Fluoroquinolones Used in Therapy: Comparison
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Antibacterial fluoroquinolones (FQs) are frequently used in treating infections. However, the value of FQs is debatable due to their association with severe adverse effects (AEs). The Food and Drug Administration (FDA) issued safety warnings concerning their side-effects in 2008, followed by the European Medicine Agency (EMA) and regulatory authorities from other countries.

  • fluoroquinolones
  • antibacterial quinolones
  • adverse effects

1. The Main FQs with Clinical Importance

The classification into generations based on the spectrum of activity and therapeutic indications is the most used. New compounds are acquired from one generation to another with a broader spectrum of activity (Table 1) and improved pharmacokinetic properties [1]. Among the representatives of the fourth generation are topical FQs (ophthalmic and otic), such as besifloxacin [2] and finafloxacin [3].
New FQs (including a nonfluorinated QN) were approved in India, Japan, South Korea, and Taiwan [4]. These representatives will be addressed in a subsequent section [3][5][6][7].
Table 1. QNs and FQs approved by the FDA and EMA from the perspective of the antibacterial spectrum and the main indications (EMA—European Medicine Agency, FDA—USA Food and Drug Administration, FQs—fluoroquinolones, QNs—antibacterial quinolones).
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 [8][9] [10][11] [12][13][14] [12][15][16]
1 Topical (skin), 2 Topical (ophthalmic), 3 Topical (otic) administration.

2. Essential Chemical Characteristics

Structural characterization of FQs (older and newer representatives) was recently described in two other papers by our group of authors [1][4]. Essential structural elements of FQs will be briefly highlighted below. FQs are based on quinoline nucleus (ciprofloxacin, norfloxacin, pefloxacin, moxifloxacin, delafloxacin. etc.). Still, some compounds are 1,8-naphthyridine derivatives (e.g., nalidixic acid and zabofloxacin) or tricyclic compounds that include a quinoline nucleus (ofloxacin/levofloxacin, nadifloxacin) (Figure 12) [4][17][18][19].
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Figure 12. Chemical structures of FQs used in therapy and approved by the EMA and FDA (EMA—European Medicine Agency, FDA—Food and Drug Administration, FQs—fluoroquinolones).
The N1 position is involved in pharmacokinetic properties and overall potency. Substitution with a cyclopropyl moiety increased the activity against Gram-negative bacteria (e.g., ciprofloxacin). Other substituents were less beneficial or associated with severe AEs (e.g., 2,4-difluorophenyl in temafloxacin) [19][20][21][22]. A 6-amino-3,5-difluoropyridinyl moiety enlarges the delafloxacin’s molecular surface and is responsible for the activity against Gram-positive pathogens [23][24].
The C2 position is optimal without substitution, and a larger substituent may hinder the C3 and C4 positions [20]. A carboxyl group in the C3 position and an oxo(keto) group in the C4 position are essential for interacting with the DNA bases and the enzyme DNA gyrase [19][20][25][26]. Small radicals substituted at the C5 position (e.g., methyl or amino) may increase activity against Gram-positive bacteria, but currently, FQs used in therapy have no substituents in this position [19][20]. The number of halogen substituents on the basic nucleus varies. Many compounds contain a single fluorine atom in the C6 position. The substitution with a fluorine atom increased the potency of the FQs [19][20]. Besifloxacin contains two different halogens in the structure (fluorine in the C6 position and chlorine in the C8 position) [27]. Other representatives have three fluorine atoms (e.g., lascufloxacin) or three fluorine and one chlorine atom (e.g., delafloxacin). Nemonoxacin is a non-fluorinated QN, approved in Taiwan in 2014 [28]. Halogen substitutions lead to increased permeability, decreased solubility, and increased lipophilicity of the compounds [29][30].
The C7 position controls the pharmacokinetics and antibacterial activity of FQs. A five- or six-membered nitrogen heterocycle is optimal, such as piperazine (second-generation FQs), pyrrolo-piperidine (e.g., moxifloxacin), hexahydro-1H-azepine (e.g., besifloxacin), 3-hydroxyazetidine (e.g., delafloxacin), and pyrrolo-oxazine (e.g., finafloxacin). The substitution with a piperazine nucleus increased activity against Gram-negative bacteria (especially for the second-generation FQs). Other heterocycles increased activity against Gram-positive bacteria [4][20][21]. In general, the C8 position controls pharmacokinetic properties and activity against anaerobic bacteria. A beneficial C8 substituent is the methoxy group found in moxifloxacin and gatifloxacin and the recent representatives, lascufloxacin and nemonoxacin (Figure 23) [19].
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Figure 23.
Chemical structures of the recently approved systemic antibacterial (fluoro)quinolones in the countries where they were produced.
Chlorine substitution at the C8 position increased the antimicrobial potency of besifloxacin by acting on the two target enzymes, DNA gyrase and topoisomerase IV [31]. The C8 cyano group in finafloxacin seems essential in activity against Gram-positive bacteria [3][15].

