Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?
Abstract
:1. Introduction
2. Materials and Methods
3. Relevant FQs Used in Therapy
3.1. The Main FQs with Clinical Importance
QNs/FQs | 1st Generation | 2nd Generation | 3rd Generation | 4th Generation |
---|---|---|---|---|
Nalidixic Acid | Ciprofloxacin, Nadifloxacin 1, Norfloxacin, Ofloxacin, Pefloxacin | Gatifloxacin 2, Levofloxacin | Besifloxacin 2, Delafloxacin, Finafloxacin 3, Moxifloxacin | |
Antibacterial spectrum | Enterobacteria. No activity against Gram-positive bacteria. | Enterobacteriaceae; some atypical pathogens; Pseudomonas aeruginosa (only Ciprofloxacin); some Gram-positive bacteria (including Streptococcus pneumoniae), moderate activity against Staphylococcus aureus (Ciprofloxacin, Norfloxacin, Ofloxacin, Pefloxacin) Staphylococcus aureus ((MRSA) and coagulase-negative staphylococci), aerobic Gram-negative and anaerobic pathogens (Nadifloxacin 1) | Broad-spectrum, including Staphylococcus aureus, Streptococcus species, and Gram-negative pathogens (Gatifloxacin 2) Enterobacteriaceae; Atypical pathogens; Streptococcus pneumoniae, penicillin-resistant (Levofloxacin) | Streptococcus pneumoniae, Staphylococcus epidermidis, Staphylococcus aureus, Hemophilus influenzae, Moraxella catarrhalis, Corynebacterium spp. (Besifloxacin 2) Broad-spectrum (including methicillin-resistant Staphylococcus aureus) (Delafloxacin) Broad-spectrum activity (Finafloxacin 3) Enterobacteriaceae; atypical pathogens; Pseudomonas aeruginosa; Streptococci; Staphylococcus aureus methicillin-sensitive; anaerobic pathogens (Moxifloxacin) |
Indications | Uncomplicated urinary tract infections (UTI) | Uncomplicated and complicated UTI, pyelonephritis, sexually transmitted diseases, prostatitis, respiratory tract infections, skin, soft tissues, bones, and joint infections (Ciprofloxacin, Norfloxacin, Ofloxacin, Pefloxacin) Acne vulgaris and other skin infections (Nadifloxacin 1). | Bacterial conjunctivitis due to susceptible pathogens (Gatifloxacin 2) Acute and chronic bronchitis, exacerbated forms, acquired pneumonia (nosocomial) (Levofloxacin) | Bacterial conjunctivitis (Besifloxacin 2) Bacterial skin and skin structure infections (Delafloxacin) Acute otitis externa (Finafloxacin 3) Sexually transmitted diseases, prostatitis, skin and tissue infections, acute and chronic bronchitis, exacerbated forms, acquired pneumonia (nosocomial), intra-abdominal infections, and gynecological infections (Moxifloxacin) |
References | [2,42] | [1,43] | [44,45,46] | [27,44,47] |
3.2. Essential Chemical Characteristics
3.3. Mechanism of Action
3.4. Safety Warnings concerning Emerging Serious AEs
No. | Year | Regulatory Entity | Document | Title of Document | Targeted AEs | The Formulations/Administration Concerned | Ref. |
---|---|---|---|---|---|---|---|
1 | 2008 | FDA | FDA alert (8 July 2008) | Information for Healthcare Professionals: Fluoroquinolone Antimicrobial Drugs Black Boxed Warning | Increased risk of tendinitis and tendon rupture | Formulations for systemic use (except ophthalmic or otic formulations) | [71,72,73] |
2 | 2011 | FDA | FDA alert (February 2011) | Information for Healthcare Professionals: Fluoroquinolone Antimicrobial Drugs Black Boxed Warning? | Worsening symptoms of patients with myasthenia gravis | Formulations for systemic use | [32,74] |
3 | 2013 | FDA | FDA Drug Safety Communication (15 August 2013) | FDA requires label changes to warn of the risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection | Side-effects of peripheral neuropathy | Formulations for systemic use except for ophthalmic or otic formulations | [75] |
