Fluoroquinolones rank among the top five most frequently prescribed antimicrobial agents. Their practical significance is considerable: these drugs are included in treatment protocols for both nonspecific and specific infections (such as tuberculosis), as well as for certain highly dangerous zoonotic diseases, including anthrax.**

Nearly all generations of fluoroquinolones are used in clinical practice to treat infections of various localizations, with urology and pulmonology being the most common clinical areas of application. There are four recognized generations of quinolones. The first generation is not considered fluoroquinolones in the strict sense, as its representatives do not contain a fluorine atom in their molecular structure. Representatives of the second, third, and fourth generations have become firmly established in clinical use, with some of them being market leaders in the prescription segment of the pharmaceutical industry.**

The safety of fluoroquinolone use in clinical practice continues to be evaluated. In 2019, a comprehensive European safety review was published, leading to new restrictions on indications for fluoroquinolone antibacterial drugs, including ciprofloxacin. The reassessment was prompted by reports of persistent, and in some cases irreversible, adverse reactions—primarily affecting the musculoskeletal and nervous systems (Bennett A.C. et al., 2019). The European Medicines Agency (EMA) concluded that fluoroquinolones should not be prescribed for mild to moderate infections (e.g., exacerbations of chronic bronchitis and chronic obstructive pulmonary disease) when alternative antibacterial agents, typically recommended for such infections, are available.**

Fluoroquinolones should only be considered when other (non-fluoroquinolone) antimicrobials cannot be used—due to proven or suspected resistance of the pathogens to first-line drugs, hypersensitivity, treatment failure, or the development of adverse reactions necessitating discontinuation of alternative therapies.

The EMA review presents data on long-lasting adverse reactions associated with the use of quinolones and fluoroquinolones, collected from spontaneous reports and published scientific literature. According to the EMA, the EudraVigilance database revealed 286 cases of serious adverse reactions reported over a 21-year period, with no identifiable alternative explanations, which led to disability and persisted for 30 days or more. While cumulative data on patient exposure to fluoroquinolones in the EU during this period are unavailable, experts estimate that more than 300 million defined daily doses of fluoroquinolone antibiotics are dispensed annually.

Despite the relatively small number of reported cases of such potentially irreversible adverse events, experts believe the actual figures are likely underestimated. Consequently, the European regulator concluded that, due to the severity of these reactions—sometimes occurring in previously healthy individuals—any decision to prescribe fluoroquinolones should be made only after a thorough benefit-risk assessment for each individual case.

Among the serious and persistent adverse effects reviewed, the following remain of particular concern: tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathy (including paresthesia), depression, fatigue, memory impairment, sleep disorders, and disturbances in hearing, vision, taste, and smell. It is important to understand that tendon damage—especially to the Achilles tendon, but also other tendons—can occur as early as 48 hours after the start of treatment or even several months after discontinuation.

The EMA placed particular emphasis on precautionary measures: patients over 60 years of age, those with impaired renal function, recipients of solid organ transplants, and individuals taking corticosteroids are at increased risk for tendon injury. Therefore, the concurrent use of fluoroquinolones and corticosteroids should be avoided, as it may amplify the risk of fluoroquinolone-induced tendinitis and tendon rupture.

The Committee for Medicinal Products for Human Use (CHMP) endorsed the recommendations of the Pharmacovigilance Risk Assessment Committee (PRAC) and concluded that the marketing authorizations for the quinolone antibiotics cinoxacin, flumequine, nalidixic acid, and pipemidic acid should be revoked. CHMP confirmed that the use of fluoroquinolone antibiotics should be restricted. Moreover, prescribing information for healthcare professionals and patient leaflets will include warnings about disabling and potentially irreversible adverse reactions, and will advise patients to discontinue fluoroquinolone treatment at the first signs of side effects affecting muscles, tendons, joints, or the nervous system.

According to the EMA experts, the restrictions on the use of fluoroquinolones pertain to the prohibition of their use for:

• Treating infections that can be cured without their use or are not serious (e.g., ENT infections);
• Treating non-bacterial infections, such as non-bacterial chronic prostatitis;
• Treating and preventing traveler's diarrhea or recurrent urinary tract infections (e.g., chronic cystitis);
• Treating bacterial infections of mild or moderate severity, except in cases where other antibacterial drugs, typically recommended for these infections, cannot be used.

It is important to note that these drugs should be avoided in patients who have previously experienced serious adverse reactions (ARs) when taking fluoroquinolone or quinolone antibiotics. They should be used with caution in elderly patients, patients with kidney disease, and those who have undergone organ transplantation, as these patients are at increased risk of tendon damage. Since the use of corticosteroids with fluoroquinolones also increases this risk, combined use of these medications should be avoided.