3. Mechanism of Action

Many papers concerning the FQs mechanism of action have already been published [18][25][32][33][34][35]. Antibacterial QNs act by inhibiting two enzymes involved in bacterial DNA replication, DNA gyrase and DNA topoisomerase IV. DNA gyrase introduces negative supercoils into DNA, an essential activity for the initiation of DNA replication. Topoisomerase IV removes the interlinking of daughter chromosomes (decatenation) to segregate chromosomes (and plasmids) into daughter cells at the end of a round of replication. The second function of topoisomerase IV (shared with the DNA gyrase) is to relax positive supercoils. In Gram-negative pathogens, the primary target is the DNA gyrase enzyme, while in Gram-positive pathogens, the primary target is the topoisomerase IV enzyme. Thus, the first FQs generations target only the DNA gyrase enzyme from Gram-negative bacteria [25][35][36][37]. Newer FQs representatives target both enzymes from Gram-negative and Gram-positive bacteria [33][38]. Due to FQ-enzyme-DNA complex formation, DNA replication is reversibly inhibited, and the DNA is cleaved in both strands [32][35]. Bacterial death occurs depending on the drug concentration [37]. At low concentrations, FQs block reversible DNA replication and transcription. Next, the inhibition of DNA and RNA synthesis occurs. Thus, the growth of bacteria will be inhibited, but only during FQs therapy [32]. A higher drug concentration (over the minimum inhibitory concentration (MIC)) leads to its binding to the topoisomerase-DNA cleavage complex. Bacterial death depends on the processing of the cleavage complex. The slow death of bacteria arises when the processing of the cleavage complex is missing, and DNA replication and transcription are blocked. Rapid death of bacteria occurs when the cleavage complex is processed, and the broken DNA repair no longer occurs. Due to chromosome fragmentation, the bacterial cell will quickly die [32][39]. These events can produce reactive oxygen species (ROS) and, consequently, more DNA breaks. The DNA damage induced by FQs can be restored with consequences concerning the survival of the bacterial cell [32].
Recent studies highlight the importance of ROS formation and FQs’ lethality [40][41]. It seems that ROS are the dominant factor in FQs’ lethality. ROS accumulation completes the primary DNA damage induced by FQs to kill bacterial cells [41][42]. Numerous studies regarding the increased oxidative stress state generated by the FQs treatment were discussed by Michalak et al. [43].

