Fluoroquinolones and quinolones - antibiotics

Quinolones and fluoroquinolones are antibiotics that prevent bacteria from reproducing. Active against Gram-negative and Gram-positive bacteria, they were the most widely used antibiotics to treat cystitis and common upper respiratory tract infections. Due to the high levels of resistance developed and the numerous reported adverse reactions, many fluoroquinolones have been withdrawn from the market and their use has been limited to unavoidable cases only.

• What they are
• When not to take them
• Sensitivity and resistance
• Side effects
• Withdrawal from the market

Fluoroquinolones and Quinolones

What are fluoroquinolones and quinolones?

Quinolones are chemotherapeutic agents (that is, synthetic antibiotics) with a bactericidal action, meaning they kill bacteria. The mechanism of action of these antibacterials is linked to the inhibition of DNA, resulting in the death of the bacterium, which cannot reproduce.

Quinolones are divided into 3 categories based on the date of synthesis:

1. First generation (1961–1977): nalidixic acid, pipemidic acid (PIPEMID, UROTRACTIN), oxolinic acid, cinoxacin (URONORM, UROCINOX, CINOBAC), piromidic acid; specific for urinary tract infections and therefore called "urinary tract antiseptics or disinfectants"
2. Second generation (from 1977): Rosoxacin, Miloxacin, and Flumequine
3. Third generation: fluoroquinolones, which are further divided into
   
   1. First generation, short-acting: ciprofloxacin (CIPROXIN, FLOCIPRIN), delafloxacin, gemifloxacin, moxifloxacin (AVALOX), norfloxacin (NOROXIN, NORFLOX, SEBERCIN, UTINOR), ofloxacin (FLOBACIN, OFLOCIN, EXOCIN), levofloxacin (LEVOXACIN, TAVANIC, PRIXAR), enoxacin
   2. First generation, long-acting: Pefloxacin (PEFLOX, PEFLOXACIN), Lomefloxacin (CHIMONO, UNIQUIN), Rufloxacin (TABRAXIN), Sparfloxacin, Fleroxacin
   3. Third generation: prulifloxacin (UNIDROX, KERAFLOX), Lomefloxacin, Fleroxacin, Sparfloxacin, Moxifloxacin, Trovafloxacin, Temafloxacin, Gemifloxacin, Gatifloxacin, Tosufloxacin, Clinafloxacin, Grepafloxacin, particularly active against Gram-positive bacterial species and anaerobic bacteria.

Specifically, first- and second-generation quinolones have been defined as urinary quinolones and used in urinary infections due to the low levels they reach in the blood and because they are primarily eliminated through the urine, where they reach high concentrations. Fluoroquinolones, on the other hand, are defined as systemic quinolones as they are characterised by widespread distribution in all tissues.

Their broad spectrum of action against both Gram-negative and Gram-positive bacteria has made them essential for combating infections caused by highly aggressive pathogens that are very resistant to other antibiotics. However, the overuse of these drugs for the treatment of cystitis and common upper respiratory tract infections (such as colds, bronchitis, and influenza, often caused by viruses that do not respond to antibiotics) has increased bacterial resistance to this family of antibiotics, reducing their curative power even against serious and potentially lethal diseases.

When not to take them

When should fluoroquinolones and quinolones not be taken?

Fluoroquinolones must not be taken concomitantly with drugs such as:

• theophylline (risk of seizures and other adverse effects from theophylline overdose)
• NSAID anti-inflammatory drugs (increased risk of seizures)
• cortisone (increased risk of tendon rupture up to about 10 times compared with using the antibiotic alone)

Extreme caution in cases of:

• patients with heart disease
• elderly people
• patients who have had a stroke
• patients with myasthenia or cerebral disorders
• people performing activities requiring alertness and quick reflexes (e.g., driving, operating machinery, working on scaffolding)
• people who need to be exposed to sunlight

They must be completely avoided:

1. in epileptic patients (risk of seizures)
2. during pregnancy and breastfeeding
3. in childhood
4. in children and adolescents with incomplete skeletal development (may cause damage to growing cartilage)

Taking them concomitantly with or close to antacids and salts of aluminium, calcium, iron, magnesium, and zinc reduces the absorption of fluoroquinolones.