4 | 2016 | FDA | FDA Drug Safety Communication (12 May 2016) | FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side-effects that can occur together | Side-effects concerning tendons, muscles, joints, nerves, and CNS | Formulations for systemic use | [76] |
5 | 2016 | FDA | FDA Drug Safety Communication (26 July 2016) | FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side-effects (safety labeling changes) | Side-effects involving nerves, the CNS, tendons, muscles, and joints | Formulations for systemic use | [32] |
6 | 2018 | FDA | FDA (10 July 2018) | FDA reinforces safety information about serious low blood sugar levels and mental health side-effects with fluoroquinolone antibiotics; requires label changes (warnings) | Serious risk of blood sugar drop and negative impact on mental health | Formulations for systemic use | [68] |
7 | 2018 | FDA | FDA Drug Safety Communication (20 December 2018) | FDA warns about the increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients (safety announcement) | Higher risk of aortic dissections or ruptures of an aortic aneurysm | Formulations for systemic use | [77] |
8 | 2018 | EMA | EMA/668915/2018 (5 October 2018) | Fluoroquinolone and quinolone antibiotics: PRAC recommends new restrictions on use following a review of disabling potentially long-lasting side-effects available online | Long-term adverse effects affecting tendons, bones, and the nervous system | Formulations for systemic and inhalation route | [34] |
9 | 2019 | EMA | EMA/175398/2019 (11 March 2019) | Disabling and potentially permanent side-effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics | Side-effects involving the CNS, bones, muscles, joints, and tendons | Formulations for systemic and inhalation route | [35] |
10 | 2020 | EMA | EMA/Direct Healthcare Professional Communication (DHPC) (29 November 2020) | DHPC: Systemic and inhaled FQs: risk of heart valve regurgitation/incompetence | Risk of heart valve regurgitation/incompetence | Formulations for systemic and inhalation route | [78] |
3.5. Withdrawal of Some FQs over Time
4. The Modern FQs
Recently Approved FQs
5. Side-Effects of FQs and Underlying Mechanisms
5.1. Aortic Aneurysm and Aortic Dissection
5.1.1. Underlying Mechanisms of Aortic Aneurysm and Aortic Dissection
5.1.2. Reported Aortic Aneurysm and Aortic Dissection Associated with Modern FQs
5.2. Tendinopathy/Tendon Rupture
5.2.1. Underlying Mechanisms of Tendinopathy/Tendon Rupture
5.2.2. Tendinopathy/Tendon Rupture Associated with Modern FQs
5.3. Retinal Detachment
5.3.1. Underlying Mechanisms of Retinal Detachment
5.3.2. Retinal Detachment Associated with Modern FQs
5.4. Peripheral Neuropathy
5.4.1. Underlying Mechanisms of Peripheral Neuropathy
5.4.2. Reported Peripheral Neuropathy Associated with Modern FQs
5.5. Neuropsychiatric Toxicity
5.5.1. Underlying Mechanisms of Neuropsychiatric Toxicity
5.5.2. Reported Neuropsychiatric Toxicity Associated with Modern FQs
5.6. Seizures
5.6.1. Underlying Mechanisms of Seizures
5.6.2. Seizures Associated with Modern FQs
5.7. Exacerbation of Myasthenia Gravis
5.7.1. Underlying Mechanisms of Exacerbation of Myasthenia Gravis
5.7.2. Reported Exacerbation of Myasthenia Gravis Associated with Modern FQs
5.8. Cutaneous Side-Effects, Hypersensitivity Reactions, Anaphylaxis
5.8.1. Underlying Mechanism of Cutaneous Side-Effects, Hypersensitivity Reactions, and Anaphylaxis
5.8.2. Cutaneous Side-Effects, Hypersensitivity Reactions, and Anaphylaxis Associated with Modern FQs
5.9. Phototoxicity