4. Safety Warnings concerning Emerging Serious AEs

Although the approved FQs are helpful in treating infections with sensitive germs, a significant disadvantage is the potential risk of associated severe AEs (involving muscles, tendons, or joints and the nervous system) [44][45]. The most reported severe AEs are tendon rupture (especially to the Achilles tendon), arthralgia, tendonitis, pain in extremities, gait disturbance, neuropathies associated with paresthesia, fatigue, memory impairment, depression, sleep disorders, impaired vision, hearing, taste and smell, phototoxicity, genotoxicity, QTc prolongation, hematological effect, hepatic eosinophilia effect, pulmonary interstitial eosinophilia, immunological side-effects, hypoglycemia, and CYP 450 inhibition [18][46]. Due to some severe AEs from those previously listed, many compounds have been withdrawn from therapy (Section 3.5). Thus, FQs are contraindicated in patients who have previously experienced side-effects during treatment with a (fluoro)quinolone antibiotic [46][47]. Since the risks exceed the benefits, the FDA and EMA have recently restricted the use of FQs in treating mild and uncomplicated infections, non-bacterial infections, preventing traveler’s diarrhea, and recurring lower UTI, unless other recommended antibacterial agents cannot be used [45][47][48][49]. Additionally, the FDA and EMA recommended that FQs should not be used as first-line therapies in treating acute sinusitis, bacterial infections among persons with chronic obstructive pulmonary disease (COPD), or UTIs, as the risks outweigh the benefits [46][49].
In 2016, the FDA mandated label revisions for all systemic FQs, along with a Black Box Warning about the possibility of irreversible AEs, including the muscles, joints, tendons, nerves, and central nervous system (CNS), that can occur together in the same patient (Table 2) [50][51]. Additionally, new warnings were made, and other parts of the FQs’ label were updated [50]. In 2018, the list of the approved FQs by the FDA comprised ciprofloxacin, delafloxacin, levofloxacin, gemifloxacin, moxifloxacin, and ofloxacin [52].
On 15 November 2018, the EMA completed an evaluation of significant, debilitating, and possibly irreversible AEs associated with QNs and FQs antibiotics administered orally, injectable, or inhaled, considering the experiences of patients, healthcare workers, and scientists. Following this evaluation, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has suggested that some medications, particularly those containing QNs, should be withdrawn from the market [1][2][6][7][9][11][12][13][14][16][21][22][23][24][26][29][30][31][35][37][38][39][40][41][42][43][44][45][46][47][49][50][51][52][53][54][55][56]. The QNs and FQs subject to these restrictions are: (a) cinoxacin, nalidixic acid, pipemidic acid (QNs), and (b) ciprofloxacin, flumequine, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, and rufloxacin (FQs) [53]. Instead, FQs should be used to treat illnesses when an antibiotic is required but other antibiotics are ineffective [56].
Table 2. FDA and EMA warnings concerning emerging severe AEs of QNs and FQs (AEs—adverse effects, EMA—European Medicine Agency, FDA—USA Food and Drug Administration, FQs—fluoroquinolones, QNs—antibacterial quinolones, Ref.—references).
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) [57][58][59]
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 [48][60]
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 [61]
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
69] evaluated the risk of the common AEs associated with FQs. Additionally, this study compared the occurrence of AEs related to FQs and the occurrence of the AEs associated with other antimicrobial agents. Prescribing FQs led to a significantly higher occurrence of gastrointestinal and CNS side-effects compared to other antimicrobial agents (e.g., macrolides and cefuroxime axetil). However, FQs were associated with fewer gastrointestinal and CNS side-effects versus fosfomycin and the combination of trimethoprim-sulfamethoxazole. In addition, FQs were not related to skin-related AEs [69][70][71].
Regulations from other countries (exclusive of the USA and EU) concerning FQ-associated AEs are discussed below.
Canada. There are five FQs (oral and injectable) approved in Canada by different companies: ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin. In 2016, Health Canada changed the labels of oral FQs due to reported cases of patients developing retinal detachment, which has become a significant concern regarding FQs. Health Canada authority emphasizes the necessity of seeing a medical professional if the patients report eye problems during or following the FQs’ administration [72]. In addition, at the beginning of 2017, other safety labeling updates informed Canadians and medical professionals about the possibility of persistent or severe AEs, such as tendinopathy, peripheral neuropathy, and CNS disorders [73].
United Kingdom. Ciprofloxacin, moxifloxacin, levofloxacin, and ofloxacin are the FQs approved for therapy in the United Kingdom. In 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) advised that FQs should not be prescribed to treat non-severe or non-bacterial diseases unless other antibiotics are ineffective. Additionally, following a review of the above-listed severe AEs of these drugs, all FQs were limited, with added health labeling concerns [74]. In 2020, a new safety warning for patients at risk for heart valve regurgitation was announced, stating that FQs should be used only following a rigorous benefit–risk evaluation of other alternative treatments [70].
Australia. Since 1976, Australia has expanded the regulatory standards for antimicrobial treatments among humans, and the use of QNs medications is known for its role as a backup antimicrobial agent. Every three years, a group of experts in infectious diseases evaluates the guidelines for antimicrobial administration in the population and hospitals. FQs are prescribed when necessary or as a better-suited therapy, such as in patients with severe CAP that have acute penicillin hypersensitivity, but in most situations, empirical regimens in national prescription guidelines advise the use of aminoglycosides, β-lactams, or macrolides [75]. There are three approved FQs in Australia: ciprofloxacin, norfloxacin, and moxifloxacin. In 2019, following the public announcements of the FDA and EMA regarding the severe AEs induced by FQs, the Therapeutic Goods Administration (TGA) began researching a rare but severe adverse event of aortic aneurysm associated with FQs [76]. During the TGA’s research, it was also decided to update the labeling of FQs to ensure that all products contain warnings concerning the potential AEs of dysglycemia and adverse mental reactions [77].

5. Withdrawal of Some FQs over Time

Although some new FQs representatives proved to have good antibacterial activity, a broader activity spectrum, or better pharmacokinetic properties compared to compounds of previous generations, they were associated with severe AEs that led to their withdrawal from the market. Approved FQs that were withdrawn after a few years of approval are alatrofloxacin/trovafloxacin, gatifloxacin, gemifloxacin, grepafloxacin, sparfloxacin, and temafloxacin (Table 3) [45][78].
Table 3. Examples of FQs withdrawn from therapy due to severe AEs (AEs—adverse effects, FQs—fluoroquinolones).
No. FQs

(Generation)		 Manufacturer Approval Year Withdrawn

Year		 Side-Effects References
1 Fleroxacin (2nd) Kyorin Pharmaceutical 1981 1990 CNS effects, phototoxicity [44][79][80]
2 Tosufloxacin (2nd) Toyama Chemical 1990 2006 Thrombocytopenia, nephritis, toxic epidermal necrosis, eosinophilic pneumonitis [44][81][82][83]
3 Temafloxacin (2nd) Abbott Laboratories 1992 1992 “Temafloxacin syndrome”: hemolytic-uremic syndrome [8][22][44][84][85][86]
4 Lomefloxacin (2nd) Serle 1992 1993 CNS effects, phototoxicity [87][88][89[62]
] 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 [48]
5 Sparfloxacin (3rd) Mylan 1996 2001 QT prolongation, phototoxicity [89][90][91][92][93][94] 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
6Formulations for systemic use Alatrofloxacin (3rd)[ Pfizer 1997 2006 Seizures, thrombocytopenia,

hepatotoxicity		 [94][95][96]52]
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
7 Trovafloxacin (3rd)[ Pfizer63]
1997 2000 Hepatotoxicity [85][94][97][98] 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 [53]
8 Grepafloxacin (3rd) Glaxo 1997 1999 QT prolongation, fatal cardiotoxicity,

gastrointestinal toxicity		 [85][94] 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 [46]
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 [64]
As a result, the EMA’s PRAC and the FDA recommend restrictions on the prescribing of QNs and FQs due to potentially life-threatening side-effects, such as tendon rupture, musculoskeletal pain, and nerve damage (Table 2) [49]. Additionally, FQs should be contraindicated in patients who have already experienced substantial AEs from a (fluoro)quinolone regimen. FQs should be used with extreme caution in elderly patients, patients with renal illness, and those who have undergone an organ transplant, due to an increased risk of tendon rupture. Additionally, combining FQs and corticosteroids raises the risk of tendon rupture. Therefore, this combination should be avoided [46].
Etminam et al. [65] found that the FQs therapy could be associated with increased aortic and mitral regurgitation. In the same year, a cellular and molecular mechanism was documented concerning FQ-associated aortopathy [66]. Consequently, prescribing advice for specialists has been issued by the EMA and other countries (e.g., the United Kingdom). Systemic or inhaled FQs should be used only after following a rigorous benefit–risk evaluation of different treatments available in the case of individuals at risk for heart valve regurgitation [64][67]. The FDA has not issued any warnings or recommendations regarding increased aortic and mitral regurgitation associated with FQs.
However, in a recent study, Strange et al. [68] demonstrated that increased valvular regurgitation rates are not significantly associated with oral FQs. Therefore, more studies must confirm or deny the link between FQs and increased aortic and mitral regurgitation.
A comprehensive review and meta-analysis published by Tandan et al. [
[
99
]
[
100
]
9
Clinafloxacin (3rd) Parke Davis 1999 1999 Hypoglycemia, phototoxicity [101]
10 Gatifloxacin (3rd) Bristol-Myers Squibb 1999 2006 Increased risk of dysglycemia [94][102][103]
11 Gemifloxacin (3rd) Vansen Pharma 1999 2009 Rash erythematous [103][104][105]
Severe AEs such as hepatotoxicity, dysglycemia, Clostridium difficile infection, fatal arrhythmia due to QT prolongation, and severe hemolytic-uremic syndrome increased the risks of FQs administration and ultimately led to the withdrawal of some FQs on the market all over the world [49]. Only five FQs representatives are approved for systemic use in the USA market (ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, and delafloxacin) [45]. In 2017, the FQs were in the top 10 topics of the Division of Drug Information (DDI), which is closely connected with the FDA Center for Drug Evaluation and Research (CDER) [106]. In addition, a situation about systemic FQs associated with potential AEs events reported to the DDI in 2013–2017 highlights 2016 as the year with the most significant number of inquiries (703) [107].

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