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Publié dans PharmacoFACT (english version).

#F009 Fluoroquinolones should be avoided in common practice

What is the subject ?

The unfavourable benefit-risk ratio of fluoroquinolones when used for non-serious infections in ambulatory practice

Why are we addressing this subject ?

On 10 January 2023, the ANSM (French competent authority for medicinal products) updated its dossier on fluoroquinolones and reiterated its recommendation that these antibiotics should only be used for bacterial infections for which the use of a fluoroquinolone is essential, in the absence of an alternative with another antibiotic (1).
Fluoroquinolones can cause serious, disabling, long-lasting and irreversible side-effects : musculoskeletal disorders (tendinopathy), cardiovascular disorders (heart rhythm disorders, aortic aneurysms and dissections, damage to heart valves), peripheral neuropathy, neuropsychiatric disorders. These effects are more frequent and/or more severe in the elderly or in patients with renal insufficiency, but can occur even in young subjects.
These adverse effects, which may appear during the first few hours of treatment, usually occur after several days of treatment, and sometimes up to several months after treatment has been stopped. Patients should be warned at the time of prescription and dispensing of the need to consult their doctor immediately if symptoms such as dyspnoea, muscle or tendon pain, nerve damage, visual disturbance or photosensitisation appear, or even require immediate care if they experience sudden and intense abdominal, chest or back pain and have taken these medicines in the preceding weeks or months.
Consumption of these antibiotics has been falling since 2014, and after the prescribing restrictions issued in 2018 by the ANSM, their consumption has been further reduced by almost half (French health medical insurance data). However, fluoroquinolones are still prescribed too widely and in an unjustified manner, as shown by a recent estimate of 3 times more off-label prescriptions than on-label prescriptions (2). Off-label prescriptions are mainly for otitis, bronchitis and urinary tract infections.
Furthermore, these antibiotics are known as ‘broad-spectrum’ because they are active on many types of bacteria, leading to the emergence of antibiotic resistance. This is another reason for reserving fluoroquinolones only for severe infections

The opinion of the SFPT (French Society of Pharmacology and Therapeutics)

In view of the risks and frequency of serious side-effects with sequelae, the benefit/risk ratio of fluoroquinolones is unfavourable in standard ambulatory practice. With a few exceptions, they should no longer be prescribed as first-line treatment, particularly for otitis, bronchitis and simple urinary tract infections. They may still be used in the absence of a duly justified antibiotic alternative, in rare cases of bacterial infection, particularly during hospitalisation.

For more information

Fluoroquinolones are a pharmacological class of antibiotics marketed in France since the mid-1980s. They are currently represented by :

  • Ciprofloxacin (Ciflox, Uniflox and generics)
  • Levofloxaxin (Tavanic and generics)
  • Ofloxacin (Oflocet, Monoflocet and generics)
  • Norfloxacin (generics)
  • Moxifloxacin (Izilox and generics)
  • Lomefloxacin (Decalogiflox and Logiflox)
  • Delafloxacin (Quofenix)

They are fast-acting, concentration-dependent bactericidal antibiotics with a broad antibacterial spectrum. These molecules have very good oral bioavailability and a very wide distribution, and are effective in many types of infection. However, due to their widespread use in the past, these antibiotics have been responsible for the emergence of resistant bacterial strains (antibiotic resistance). Additionally, these antibiotics can cause various types of serious and sometimes long-lasting side-effects. For these two reasons, the indications for these antibiotics have been strictly restricted by health authorities, and their benefit/risk balance has been assessed as unfavourable in many situations.

Fluoroquinolones are therefore indicated for the treatment of several types of bacterial infections, some of which may be life-threatening. These antibiotics should be reserved for certain bacterial infections for which the use of a fluoroquinolone is essential, and should be avoided in situations where other antibiotics can be used.