The CHMP's conclusions were forwarded to the European Commission, which, on February 14, 2019, adopted a final legally binding decision for orally and parenterally administered quinolones and fluoroquinolones. Given the sufficient available data confirming the causal relationship between the use of fluoroquinolones and the development of the aforementioned safety issues, a decision was made on September 28, 2020, requiring the marketing authorization holders of fluoroquinolone-containing medicines to make the necessary amendments to the medical use recommendations to reduce the risk of these adverse effects.

Unlike the recommendations from the U.S. Food and Drug Administration (FDA), the European regulator expanded the warnings for the use of fluoroquinolones and indicated that these drugs should be used only after a careful benefit-risk assessment and consideration of other possible treatment options in patients with a history of aneurysm or congenital heart valve defects, or those with an existing aneurysm and/or aortic dissection or heart valve disease, as well as other risk factors or conditions predisposing to their development:

• In the case of aneurysm and signs of aortic dissection, and valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, hypertension, rheumatoid arthritis), or;
• In the case of aneurysm and signs of aortic dissection (e.g., vascular diseases such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren's syndrome), or;
• In the case of valve regurgitation/insufficiency (e.g., after a history of infectious endocarditis).
• It is also indicated that the risk of aortic rupture may be increased in patients concurrently taking systemic corticosteroids.

By 2021, the new EU restrictions were fully synchronized with existing national guidelines of the Russian Federation and other CIS countries. The changes made to the drug safety information, including for INNs such as ciprofloxacin, levofloxacin, and moxifloxacin, indicate that these restrictions should not prevent the use of fluoroquinolones in serious or severe infections, if this is in accordance with existing guidelines, has microbiological justification, and/or when the benefits of their use outweigh the risks.

In December 2018, the US FDA issued new warnings regarding fluoroquinolones. Specifically, an analytical review by the FDA showed that fluoroquinolone antibiotics, administered orally or by injection, may increase the frequency of rare but serious adverse reactions, including tendon ruptures or aortic ruptures in patients with risk factors. These reactions may lead to life-threatening bleeding or even death. The FDA issued recommendations, including avoiding the prescription of fluoroquinolones to patients with aortic aneurysm or those at risk of developing an aortic aneurysm, such as patients with peripheral atherosclerotic vascular diseases, hypertension, certain genetic conditions like Marfan syndrome and Ehlers-Danlos syndrome, and elderly patients. These patients should only be prescribed fluoroquinolones in the absence of other therapeutic options. Furthermore, the Patient Information Leaflet includes a recommendation to seek medical attention immediately if a patient experiences sudden, severe, and persistent pain in the abdomen, chest, or back, and lists conditions that the patient should inform their physician about before starting fluoroquinolone treatment, including a history of aneurysm, episodes of thrombosis and embolism, high blood pressure, or genetic diseases such as Marfan syndrome or Ehlers-Danlos syndrome.

The FDA also reviewed cases published in medical literature describing patients without endocrine and psychiatric disorders who experienced significant mood changes, behavioral disturbances, and blood sugar level alterations during systemic fluoroquinolone treatment. As a result, starting from 2018, regulatory requirements led to updates in the product information regarding the effects of fluoroquinolones on blood glucose levels and the risk of side effects related to mental health. Specifically, the "Warnings and Precautions" section now includes additional information stating that fluoroquinolone treatment, including ciprofloxacin, may significantly lower blood glucose levels (hypoglycemia), potentially leading to hypoglycemic coma. Additionally, adverse reactions related to mental health have been highlighted and organized, including:

• Attention impairment
• Disorientation
• Anxiety
• Nervousness
• Memory impairment
• Severe cognitive disturbances (delirium)

Additionally, adverse reactions have been identified and categorized as endocrine disorders, which are signs and symptoms of low blood sugar (hypoglycemia) that may occur after a single dose, including:

• Confusion

• Increased heart rate or very rapid pulse

• Dizziness

• Paleness of the skin

• Feelings of insecurity

• Sweating

• Severe hunger

• Shaking

• Headaches

• Irritability

• Episodes of anxiety

For healthcare professionals, the risk groups for hypoglycemia, which can sometimes lead to coma, include elderly patients and patients with diabetes mellitus who are taking oral hypoglycemic agents or insulin.