5.9.1. Underlying Mechanisms of Phototoxicity
5.9.2. Reported Phototoxicity Associated with Modern FQs
5.10. Clostridium difficile Infection
5.10.1. Underlying Mechanisms of Clostridium difficile Infection
5.10.2. Reported Clostridium difficile Infections Associated with Modern FQs
5.11. QT Prolongation (Fatal Arrhythmia) and Torsade de Pointes
5.11.1. Underlying Mechanisms of QT Prolongation (Fatal Arrhythmia) and Torsade de Pointes
5.11.2. QT Prolongation (Fatal Arrhythmia) and Torsade de Pointes Associated with Modern FQs
5.12. Dysglycemia/Hypoglycemia and Hyperglycemia
5.12.1. Underlying Mechanisms of Dysglycemia
5.12.2. Reported Dysglycemia and Hypoglycemia Associated with Modern FQs
5.13. Hepatotoxicity
5.13.1. Underlying Mechanisms of Hepatotoxicity
5.13.2. Reported Hepatotoxicity Associated with Modern FQs
5.14. Genotoxicity
5.14.1. Underlying Mechanism of Genotoxicity
5.14.2. Genotoxicity Associated with Modern FQs
5.15. Severe Hemolytic-Uremic Syndrome
5.15.1. Underlying Mechanisms of Severe Hemolytic-Uremic Syndrome
5.15.2. Severe Hemolytic-Uremic Syndrome Associated with Modern FQs
5.16. Acute Renal Failure
5.16.1. Underlying Mechanisms of Acute Renal Failure
5.16.2. Acute Renal Failure Associated with Modern FQs
6. Management of Side-Effects
- Discontinuation of the regimen
- 2.
- Rest and decrease of physical load on the tendon alongside physical therapy
- 3.
- Avoiding FQs regimens in patients with pre-existing conditions of aortic aneurysm or aortic dissection
- 4.
- Reducing the duration of FQs’ administration may decrease the risk of peripheral neuropathy side-effect occurrence
- 5.
- Monitoring the serum folate level and supplementation in FQ-induced neuropathy
- 6.
- Avoiding the FQs therapy in patients with a history of seizures
- 7.
- Collaboration between the health professional team to prevent and treat hypersensitive syndrome to FQs
- 8.
- Avoiding exposure to sunlight
- 9.
- Increase the Clostridium difficile infection control measures
- 10.
- Reversing severe induced hypoglycemia by FQs
- 11.
- Replacing the culprit drug for the elevation of hepatic transaminases
- 12.
- Combating potential crystalluria produced by FQs in the kidney
- 13.
- Avoiding the co-administration of FQs and renin–angiotensin system blockers
- 14.
- Lower doses of FQs in older patients with advanced chronic kidney disease
7. Rational Use and Caution of Modern FQs
8. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | FQs (Generation) | Manufacturer | Approval Year | Withdrawn Year | Side-Effects | References |
---|---|---|---|---|---|---|
1 | Fleroxacin (2nd) | Kyorin Pharmaceutical | 1981 | 1990 | CNS effects, phototoxicity | [37,93,94] |
2 | Tosufloxacin (2nd) | Toyama Chemical | 1990 | 2006 | Thrombocytopenia, nephritis, toxic epidermal necrosis, eosinophilic pneumonitis | [37,95,96,97] |
3 | Temafloxacin (2nd) | Abbott Laboratories | 1992 | 1992 | “Temafloxacin syndrome”: hemolytic-uremic syndrome | [2,37,49,98,99,100] |
4 | Lomefloxacin (2nd) | Serle | 1992 | 1993 | CNS effects, phototoxicity | [101,102,103] |
5 | Sparfloxacin (3rd) | Mylan | 1996 | 2001 | QT prolongation, phototoxicity | [103,104,105,106,107,108] |
6 | Alatrofloxacin (3rd) | Pfizer | 1997 | 2006 | Seizures, thrombocytopenia, hepatotoxicity | [108,109,110] |
7 | Trovafloxacin (3rd) | Pfizer | 1997 | 2000 | Hepatotoxicity | [99,108,111,112] |
8 | Grepafloxacin (3rd) | Glaxo | 1997 | 1999 | QT prolongation, fatal cardiotoxicity, gastrointestinal toxicity | [99,108,113,114] |
9 | Clinafloxacin (3rd) | Parke Davis | 1999 | 1999 | Hypoglycemia, phototoxicity | [115] |