Bacterial sensitivity and resistance

Has bacterial sensitivity and resistance developed?

Fluoroquinolones include a vast range of molecules, making this family active against a very large group of Gram-positive and Gram-negative pathogenic bacteria. In addition to the most common germs (Enterobacteriaceae, Escherichia coli, Streptococci, Enterococci, Staphylococci, etc.), they can also eradicate many atypical pathogens such as:

• Chlamydia
• Legionella
• Mycoplasma
• Mycobacterium tuberculosis
• Hemophilus influenzae
• Moraxella catharralis
• Pseudomonas aeruginosa
• Chlamydophil
• beta-lactamase–producing strains

Unfortunately, the overuse of this category of antibiotics has led to resistance in Enterobacteriaceae, P. aeruginosa, S. pneumoniae, and Neisseria, particularly to older fluoroquinolones.
Resistance of Escherichia coli to fluoroquinolones has been widespread since 1997.

However, some studies have shown that for both fosfomycin (Monuril) and fluoroquinolones, resistance is associated with decreased virulence of these bacterial strains. Resistant bacteria appear to reproduce more slowly compared with sensitive bacteria. As a result, they are quickly overtaken by faster-growing strains that are sensitive to fluoroquinolones. Consequently, the persistence of fluoroquinolone-resistant strains is considered unlikely.
Finally, resistant strains appear to produce less haemolysin (an irritating substance that inflames the mucous membranes) and fewer fimbriae (which bacteria use to anchor to the bladder mucosa), reducing their adhesive capacity by 10–50% compared with sensitive strains. Since the ability to adhere to the bladder walls is crucial for triggering an episode of cystitis, resistant bacteria are consequently less capable of causing a urinary tract infection.

All of this should support the use of antibiotics for treating urinary infections. In reality, however, fluoroquinolones should still remain a last resort for cystitis or other simple infections due to the potential for serious side effects, which makes other categories of antibiotics preferable when the infection cannot be resolved naturally.

In the case of symptomatic cystitis, in fact, an antibiotic should only be taken if adequate hydration combined with D-mannose or other natural methods is not sufficient to resolve the infection. It should generally not be taken for asymptomatic cystitis (asymptomatic bacteriuria).

Further reading: How to treat cystitis naturally

Side effects

What are the side effects of fluoroquinolones and quinolones?

Quinolones and fluoroquinolones have numerous side effects affecting various body systems.

• Cartilage and muscles
  Tendinopathy, tendinitis, tendon rupture, arthralgia, pain in the extremities, walking difficulties.
  Tendinopathies (ranging from tendinitis to actual tendon rupture) are fairly common side effects: they occur in 1 patient out of 1,000. Symptoms may appear shortly after taking the antibiotic or months after discontinuation. The most affected tendon is the Achilles tendon, more frequently in athletes and in those taking cortisone, but other tendons can also be involved.
• Central nervous system
  Mild headache, drowsiness, insomnia, dizziness, mood changes, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, and impairment of hearing, vision, taste, and smell
• Peripheral nervous system
  Pain, burning, tingling, numbness, weakness, changes in sensitivity in organs or parts of the body.
  Peripheral neuropathies are linked to a more or less marked inhibition of the neurotransmitter GABA. Fluoroquinolone-induced pelvic neuropathy deserves a separate paragraph, given how frequently it occurs in those who have overused these antibiotics for recurrent urinary infections. This neuropathy can cause pelvic pain, genital discomfort, and pain similar to that caused by cystitis, candida, and other vaginal infections.
  
  

  Further reading: Fluoroquinolones-induced pelvic neuropathy
  
  Consult the list of professionals specialised in neuropathy

• FQAD (Fluoro Quinolones Associated Disability)
  A potentially disabling and permanent syndrome characterised by widespread neuromuscular symptoms affecting multiple organs and body systems.
  