In December 2020, the European regulatory body PRAC EMA released new, previously unpublished safety data regarding fluoroquinolones, specifically related to the occurrence of adverse reactions from the cardiovascular system, such as aortic and mitral valve regurgitation. In the Russian Federation, this information from the regulatory authorities was presented in a letter by Sanofi-Aventis Group, which was published by Roszdravnadzor. The letter indicates that a recent study found several cases of valve regurgitation or insufficiency in patients taking fluoroquinolones. The risk of regurgitation in patients receiving systemic fluoroquinolones was found to be approximately twice as high as that in those who took other classes of antibiotics (amoxicillin or azithromycin). The relationship between fluoroquinolones and these adverse events was assessed as possible. Therefore, it is recommended to carefully weigh the "benefit-risk" ratio when prescribing fluoroquinolones and consider alternative therapies for patients at risk of developing heart valve insufficiency or blood flow disturbances. Such patients include those with arterial hypertension, rheumatoid arthritis, congenital or acquired heart valve diseases, connective tissue pathologies (such as Marfan syndrome or Ehlers-Danlos syndrome), Shereshevsky-Turner syndrome, Behçet’s disease, and infective endocarditis. It is also important to inform patients about potential risks and advise them to seek immediate medical attention if symptoms such as dyspnea, tachycardia, or swelling of the subcutaneous adipose tissue of the abdomen or legs develop.

The basis for the new warnings came from an in vitro study, which showed that exposure to fluoroquinolones, particularly ciprofloxacin, leads to collagen degradation in myofibroblast cells from the aorta of patients with aortic pathology, including aortic regurgitation (Guzzardi D.G. et al., 2019). It is hypothesized that the risk of tendon and aortic damage associated with fluoroquinolones may also be linked to collagen degradation.

But does the risk of disabling adverse reactions associated with the use of fluoroquinolones mean that these drugs will be relegated to the deep reserve list? It is clear that over time, more counterarguments in the form of evidence-based studies will emerge, challenging the fairness of the strict restrictions placed on these drugs.

For example, the results of several studies published in the JAMA Internal Medicine journal did not confirm a link between fluoroquinolones and adverse effects such as aneurysm or aortic dissection. In one of the studies, researchers analyzed insurance database data from Taiwan (Dong Y.H., et al., 2020). They compared patients with similar infections: approximately 30,000 with an aortic aneurysm or dissection and 290,000 without such conditions. According to the findings, compared to other antibiotics, fluoroquinolones did not increase the risk of aortic damage.

In another study, outcomes were examined in American patients, nearly 280,000 of whom started taking fluoroquinolones or antibiotics from another class for pneumonia, and approximately 950,000 for urinary tract infections (Gopalakrishnan C., et al., 2020). In the case of pneumonia, the risk of aortic disease was slightly higher in patients treated with fluoroquinolones compared to those who took azithromycin (0.03% vs. 0.01%). Regarding urinary tract infections, the frequency of adverse reactions with fluoroquinolones and amoxicillin was less than 0.01% for each class of antibiotics. According to the authors, although earlier studies showed an increased risk of aneurysm or aortic dissection with fluoroquinolones, sometimes more than doubling, these studies did not account for patients' comorbid infections and did not compare the risks with other classes of antibiotics.

According to information published by Russian authors, fluoroquinolones of the second, third, and fourth generations are equitoxic when administered once (Avdeeva O.I., et al., 2017). However, moxifloxacin demonstrates statistically significantly less pronounced toxic properties toward the main organs/tissues of concern (central nervous system, kidneys, and liver). When administered multiple times, fluoroquinolones of the fourth generation show less toxicity than second and third-generation fluoroquinolones. Overall, preclinical toxicity assessments of fluoroquinolones from different generations, administered once or multiple times, showed that fluoroquinolones are low-toxicity compounds, causing toxic effects on laboratory animals at doses significantly higher than therapeutic doses, both when administered orally and intravenously.