10 | Gatifloxacin (3rd) | Bristol-Myers Squibb | 1999 | 2006 | Increased risk of dysglycemia | [108,116,117] |
11 | Gemifloxacin (3rd) | Vansen Pharma | 1999 | 2009 | Rash erythematous | [117,118,119] |
Approval Year(s) | QNs/FQs | Antibacterial Spectrum | Indications | Formulations | Administration | Observations | Ref. |
---|---|---|---|---|---|---|---|
1998 2000 | Nadifloxacin | G(+) (including MRSA and coagulase-negative staphylococci), G(−), and anaerobic bacteria | Acne vulgaris Other skin infections | Topical (1% cream) | Twice daily | Approved in Japan Approved by EMA | [42,43,122,123,127] |
2008 2012 | Sitafloxacin | Broad-spectrum: G(+) and G(−) bacteria, including anaerobic bacteria, atypical pathogens (particularly against bacteria resistant to other FQs) | Respiratory infections and UTI | Oral formulation (tablets 50 mg) | 50–100 mg twice daily | Approved in Japan Approved in Thailand | [128,129,130,131,132,133,134,135,136,137,138,139,140] |
2009 | Besifloxacin | Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus epidermidis, Moraxella catarrhalis, Hemophilus influenzae, Corynebacterium spp. | Bacterial conjunctivitis | Ophthalmic suspension (0.6%) | One drop in the affected eye(s), three times daily, 4 to 12 h apart (for 7 days) | Approved by the FDA Approved in Canada and later in other countries (Argentina, South Korea, Brazil etc.) | [141,142,143] |
2014 | Finafloxacin | Broad-spectrum (particularly against Staphylococcus aureus and Pseudomonas aeruginosa) | Acute otitis externa | Otic suspension (0.3%) | Four drops in the affected ear(s), twice daily (for seven days) | Approved by the FDA | [27,144,145,146] |
2014 2016 | Nemonoxacin 1 | Broad spectrum: typical and atypical respiratory pathogens (particularly against resistant G(+) cocci, including penicillin-resistant Streptococcus pneumoniae and MRSA) | CAP (pending for diabetic foot ulcer infections, Skin and soft tissue infections approval) | Oral formulation (capsules 250 mg) Intravenous (i.v.) formulation | 500 mg once a day | Approved in Taiwan Approved in China | [28,29,147,148] |
2015 | Zabofloxacin | Broad-spectrum (particularly against major respiratory tract pathogens) | Acute bacterial exacerbation of COPD | Oral (tablets) | 367 mg once daily (for five days) | Approved in South Korea, the Middle East, and North-African countries FDA’s Clinical phase 3 trial approval for CAP patients | [21,149,150,151] |
2017 2019 | Delafloxacin | Broad-spectrum: G(+) (including MRSA) and G(−) bacteria | ABSSSI, CAP | Oral (tablets) Parenteral (i.v. infusion) | Oral: 450 mg every 12 h (for 5 to 14 days) Parenteral: 300 mg by i.v. infusion over 60 min every 12 h. | Approved by the FDA Approved by the EMA | [21,152,153,154,155] |
2017 2018 2019 | Ozenoxacin | Staphylococcus aureus, Staphylococcus pyogenes, and other G(+) bacteria sensitive and resistant to methicillin, QNs, mupirocin and fusidic acid | Impetigo | Topical (1% cream) | Twice daily (for five days) | Approved by the FDA Approved in Spain Approved in 12 EU countries | [126,156,157,158] |
2019 2022 | Lascufloxacin | Major respiratory tract pathogens (e.g., Streptococcus pneumoniae, Moraxella catarrhalis, Hemophilus influenzae, and Mycoplasma pneumoniae) | Respiratory tract and ear, nose, and throat infections, CAP, otorhinolaryngological infections | Oral (tablets) | 75 mg once daily | Approved in Japan Approved in China | [23,159,160,161] |