In accordance with ANSM recommendations, these antibiotics should not be prescribed:

  • in non-severe or self-resolutive infections;
  • as prevention in TD (traveler's diarrhea) or recurrent lower urinary tract infections;
  • in non-bacterial infections, such as non-bacterial (chronic) prostatitis;
  • in infections of mild to moderate severity (uncomplicated cystitis, bronchitis including acute exacerbation of COPD, rhino-sinusitis and acute otitis media), with some exceptions;
  • in patients who have already experienced serious adverse reactions with an antibiotic in the same fluoroquinolone family.

These restrictions were introduced in 2019. They are the result of a re-evaluation of the potentially serious adverse effects of fluoroquinolones carried out at European level.

According to the current recommendations of the French health authorites (HAS), one of the only exceptions to prescribing a fluoroquinolone as probabilistic antibiotic therapy while awaiting an antibiogram is acute pyelonephritis in the absence of fluoroquinolone treatment in the previous 6 months (3). Fluoroquinolones are also indicated as a probabilistic treatment for prostatitis, as other antibiotics (3rd generation injectable cephalosporins) which should therefore be preferred whenever possible, particularly in elderly patients.

Adverse effects

Fluoroquinolones are widely distributed in many tissues. This advantage, which makes them effective in many infections, including osteoarticular ones, also explains most of the adverse effects of these drugs. Fluoroquinolones diffuse and bind to the collagen matrix of many tissues (tendons, vessels), leading to toxicity with a reduction in the proliferation of certain cells, the fibroblasts, associated with an increase in the synthesis of extracellular metalloproteinases and thus changes in tissue conformation, probably causing tendinopathy or cardiovascular damage (aortic aneurysm, valvulopathy). Finally, fluoroquinolones also have a cardiac tropism, and the blocking of ion channels in cardiomyocytes leads to heart rhythm disorders under certain conditions. Finally, fluoroquinolones also diffuse to the central nervous system, causing neuro-psychiatric disorders.

Tendinopathy

Fluoroquinolones are associated with a two- to four-fold increased risk of acute tendinopathy (defined as pain or reduced function without rupture) and tendon rupture compared with the general population (4). The incidence of these adverse effects can be as high as 2% in patients aged 65 and over, whereas the rate of tendon rupture is around 0.9% in the general population (5,6). The risk factors identified are age (elderly subjects) and concomitant use of glucocorticoids.

Tendinopathy appears early, from the first days of treatment and particularly during the first month following exposure to the drug. The Achilles tendon is most often affected, with sudden severe pain being a typical clinical presentation. Rapid discontinuation of the drug is recommended. The majority of patients (90%) do not need surgical intervention, with symptoms usually regressing within a month (4). In some cases, long-term sequelae may occur in up to 10% of patients.

Aneurysm and aortic dissection

A recent French study showed an increased risk of aortic aneurysm or dissection (risk increased by 2.4, 95% confidence interval 1.3 to 4.6) in the 30 days following exposure to a fluoroquinolone, compared with exposure to another reference antibiotic (amoxicillin) (7). Although residual confounding factors are present in observational studies, similar results were found in a meta-analysis with the occurrence of aortic dissection estimated at one in 1301 treated patients (8). Factors predisposing to the development of aneurysms and aortic dissections include a family history of aneurysm, pre-existing aneurysm or aortic dissection, Marfan syndrome, Ehlers-Danlos vascular syndrome, Takayasu arteritis, giant cell arteritis (or Horton's disease), Behçet's disease, hypertension and atherosclerosis. This serious risk, associated with high mortality, concerns all fluoroquinolones and was communicated in 2018 by the EMA and the ANSM (9).

Cardiac rhythm disorders

Fluoroquinolones, in particular moxifloxacin, cause cardiac repolarisation disorders with prolongation of the QT interval on the ECG and a risk of torsade de pointes. The risk is very low (estimated at 1.6 cases of serious arrhythmia per 10,000 patients exposed) but serious and possibly lethal (10,11). Risk factors include hypokalaemia, hypomagnesaemia and association with other torsadogenic drugs.

Peripheral neuropathy

Observational studies suggest that fluoroquinolones increase the risk of peripheral neuropathy and carpal tunnel syndrome compared to other standard antibiotics (12 -14). However, the occurrence of neuropathy in patients exposed to fluoroquinolones remains rare, with an increase in absolute risk in a large database study of only 0.02% per year in all patients, and 0.04% per year in those aged 60 years and more (12). Risk factors for fluoroquinolone-associated neuropathy include obesity, as well as other known causes of neuropathy (amyloidosis, alcoholism...)