  

  Further reading: Fluoroquinolone-associated disability

• Stomach and intestines
  Significant alteration of the bacterial flora, which can persist for up to 6 months after discontinuation of therapy (Huse et al., Doi: 10.1371/journal.pgen.1000255) and pseudomembranous colitis induced by Clostridioides (formerly called Clostridium difficile).
• Skin
  Photosensitivity
• Heart
  Ventricular arrhythmias
• Blood
  Leukopenia, anaemia
• Allergies
  Skin rashes, fever, facial or laryngeal swelling
• Other
  Liver disorders, blood sugar alterations

To avoid irreversible damage, therapy with fluoroquinolones must be immediately discontinued at the first sign of a side effect involving muscles, tendons, or bones, like:

• tendinitis
• muscle pain or weakness
• joint pain or swelling

or the central nervous system:

• fatigue
• depression
• confusion
• suicidal thoughts
• sleep disturbances

or the peripheral nervous system:

• pins and needles sensation
• burning
• tingling
• numbness
• weakness
• changes in local sensitivity of a body area or organ

Contact your general practitioner as soon as possible to inform them of the onset of these symptoms.

Withdrawal from the market

Why have they been withdrawn from the market?

The numerous antibiotic resistances developed against fluoroquinolones and the very high number of reported adverse reactions have led pharmacovigilance agencies (i.e., the bodies responsible for controlling and monitoring drugs on the market) to review the prescriptions of these antibiotics to avoid these potentially serious, disabling, and permanent side effects.

Already before 2000, in the United States, some last-generation fluoroquinolones were withdrawn from the market due to their confirmed toxicity: trovafloxacin (severe liver toxicity), grepafloxacin (cardiac toxicity), temafloxacin (acute kidney failure, hepatotoxicity, haemolytic anemia, coagulopathy, and hypoglycaemia).

In 2006, gatifloxacin was also withdrawn from the market due to hypoglycaemia and hyperglycaemia.

From the 1980s until the end of 2015, the FDA (United States Food and Drug Administration) received more than 60,000 reports of “serious adverse events” (including 6,575 deaths) associated with the five most commonly used fluoroquinolones still on the market, and in 2016 recommended that this class of antibiotics be prescribed only for very serious infections.

In 2018, the FDA requested that the patient information leaflets be updated to more clearly highlight the risks of hypoglycaemia and neurological disorders associated with the use of these drugs.

In October 2018, the AIFA (Italian Medicines Agency) highlighted the risk of aortic aneurysm and dissection.

Also in April 2019, the AIFA, in agreement with the EMA (European Medicines Agency), issued an official statement that:

• recognises the serious adverse reactions, disabling, long-lasting and potentially permanent, affecting the musculoskeletal system and the nervous system caused by quinolones and fluoroquinolones;
• withdraws from the market medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid, proceeding with their removal from points of sale;
• strongly restricts the use of the remaining fluoroquinolones (ciprofloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin and rufloxacin);
• invites doctors to inform the patient to discontinue treatment at the first signs of tendinitis, muscle pain, muscle weakness, joint pain, joint swelling, peripheral neuropathy and effects affecting the central nervous system;
• invites doctors to prescribe these drugs “only for those serious infections that do not resolve with antibiotics from other classes”, avoiding their use in cases of non-serious infections such as:
  
  • uncomplicated urinary tract infections (acute cystitis, recurrent cystitis, post-coital cystitis, etc.)
  • upper respiratory tract infections (colds, influenza, pharyngitis, tonsillitis, acute bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, acute bacterial rhinosinusitis, and acute otitis media)
  • for the prevention of traveler's diarrhea
  • for non-bacterial infections (such as chronic non-bacterial prostatitis and abacterial cystitis)

Further reading: Read the 2019 AIFA notice

Despite this, data from recent studies (EUPAS37856) have found that fluoroquinolones continue to be prescribed outside the uses recommended by the 2019 AIFA notice. The AIFA therefore issues a reminder reiterating to doctors the significant restrictions on the use of these medicines due to the risk of serious, disabling, and potentially irreversible adverse reactions affecting the musculoskeletal, nervous, psychiatric, and sensory systems.

Further reading: Read the 2023 AIFA reminder

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