2020 | Levonadifloxacin | Broad-spectrum: G(+) (including MRSA and FQs-resistant Staphylococcus aureus) and G(−) bacteria, atypical bacteria, anaerobic bacteria, bioterror pathogens | ABSSSI with concurrent bacteraemia and diabetic foot infections | Oral (tablets) I.v. injection | 500 mg twice daily 800 mg twice daily | Approved in India | [162,163,164] |
No. | Substituents on Chemical Structure (X and Y: C or N) | Associated Side-Effects | Ref. |
---|---|---|---|
1 | N1: Cyclopropyl, Ethyl, 2,4-Diphluorophenyl | Interactions with the cytochrome P450 | [167] |
N1: Cyclopropyl ≥ Ethyl > 2,4-Diphluorophenyl > Fluorethyl | Theophylline interactions | [168] | |
N1: Cyclopropyl ≥ Tert-Butyl > 2,4-Diphluorophenyl > Ethyl | Genotoxicity | [168] | |
N1: 2,4-Diphluorophenyl (combined with halogen at position 8) | Phototoxicity | [169] | |
N1: Cyclopropyl, Ethyl | Phototoxicity | [169] | |
N1: Aminodifluorophenyl, 1-Isoxazolyl | Phototoxicity | [169] | |
2 | C2: No substitution | No side-effects | [168,170] |
3 | C3: Carboxyl | Decrease absorption of biological metals; interactions with antacids, multimineral supplements, and milk products (due to metal binding and chelating) | [168] |
C3: Carboxyl | Chondrotoxicity (due to specific chelation of Mg2+) | [167,170] | |
4 | C4: Oxo | Decrease absorption of biological metals; interactions with antacids, multimineral supplements, and milk products (due to metal binding and chelating) | [168] |
C4: Oxo | Chondrotoxicity (due to specific chelation of Mg2+) | [167,170] | |
5 | C5: Methyl/amino substituents | QT prolongation | [104,168,170] |
5 | C5: Methyl >> H > Amino substituents | Phototoxicity | [167,168] |
5 | C5: Methyl > Amino substituents > H | Genotoxicity | [167,168] |
6 | C6: Fluorine substituent | Genotoxicity | [167] |
7 | C7: Pyrrolidine > Piperazine > Alkyl | Genotoxicity | [167] |
C7: Pyrrolidine (unsubstituted) > Piperazine (unsubstituted) > Pyrrolidine (substituted) > Piperazine (substituted) | Genotoxicity | [168] | |
C7: Alkyl > Piperazine (unsubstituted) > Pyrrolidine (unsubstituted) > Piperazine (substituted) or Pyrrolidine (substituted) | Neuropsychiatric toxicity, seizures (GABA receptor binding) | [8,44,117,167,168,171] | |
C7: Piperazine (unsubstituted) | Crystalluria | [167] | |
C7: Piperazine (unsubstituted) > Pyrrolidine (unsubstituted) > Piperazine (substituted) or Pyrrolidine (substituted) | Some NSAIDs interactions | [167] | |
C7: Pyrrolidine (unsubstituted) > Piperazine (unsubstituted) > Piperazine (substituted) or Pyrrolidine (substituted) | Theophylline interactions | [168] | |
8 | C8: Fluorine/chlorine substituents (F > Cl) | Phototoxicity, Genotoxicity | [167,170] |
C-F > C-Cl > N > C-H > C-O-Methyl, C-CF3 | Phototoxicity | [168] | |
C-F > C-Cl ≥ C-O-Methyl > N > C-H | Genotoxicity | [168] | |
C8: Fluorine/chlorine, methoxy substituents | Crystalluria | [167] | |
C8: Bulky substituent | Decreased interactions with the cytochrome P450 | [167] | |
N8: Naphtiridone nucleus | Increased interactions with the cytochrome P450 | [167,170] |
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Rusu, A.; Munteanu, A.-C.; Arbănași, E.-M.; Uivarosi, V. Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile? Pharmaceutics 2023, 15, 804. https://doi.org/10.3390/pharmaceutics15030804
Rusu A, Munteanu A-C, Arbănași E-M, Uivarosi V. Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile? Pharmaceutics. 2023; 15(3):804. https://doi.org/10.3390/pharmaceutics15030804
Chicago/Turabian StyleRusu, Aura, Alexandra-Cristina Munteanu, Eliza-Mihaela Arbănași, and Valentina Uivarosi. 2023. "Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?" Pharmaceutics 15, no. 3: 804. https://doi.org/10.3390/pharmaceutics15030804