Neuropsychiatric disorders

Fluoroquinolones are associated with anxiety, euphoria, confusion, nightmares, depression and, more rarely, convulsions. These effects are transient and improve when the drug is stopped. They are more frequent in elderly patients.

References

  1. Actualité - L’ANSM publie un dossier thématique sur les antibiotiques fluoroquinolones - ANSM. Accessed February 3, 2023. https://ansm.sante.fr/actualites/lansm-publie-un-dossier-thematique-sur-les-antibiotiques-fluoroquinolones-1
  2. ENCEPP. Study of Impact of EU Label Changes for Fluoroquinolone Containing Medicinal Products for Systemic and Inhalation Use - Post-Referral Prescribing Trends.; Mise à jour Juin 2024. https://catalogues.ema.europa.eu/print/pdf/node/3213
  3. HAS. Choix et durée de l’antibiothérapie : Pyélonéphrite aiguë de la femme. Haute Autorité de Santé. Published 2021. Accessed February 3, 2023. https://www.has-sante.fr/jcms/c_2722914/fr/choix-et-duree-de-l-antibiotherapie-pyelonephrite-aigue-de-la-femme
  4. Alves C, Mendes D, Marques FB. Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2019;75(10):1431-1443. doi:10.1007/s00228-019-02713-1
  5. Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015;5(11):e010077. doi:10.1136/bmjopen-2015-010077
  6. Yasui Y, Tonogai I, Rosenbaum AJ, Shimozono Y, Kawano H, Kennedy JG. The Risk of Achilles Tendon Rupture in the Patients with Achilles Tendinopathy: Healthcare Database Analysis in the United States. BioMed Res Int. 2017;2017:7021862. doi:10.1155/2017/7021862
  7. Maumus-Robert S, Bérard X, Mansiaux Y, Tubert-Bitter P, Debette S, Pariente A. Short-Term Risk of Aortoiliac Aneurysm or Dissection Associated With Fluoroquinolone Use. J Am Coll Cardiol. 2019;73(7):875-877. doi:10.1016/j.jacc.2018.12.012
  8. Dai XC, Yang XX, Ma L, Tang GM, Pan YY, Hu HL. Relationship between fluoroquinolones and the risk of aortic diseases: a meta-analysis of observational studies. BMC Cardiovasc Disord. 2020;20(1):49. doi:10.1186/s12872-020-01354-y
  9. Information de sécurité - Fluroquinolones par voie systémique ou inhalée: risque de survenue d’anévrisme et de dissection aortique - ANSM. Accessed February 3, 2023. https://ansm.sante.fr/informations-de-securite/fluroquinolones-par-voie-systemique-ou-inhalee-risque-de-survenue-danevrisme-et-de-dissection-aortique
  10. Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120(2):103-110. doi:10.1159/000334441
  11. Liu X, Ma J, Huang L, et al. Fluoroquinolones increase the risk of serious arrhythmias: A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(44):e8273. doi:10.1097/MD.0000000000008273
  12. Morales D, Pacurariu A, Slattery J, Pinheiro L, McGettigan P, Kurz X. Association Between Peripheral Neuropathy and Exposure to Oral Fluoroquinolone or Amoxicillin-Clavulanate Therapy. JAMA Neurol. 2019;76(7):827-833. doi:10.1001/jamaneurol.2019.0887
  13. Etminan M, Brophy JM, Samii A. Oral fluoroquinolone use and risk of peripheral neuropathy: a pharmacoepidemiologic study. Neurology. 2014;83(14):1261-1263. doi:10.1212/WNL.0000000000000846
  14. Cheng JZ, Sodhi M, Etminan M, Carleton BC. Fluoroquinolone Use and Risk of Carpal Tunnel Syndrome: A Pharmacoepidemiologic Study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2017;65(4):684-686. doi:10.1093/cid/cix362
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