As for the most frequently prescribed and used fluoroquinolone – ciprofloxacin, all authors reporting adverse reactions indicate that there is no strict pattern regarding the development of adverse reactions affecting the musculoskeletal system, central and peripheral nervous systems, in relation to the duration of the drug's use, as the risk of adverse reactions persists even after completing the therapy. A retrospective analysis published in 2019 of spontaneous reports received by the "Pharmacovigilance" database of Roszdravnadzor for the period from November 24, 2008, to December 31, 2018 (Molchan N.V., et al., 2019) deserves attention. The criterion for selecting reports for the study was the presence of information about ciprofloxacin use and subsequent adverse reactions. During this period, 2083 spontaneous reports were received, containing information on 3403 adverse reactions from ciprofloxacin use. The vast majority of the cases, represented in the 2083 spontaneous reports, ended with the patient's recovery (61.7%) or improvement (26.2%). In 8 cases (0.4%), the outcome was fatal. The most common adverse reactions – 1269 cases out of 3403 (37.3%) – were skin and subcutaneous tissue disorders, 719 (21.1%) were general disorders and site reactions, and 508 (14.9%) were gastrointestinal disturbances, which ranked third in the domestic database. In a single case of pseudomembranous colitis (diagnosed at autopsy), the patient died due to multiple organ failure. Around 10% of spontaneous reports of adverse reactions with ciprofloxacin concerned immune system disorders. The authors suggest that the increased use of fluoroquinolones in recent decades has led to a rise in allergic reactions to these drugs and an increase in their severity. As a rule, these conditions were reversible and not life-threatening. The "Pharmacovigilance" database of Roszdravnadzor identified only 8 cases of musculoskeletal and tendon-related adverse reactions (0.2%), including: joint pain (3 cases), myalgia (2 cases), and one case of tendon pain, muscle hypertonia, and muscle cramps. Additionally, 11 reports of ciprofloxacin-induced hepatotoxicity were identified, most of which manifested as drug-induced hepatitis, and 11 reports of renal adverse reactions, including acute renal failure, interstitial nephritis, and toxic nephropathy. Among gastrointestinal adverse reactions, 184 cases of antibiotic-associated diarrhea (5.4%) were reported, 20 of which led to colitis, and one case also involved electrolyte imbalance and hypovolemia. Diarrhea not associated with Clostridium difficile (48 adverse reactions – 1.4%), nausea (135 adverse reactions – 4.0%), vomiting (92 adverse reactions – 2.7%), abdominal pain (33 adverse reactions – 1.0%), and isolated cases of gastritis, enterocolitis, dyspepsia, heartburn, bloating, dry mouth, and stomatitis were also noted. One case of necrotizing pancreatitis was observed. Among adverse reactions from the hematopoietic and lymphatic systems, a single case of severe granulocytopenia was recorded. Mental health-related adverse reactions included hallucinations (5 adverse reactions), psychomotor agitation (3 adverse reactions), anxiety (2 adverse reactions), and one case of acute psychosis. From the central nervous system, dizziness (49 adverse reactions – 1.4%) and headache (24 adverse reactions – 0.7%) were reported. Two cases of epileptiform seizures and 8 cases of convulsions were also reported. Changes in taste were noted in 10 cases. Cardiovascular adverse reactions included 26 (0.8%) cases of tachycardia, 3 cases of bradycardia, and 3 cases of arrhythmia. Two cases showed QT interval prolongation on the patient's ECG. Vascular adverse reactions were mostly related to changes in blood pressure (50 adverse reactions – 1.5%) and facial flushing (41 adverse reactions – 1.2%). Nine cases of unconsciousness and two cases of pre-syncope were recorded.

Fluoroquinolones are antimicrobial drugs that combine a broad spectrum of activity, including against intracellular pathogens, favorable pharmacokinetics, such as the ability to achieve bactericidal concentrations at the site of infection and penetrate into cells, as well as proven good tolerability. Serious disabling adverse reactions (ARs) identified during post-marketing use of these drugs typically occur sporadically, and statistical data on them is not available. When evaluating these risks, it is important to note the extremely high levels of exposure (consumption volumes) of fluoroquinolones in the population: these drugs are prescribed to a large number of patients, including those with risk factors.

Therefore, the higher the consumption of these drugs, the more likely and frequent certain risks will be identified, which were not previously considered during clinical trials.

It is even more critical to project the risk of developing severe disabling adverse reactions with the use of parenteral fluoroquinolones. Clearly, due to the short duration of their use, the likelihood of developing a "disability syndrome" associated with fluoroquinolone use ("Fluoroquinolone-Associated Disability" - FQAD) will be extremely low. However, despite this, regulatory decisions concern all dosage forms of fluoroquinolones for systemic use.

It is also undeniable that by imposing restrictions, regulators aim to draw medical professionals' attention to the rationality and justification for using fluoroquinolones. This issue affects all levels of healthcare services that use drug therapy, with the greatest concern likely being the outpatient use of oral forms for prolonged treatment.

Primum non nocere – this phrase fully applies to the entire field of clinical medicine. Today, the discussion around fluoroquinolones continues, and when choosing drugs from this group, it is strongly recommended to objectively assess the benefits versus possible risks. Tomorrow, attention may be drawn to other widely used medications. However, in all cases, drug treatment should be conducted within approved indications, following the recommended dosage regimens and course durations based on the identified pathology.

* - «First, do no harm» (лат.)

References:

1. Quinolone and fluoroquinolone Article-31 referral - Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics. Available at: EMA Document

2. Suter C, et al. "Ciprofloxacin-induced" bilateral quadriceps tendon rupture: A case report and conclusions of the recent literature. Case Reports Trauma Case Rep. 2021 Feb 10;32:100423.

3. Wang S, et al. Meta-analysis of Efficacy and Safety of Inhaled Ciprofloxacin in Non-cystic Fibrosis Bronchiectasis Patients. Intern Med J. 2021 Jan 19. doi: 10.1111/imj.15210. Online ahead of print.

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13. Available at: Roszdravnadzor Document.

14. Available at: EMA Document on Heart Valve Regurgitation.

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