Mechanism of action

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 the 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.

Mechanism of toxicity

The mechanisms of the toxicity of fluoroquinolones have 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 and oxidative stress.

Interactions

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. Other drugs that interact with fluoroquinolones include sucralfate, probenecid, cimetidine, theophylline, warfarin, antiviral agents, phenytoin, cyclosporine, rifampin, pyrazinamide, and cycloserine.

Administration of quinolone antibiotics to a benzodiazepine dependent individual can precipitate acute benzodiazepine withdrawal symptoms due to quinolones displacing benzodiazepines from their binding site.

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.

Antibiotic misuse and bacterial resistances

See also: Antibiotic misuse and Antibiotic resistance

Resistance to quinolones can evolve rapidly, even during a course of treatment. Numerous pathogens, including Escherichia coli, commonly exhibit resistance. Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.

Fluoroquinolones had become the class of antibiotics most commonly prescribed 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. In addition, they are commonly prescribed for medical conditions, such as acute respiratory illness, that are usually caused by viral infections.

Three mechanisms of resistance are known. 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 drugs' effectiveness.

History

The first quinolone was nalidixic acid - introduced in 1962 for treatment of urinary tract infections in humans. Nalidixic acid was discovered by George Lesher and coworkers in a distillate during an attempt at chloroquine synthesis. Nalidixic acid is thus 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.

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.

Boxed warnings

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, or having 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.

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.

Generations

Researchers divide the quinolones into generations based on their antibacterial spectrum. 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 assignment of the nonfluorinated drugs found within this class (quinolones) to 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. 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

• cinoxacin (Cinobac)
• nalidixic acid (NegGram, Wintomylon)
• oxolinic acid (Uroxin)
• piromidic acid (Panacid)
• pipemidic acid (Dolcol)
• rosoxacin (Eradacil)

Second-generation

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

• ciprofloxacin (Cipro)
• enoxacin (Enroxil, Penetrex)
• fleroxacin (Megalone, Roquinol)
• lomefloxacin (Maxaquin)
• nadifloxacin (Acuatim, Nadoxin, Nadixa)
• norfloxacin (Lexinor, Noroxin, Quinabic, Janacin)
• ofloxacin (Floxin, Oxaldin, Tarivid)
• pefloxacin (Peflacine)
• rufloxacin (Uroflox)

Third-generation

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

• balofloxacin (Baloxin)
• grepafloxacin (Raxar) (removed from clinical use)
• levofloxacin (Leflox, Cravit, Levaquin, Tavanic)
• pazufloxacin (Pasil, Pazucross)
• sparfloxacin (Zagam)
• temafloxacin (Omniflox) (removed from clinical use)
• tosufloxacin (Ozex, Tosacin)

Fourth-generation

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

• clinafloxacin
• gatifloxacin (Zigat, Tequin) (Zymar -opth.) (Tequin removed from clinical use)
• gemifloxacin (Factive)
• moxifloxacin (Acflox Woodward, Avelox,Vigamox)
• sitafloxacin (Gracevit)
• trovafloxacin (Trovan) (removed from clinical use)
• prulifloxacin (Quisnon)

In development

• delafloxacin — an anionic fluoroquinoline in clinical trials
• JNJ-Q2 — completed Phase II for MRSA
• nemonoxacin

Veterinary use

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

• 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)

However, the agricultural use of fluoroquinolones in the US has been restricted since 1997, due to concerns over the development of antibiotic resistance.

External links

• Quinolone at DMOZ
• Healthcare-associated Infections (HAIs)- Quinolones and the Clinical Laboratory CDC
• Information for Healthcare Professionals: Fluoroquinolone Antimicrobial Drugs from the U.S. Food and Drug Administration
• Fluoroquinolones "Family Practice Notebook" entry page for Fluoroquinolones
• Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD