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Delafloxacin, a superior antibacterial agent to its competitor fluoroquinolones
Korean J. Microbiol. 2021;57(3):133-141
Published online September 30, 2021
© 2021 The Microbiological Society of Korea.

Md. Ferdaus Azam1, Mohammad Saydur Rahman1, G M Al Amin2, Md. Ibrahim Miah3, and Young-Sang Koh4*

1Department of Pharmacy, Jagannath University, Dhaka-1100, Bangladesh
2Department of Botany, Jagannath University, Dhaka-1100, Bangladesh
3Department of Microbiology, University of Dhaka, Dhaka-1000, Bangladesh
4Department of Microbiology and Immunology, College of Medicine, and Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
Correspondence to: E-mail: yskoh7@jejunu.ac.kr; Tel.: +82-64-754-3851; Fax: +82-64-702-2687
Received June 7, 2021; Revised July 13, 2021; Accepted July 14, 2021.
Abstract
The resistance of currently used antibiotics has emerged the necessity of a new one. Delafloxacin is a new fluoroquinolone derivative that is distinct from its competitors. Among the fluoroquinolone antibiotics, delafloxacin shows a broad spectrum of efficacy against a variety of microorganisms. Delafloxacin has large treatment potential for complicated intra-abdominal infections, acute bacterial exacerbation of chronic bronchitis (ABECB), urogenital infections, etc. Delafloxacin exhibits a potent efficacy against methicillin-resistant Staphylococcu aureus (MRSA), Pseudomonas aeruginosa, Enterococcus faecalis, S. aureus, and Enterobacteriaceae compared to levofloxacin and moxifloxacin. The potency of delafloxacin increases in acidic environment whereas other fluoroquinolones exhibit decreased potency in acidic media. The probability of antibiotic resistance cases is comparatively low for delafloxacin because its dual affinity for both DNA gyrase and topoisomerase IV is nearly equal. Delafloxacin usually eliminates via renal either as glucuronide conjugates or intact drugs. Dosage adjustment is necessary for severe renal impairment patients but not necessary for hepatic or mild to moderate renal impairment patients. The commonly observed adverse effects of delafloxacin are diarrhea, nausea, headache, vomiting, and transaminase elevations. Other fluoroquinolones have been reported to cause phototoxicity but it was not found in delafloxacin treatment. The overall information showed delafloxacin a superior antibacterial agent over other fluoroquinolones. In this review, we pointed out the upcoming use of delafloxacin for treating bacterial infections.
Keywords : ciprofloxacin, delafloxacin, fluoroquinolones, levofloxacin, moxifloxacin
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These days, antibiotic resistance is a serious issue that predominantly affects community health (Rahman and Koh, 2018, 2020). Therefore, novel antibiotics development is required for treatment of infectious diseases. A novel anionic fluoroquinolone, delafloxacin is a US-FDA (United States Food and Drug Administration) approved fluoroquinolone derivative that exerts a wide range of efficacy against Gram-negative bacteria, Gram-positive bacteria, a typical and anaerobic organism such as Enterobacteriaceae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, Escherichia coli, methicillin resistant Staphylococcus aureus (MRSA), etc. (McEwen et al., 2015; Thabit et al., 2016; Iregui et al., 2020). Delafloxacin is the fourth generation fluoroquinolone class antibiotic (Anwer et al., 2020). In the United States (US), fluoroquinolones were one of the most frequently prescribed antibiotics because of their attractive features such as a good pharmacokinetic property and a good clinical activity against a wide range of microorganisms (Jorgensen et al., 2018). The discoverer of delafloxacin (as WQ-3034) is Wakunaga Pharmaceutical Company Limited, Osaka & Hiroshima, Japan (Lemaire et al., 2011; Kocsis and Szabo, 2016). Since 2006, the development of delafloxacin (BaxdelaTM) has been pursued by Melinta Pharmaceuticals (formerly named Rib-X Pharmaceuticals) and then, the phase-2 trials have been completed successfully for community acquired pneumonia (CAP), bronchitis, and complicated skin and skin structure infections (Kocsis and Szabo, 2016; Markham, 2017). The available dosage forms of delafloxacin in the market are both oral and intravenous (IV) (Millar et al., 2021). Recently it has been approved by the FDA in the US for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) (Dawe et al., 2018; Millar and Moore, 2020). The FDA in June 2017 as well as the European Medicines Agency in 2019 approved this antibiotic to treat ABSSSIs (Fan et al., 2020; Shortridge et al., 2020). In 2019, the FDA also approved it for the treatment of CAP (Shortridge et al., 2020). Delafloxacin has a large treatment potential for the treatments of various types of infectious diseases including complicated intra-abdominal infections, ABSSSIs and hospitalized CAP (McEwen et al., 2015; Markham, 2017). The susceptibility profile against respiratory pathogens and the favorable safety profile of this drug promote its use in the treatment of CABP (Community-Acquired Bacterial Pneumonia) (Horcajada et al., 2020). Like other fluoroquinolones, both oral (450 mg) and intravenous (300 mg/vial) formulations of delafloxacin are available however, the difference is the minimal effect of delafloxacin on the CYP450 enzymes and the corrected QT interval (Mogle et al., 2018; Millar and Moore, 2020). Delafloxacin is a dual targeting anionic fluoroquinolone because it inhibits DNA synthesis by targeting both bacterial DNA gyrase and topoisomerase IV enzymes (Kocsis and Szabo, 2016; Millar et al., 2021). It acts as a weak acid (pKa-5.4) due to the absence of a potent basic group at the C-7 position of delafloxacin (Mogle et al., 2018). This weak acidic property enhances the potency of delafloxacin in acidic media (Mogle et al., 2018).

Comparative Activity of Delafloxacin with Other Fluoroquinolones

Delafloxacin exhibits powerful activity against S. aureus and coagulase-negative staphylococci such as methicillin and levofloxacin-resistant strains (Thabit et al., 2016; Markham, 2017). In a phase two study, the use of delafloxacin in the treatment of patients suffering from an acute bacterial exacerbation of chronic bronchitis (ABECB) exhibited that both levofloxacin and delafloxacin had nearly equal microbiological and clinical efficacy against Staphylococcus aureus (n = 19 patients) as well as S. pneumoniae (n = 46 patients) (Thabit et al., 2016). Delafloxacin’s microbiological and clinical effectivity is as high as its comparators in the treatment ABSSSIs (Lan et al., 2019). Delafloxacin also showed a similar spectrum of activity like levofloxacin and moxifloxacin against Klebsiella pneumoniae, methicillin susceptible Staphylococcus aureus (MSSA), and S. pneumoniae (Thabit et al., 2016). The rate of resistance of delafloxacin is comparatively lower than moxifloxacin and levofloxacin against methicillin resistant strains of S. aureus and Staphylococcus epidermidis (Fan et al., 2020). In addition, delafloxacin showed strong activity against Helicobacter pylori compared to levofloxacin (Boyanova et al., 2020a). On the other hand, the in vitro efficacy of delafloxacin was higher than levofloxacin against most of the Gram-positive microorganisms including levofloxacin non-susceptible isolates (Pullman et al., 2017). The MIC90 (minimum inhibitory concentration) of delafloxacin was found at least eight times more active compared to levofloxacin against MRSA isolates (Sharma et al., 2020). Delafloxacin showed remarkably stronger potency over levofloxacin against Clostridium difficile (Boyanova et al., 2020b). MRSA is generally resistant to most of the fluoroquinolones but the high efficacy of delafloxacin has been demonstrated against it in vivo (Thabit et al., 2016). Delafloxacin showed better efficacy against MRSA blood isolates compared to levofloxacin (Saravolatz et al., 2020). Delafloxacin exhibited 128-times (MIC50) and 64-times (MIC90) more effective compared to levofloxacin against all isolates of S. pneumoniae (Flamm et al., 2016). Levofloxacin (> 4 µg/ml) activity against P. aeruginosa, E. faecalis, and Enterobacteriaceae is comparatively lower than in vitro activity of delafloxacin (Markham, 2017). The in vitro bactericidal activity of delafloxacin is demonstrated against MRSA with minimal bactericidal concentrations (MBC) of 0.008 µg/ml against MRSA strain 110 (susceptible to levofloxacin), 0.5 µg/ml against MRSA strain 124 (triple mutant) and 8 µg/ml against MRSA strain 165 (quadruple mutant) compared to levofloxacin concentrations of 0.5 µg/ml, 8 µg/ml, and > 32 µg/ml against those strains (Markham, 2017). The favorable clinical response and anti-MRSA activity against MRSA infections distinguishes delafloxacin from other fluoroquinolone derivatives (Saravolatz and Stein, 2019). Delafloxacin exhibits not only bactericidal effect but also inhibits biofilm formation of S. aureus (Kocsis and Szabo, 2016). In comparison to moxifloxacin, delafloxacin exhibited 3 to 5 log2 dilutions lower MIC ranges against 35 strains of S. aureus with pertinent resistance mechanisms (Lemaire et al., 2011). It was also 10 fold more effective than moxifloxacin against intracellular S. aureus ATCC-25923 strains (Lemaire et al., 2011). In comparison to most of the fluoroquinolones, delafloxacin retains activity in low pH environment such as vaginal tract, skin, urinary tract and intracellularly within the phagosomes (Gould and Bal, 2013). The use of delafloxacin may be advantageous in treating S. aureus infections in acidic media (pH 5 to 5.5) such as urinary tracts, vagina and phagolysosomes of infected cells because these bacteria have a higher tolerance to low pH (Lemaire et al., 2011). At pH 5.5, the MICs of delafloxacin are nearly 5 to 7 times lower than that of pH 7.4 against S. aureus (Candel and Peñuelas, 2017). Delafloxacin potency was found ten times higher at pH 5.5 than pH 7.4 against S. aureus while moxifloxacin showed opposite result (So et al., 2015). It is demonstrated that the MIC values of delafloxacin against Gram-positive bacteria are about 3 to 5 fold lower compared to other fluoroquinolones because delafloxacin is thought to have a greater attraction to DNA gyrase (Jorgensen et al., 2018). Both moxifloxacin and delafloxacin showed nearly equal in vitro efficacy against Mycoplasma pneumoniae isolates (containing 2 macrolide-resistant) but in case of Legionella pneumophila isolates, delafloxacin showed greater efficacy than moxifloxacin (McCurdy et al., 2020). Delafloxacin showed 8 times higher potency against Haemophilus influenzae and Moraxella catarrhalis compared to levofloxacin (Shiu et al., 2019). Overall, all data showed that the in vitro activity of delafloxacin is greater than ciprofloxacin with P. aeruginosa isolated from adult CF (cystic fibrosis) patients (Table 1) (Millar et al., 2021). Delafloxacin and ciprofloxacin showed similar activity both in vivo and in vitro against most isolates of K. pneumoniae, P. aeruginosa, E. coli, and Enterobacter cloacae (Giordano et al., 2019). The value of MIC50 and MIC90 of delafloxacin were 64 and 128 fold lower than those of ciprofloxacin against 117 strains of Neisseria gonorrhoeae (Table 1) (Soge et al., 2016). The susceptibility of both S. aureus and MRSA to delafloxacin is higher than levofloxacin and moxifloxacin but the susceptibility of E. coli to delafloxacin is nearly similar to levofloxacin and moxifloxacin (Table 1) (Shortridge et al., 2020). The comparative activity of delafloxacin and other fluoroquinolones against different types of microorganisms are given in Table 1 with their MIC values.

MIC values of delafloxacin and its comparators against different types of microorganisms

Fluoroquinolones Bacteria MIC Range (mg/L) MIC50 (mg/L) MIC90 (mg/L) References
Ciprofloxacin P. aeruginosa isolate (n = 50) 0.047 to 32 1.69 8.0 Millar et al. (2021)
Delafloxacin P. aeruginosa isolate (n = 50) 0.064 to 32 0.56 2.19 Millar et al. (2021)
Delafloxacin S. aureus ≤ 0.004 to 8 ≤ 0.004 0.25 Pfaller et al. (2017)
Shortridge et al. (2020)
Levofloxacin S. aureus ≤ 0.12 to > 4 0.25 > 4 Pfaller et al. (2017)
Shortridge et al. (2020)
Moxifloxacin S. aureus ≤ 0.06 to > 4 ≤ 0.06 2 Shortridge et al. (2020)
Delafloxacin MRSA ≤ 0.004 to 8 0.25 1 Shortridge et al. (2020)
Levofloxacin MRSA 0.12 to > 4 > 4 > 4 Shortridge et al. (2020)
Moxifloxacin MRSA ≤ 0.06 to > 4 2 > 4 Shortridge et al. (2020)
Delafloxacin E. coli ≤ 0.004 to > 4 0.06 4 Shortridge et al. (2020)
Levofloxacin E. coli ≤ 0.12 to > 4 ≤ 0.12 > 4 Shortridge et al. (2020)
Moxifloxacin E. coli ≤ 0.25 to > 4 ≤ 0.25 > 4 Shortridge et al. (2020)
Delafloxacin N. gonorrhoeae 0.0005 to 0.06 0.0005 0.03 Hook et al. (2019)
Delafloxacin Haemophilus influenza ≤ 0.001 to 0.25 0.001 0.004 Soge et al. (2016)
Jorgensen et al. (2018)
Levofloxacin Haemophilus influenza 0.008 to > 2 0.015 0.03 Soge et al. (2016)
Jorgensen et al. (2018)
Ciprofloxacin Haemophilus influenza 0.004 to > 2 0.015 0.015 Soge et al. (2016)
Jorgensen et al. (2018)
Delafloxacin Enterococcus faecalis (all) ≤ 0.004 to 2 0.06 1 Jorgensen et al. (2018)
Pfaller et al. (2017)
Levofloxacin Enterococcus faecalis (all) 0.25 to > 4 1 > 4 Pfaller et al. (2017)
Jorgensen et al. (2018)
Delafloxacin Streptococcus pneumoniae (all) ≤ 0.004 to 0.25 0.03 Jorgensen et al. (2018)
Levofloxacin Streptococcus pneumoniae (all) 0.5 to > 4 1 Jorgensen et al. (2018)
Moxifloxacin Streptococcus pneumoniae (all) ≤ 0.12 to 4 0.25 Jorgensen et al. (2018)
Delafloxacin Viridans group Streptococci ≤ 0.004 to 2 0.015 0.03 Pfaller et al. (2017)
Levofloxacin Viridans group Streptococci ≤ 0.12 to > 4 1 2 Pfaller et al. (2017)
Moxifloxacin Viridans group Streptococci ≤ 0.12 to 4 0.25 Jorgensen et al. (2018)
Delafloxacin N. gonorrhoeae strains ≤ 0.001 to 0.25 0.06 0.125 Soge et al. (2016)
Ciprofloxacin N. gonorrhoeae strains 0.004 to > 16 4 16 Soge et al. (2016)
Delafloxacin M. catarrhalis 0.004 to 0.015 0.008 0.008 Flamm et al. (2016)
Levofloxacin M. catarrhalis 0.03 to 0.12 0.06 0.06 Flamm et al. (2016)
Ciprofloxacin M. catarrhalis 0.015 to 0.06 0.03 0.06 Flamm et al. (2016)

Chemistry and Structural Description

Delafloxacin (1-[6-amino-3, 5-difluoropyridin-2-yl]-8-chloro-6-fluoro-7-[3-hydroxy azetidine-1-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid) is a new broad-spectrum fluoroquinolone that demonstrates strong in vivo and in vitro efficacy against many pathogens (McEwen et al., 2015; Kocsis and Szabo, 2016; Thabit et al., 2016). The molecular weight of delafloxacin is 440 Da (Iregui et al., 2020). Previously delafloxacin was referred to as ABT 492 (Saravolatz and Stein, 2019). Delafloxacin contains the ordinary bicyclic ring structure with additional chlorine substitution at C-8 position as well as a heteroaromatic ring substitution at N-1 position (Kocsis and Szabo, 2016). This structure of delafloxacin contains three unique features: firstly, the deficiency of a strong basic group at position C-7 makes it a weak acid (pKa 5.4); secondly, the presence of a chlorine atom at position C-8 gives it a powerful electron withdrawn action on the aromatic ring; thirdly, the substitution of a heteroaromatic ring at N-1 position gives it a more surface area than other fluoroquinolone derivatives (Kocsis and Szabo, 2016; Mogle et al., 2018). The N-1 position contains a heteroaromatic ring that enhances both the solvent-accessible surface area and collaboration between the large substituent (Jorgensen et al., 2018). On the other hand, the C-8 position contains a weakly polar group that is thought to affect the efficacy against quinolone-resistant Gram-positive bacteria (Jorgensen et al., 2018). The presence of chlorine at the C-8 position stabilizes this drug and may decrease the resistance capability (Saravolatz and Stein, 2019). The anionic structure makes delafloxacin special among other fluoroquinolones due to enhancing potency at the infection site where pH is acidic (e.g. skin and soft tissue infections, Fig. 1) (Kocsis and Szabo, 2016). Besides, both moxifloxacin and ciprofloxacin exhibits decreased antimicrobial efficacy in the acidic environment (Kocsis and Szabo, 2016). One of the unique properties of delafloxacin is the existence as an unchanged molecule in an acidic environment that enhances transmembrane passage and concentration within the pathogen (Mogle et al., 2018). The MICs of delafloxacin decrease about 4 to 7 fold against a wide spectrum of bacteria when the surrounding media pH decreases from 7.2 to 5.5 (Jorgensen et al., 2018). Once the molecule gets access into the cell containing neutral a pH environment, delafloxacin donates a proton and resides in an ionic form within the bacterium (Mogle et al., 2018). On the other hand, moxifloxacin remains in the form of a zwitterion to a lesser degree in an acidic environment resulting in a poorer transmembrane passage (Candel and Peñuelas, 2017). With moxifloxacin, most of the fluoroquinolones remain in the form of zwitterion within the bacteria, so they return to the exterior very easily (Candel and Peñuelas, 2017). The anionic property of delafloxacin is unique that enhances its potency in acidic pH and so a reduction in MICs is found about 2 to 32 fold (Candel and Peñuelas, 2017; Mogle et al., 2018). The enhanced activity of delafloxacin in acidic media makes it an attractive alternative treatment options for infections caused by Helicobacter pylori because of increasing resistance of the currently used antibiotics (metronidazole, macrolides, rifamycins, amoxicillin) (Candel and Peñuelas, 2017).

Fig. 1. Chemical structure of delafloxacin and other selected fluoroquinolone derivatives.
Mechanism of Action

Delafloxacin inhibits bacterial DNA synthesis by targeting both topoisomerase IV and DNA gyrase of bacteria (Kocsis and Szabo, 2016; Mogle et al., 2018; Iregui et al., 2020). It requires multiple mutations involving these two enzymes to be resistant (Tulkens et al., 2019; Iregui et al., 2020). The use of delafloxacin is more advantageous over most of the older fluoroquinolones because it equally targets both DNA gyrase and topoisomerase IV (Boyanova et al., 2020b). It is assumed that the DNA gyrase enzyme has more susceptibility to inhibition by fluoroquinolones in Gram-negative bacteria (Mogle et al., 2018). On the other hand, it is also assumed that the topoisomerase IV enzyme has more susceptibility to inhibition by fluoroquinolones in Gram-positive bacteria (Mogle et al., 2018). The affinity and selectivity of the above target enzymes are mainly ascertained by the substitutions present at position C-7 as well as C-8 of the fluoroquinolone nucleus (Mogle et al., 2018). Unlike other fluoroquinolones, delafloxacin exhibits a great range of in vitro efficacy against extensive variety of bacteria such as MRSA, because it is a dual targeting fluoroquinolone that shows a nearly equal affinity for both DNA gyrase as well as topoisomerase IV enzymes (Mogle et al., 2018).

Pharmacokinetics and Pharmacodynamics

It is demonstrated that delafloxacin is highly penetrable into the compartment of the lung, as the concentration of epithelial lining fluid is significantly greater than the amount of free drug in plasma (Thabit et al., 2016). Delafloxacin is absorbed quickly after administration of its oral dose because peak plasma concentration of this drug is reached within 1–2.5 h (Alam et al., 2020). The absolute bioavailability of delafloxacin is low (58%) compared to other fluoroquinolones, which may be due to the poor solubility of delafloxacin in water (≈0.06 mg/ml) (Alam et al., 2020; Anwer et al., 2020). The intravenous (IV) 300 mg delafloxacin every 12 h showed Vd (volume of distribution) of 35–48 L, Cmax of 9.29 mg/L, protein binding of 84%, and T1/2 of 3.7 h but orally administered 450 mg delafloxacin every 12 h showed Cmax of 7.45 mg/L, T1/2 of 4.2–8.5 h and oral bioavailability of 58.8% (Jorgensen et al., 2018; Lee et al., 2019). The orally administered delafloxacin excreted 48% hepatically and 50% renally while the intravenously administered delafloxacin cleared 28% hepatically and 65% renally (Lee et al., 2019). Glucuronidation is the main metabolic pathway of delafloxacin and about 65% of delafloxacin is eliminated via urine as glucuronide metabolites and unchanged forms with most of the residual portion excreted as unchanged drug in the feces (Hussar and Walter, 2018). The main elimination pathway of delafloxacin is renal, with a minor portion excreted in the feces (Tulkens et al., 2019). The distribution of delafloxacin to body fluids are characterized by a plasma protein binding of 83–84% and Vd (ss) (Vd at steady-state) of 34–41 L in human (Anwer et al., 2020). Another study showed that the Vd of delafloxacin is about 0.4 L/kg that approximates total body water (Saravolatz and Stein, 2019). A single 300 mg IV administered dose of delafloxacin showed a total body clearance of 14.1 ± 2.81 L/h compared to total body clearance of 20.6 ± 6.07 L/h for a single 450 mg orally administered delafloxacin (Ocheretyaner and Park, 2018). An approximate total clearance of delafloxacin is 13 L/h and the liver is also involved in the elimination process (Hoover et al., 2018). Adjustment of dosage is not needed for mild to moderate renal impairment patients or for hepatic impairment patients but adjustment of dosage is needed for severe renal impairment patients (estimated glomerular filtration rate [eGFR], 15–29 ml/min/1.73m2) for whom intravenous dosage of delafloxacin should be reduced due to potential accumulation of the IV vehicle, sulfobutylether-betacyclodextrin (Adler et al., 2018; Bassetti et al., 2018; Hussar and Walter, 2018). IV dosage of delafloxacin is recommended to reduce to 200 mg b.i.d. for severe renal hindrance patients (Rehman and Naveed, 2020). Delafloxacin dose ranges from 300 to 1,200 mg showed an increase of Cmax proportionally with increasing dose, an increase of T1/2 from 8 to 17 h, and an increase of Vd (ss) from 30.21 L to 38.46 L (Candel and Peñuelas, 2017). The severe and moderate renal function impairment group showed a mean AUC nearly 1.5 times higher than the normal renal function group (Hoover et al., 2018). The use of delafloxacin should be discontinued if eGFR reduces to < 15 ml/min/1.73 m2 and is not advised for patients who have end-stage renal dysfunction (Hussar and Walter, 2018). The total clearance of delafloxacin reduces with reducing renal function with a corresponding enhance in AUC0-∞ (Hoover et al., 2018). The overall binding of plasma protein showed a slight decrease with reducing renal function (Hoover et al., 2018). Two daily IV doses of delafloxacin for 14 days did not show any accumulation of the drug and on day 14, clearance was nearly the same as day 1 (Candel and Peñuelas, 2017; Sain et al., 2018). A 900 mg dose of delafloxacin 30 min after taking a high caloric meal decreased Cmax by about 21% compared to subjects who were in fasting condition and took meal after dosing (Shiu et al., 2019).

Doses and Precautions

Delafloxacin recommended dose for ABSSSI is 450 mg oral or 300 mg IV twice daily (Markham, 2017). A single 300 mg IV and 450 mg oral dose of delafloxacin exhibits similar bioavailability (Hussar and Walter, 2018). Sulfobutylether beta-cyclodextrin is added in IV formulations of delafloxacin to enhance its stability and solubility (Cho et al., 2018). In case of biofilm, the activity of delafloxacin depends on biofilm pH and penetration capability of this drug within the biofilm (Siala et al., 2014). Destruction of biofilm matrix by adding norspermine or nospermidine enhances the efficacy of delafloxacin by improving its diffusion (Siala et al., 2014). Food does not have any impact on its absorption, so it can be taken without considering diet (Iqbal et al., 2020). It also requires 5~14 days for the treatment of infection (Hussar and Walter, 2018). 200 mg IV dose twice daily is recommended for patients with severe renal impairment but dose adjustment is not needed for orally administered delafloxacin (Hoover et al., 2018; Hussar and Walter, 2018). Delafloxacin is recommended for ABSSSIs as 450 mg oral dose twice daily or 300 mg IV infusion over 1 h every 12 h (Ocheretyaner and Park, 2018; Sain et al., 2018). Delafloxacin safety data is insufficient for pregnancy and nursing mothers and it is not recommended for those patients who are under 18 years old (Eudaley, 2018; Hussar and Walter, 2018). Delafloxacin should not be administered in patients who are suffering from end-stage renal disease and who are undergoing hemodialysis (Eudaley, 2018). Delafloxacin should not be orally taken with antacids that contain magnesium or aluminum ion, multivitamins that have zinc or iron cations or any formulation that contain divalent or trivalent cations (Bassetti et al., 2018).

Adverse Effects

A wide array of adverse effects is related to fluoroquinolone treatments such as phototoxicity, hepatotoxicity, hypoglycemia, tendinitis, myasthenia gravis, peripheral neuropathy, seizures, central nervous system (CNS) toxicity, Clostridium difficile diarrhea, acute kidney injury, prolongation of QT interval (the time between Q and T wave), and tendon rupture (Ocheretyaner and Park, 2018; Lee et al., 2019; Sharma et al., 2020). In clinical studies, delafloxacin was proved well tolerated (Hussar and Walter, 2018). The most common adverse effects of delafloxacin are diarrhea (8%), nausea (8%), headache (3%), vomiting (2%), transaminase elevations (3%), and infusion site pain (Adler et al., 2018; Hussar and Walter, 2018; Lodise et al., 2018). In a 2 phase 3 trials, the treatment emergent adverse effects of orally administered delafloxacin was similar to IV formulations of delafloxacin (Lodise et al., 2018). The patient who experiences diarrhea at the time of delafloxacin treatment, the possibility of Clostridium difficile associated diarrhea should be considered (Hussar and Walter, 2018). The clinical studies of delafloxacin did not show phototoxicity and QT interval prolongation but it has been reported in case of other fluoroquinolones (Adler et al., 2018; Dawe et al., 2018; Hussar and Walter, 2018). The 2nd most commonly observed adverse effects of fluoroquinolone toxicity are involved with CNS (this is thought to occur due to the blockade of GABA receptors) which results in a variety of effects such as headache, seizures, acute psychosis, and dizziness (Jorgensen et al., 2018). On the other hand, an in vitro experiment suggests that the concentration of delafloxacin requires much fold higher to inhibit GABA receptors (Jorgensen et al., 2018).

Resistance and Treatment Failure

Greater stability of delafloxacin is found against target enzyme mutations in Gram-positive bacteria rather than other fluoroquinolone derivatives (Mogle et al., 2018). Delafloxacin exhibits nearly an equal affinity for both DNA gyrase enzymes and DNA topoisomerase enzymes (Candel and Peñuelas, 2017). So, to be resistant, delafloxacin needs multiple mutations that collectively influence both these targets (Candel and Peñuelas, 2017). The most common resistance mechanism of fluoroquinolones are the mutations in DNA gyrase (gyrA and gyrB) or topoisomerase IV (parC and parE) genes (Cho et al., 2018). Drug efflux pumps including NorA, NorB, and NorC act as a contributing factor for fluoroquinolone resistance but they have no impact on the in vitro efficacy of delafloxacin (Mogle et al., 2018). In comparison to gatifloxacin, levofloxacin and moxifloxacin, delafloxacin was shown to be more effective for prevention of mutant generation in H. influenzae, S. pneumoniae, and M. catarrhalis (Cho et al., 2018). The dual-targeting activity, specific molecular shape, size, and polarity are hypothesized for retaining the susceptibility of delafloxacin against Gram-positive bacteria compared to other fluoroquinolones (Jorgensen et al., 2018; Mogle et al., 2018). Urogenital cure rates of delafloxacin were 85.1% (194 out of 228) but its treatment failure is more often related to N. gonorrhoeae with high MIC values (Hook et al., 2019). In microbiologically evaluable participants, delafloxacin MICs < 0.008 µg/ml showed treatment failure in 1 of 177 urogenital infections (0.6%) caused by N. gonorrhoeae isolates whereas MICs ≥ 0.008 µg/ml showed treatment failure in 31 of 48 infections (64.6%) caused by the same isolates (Hook et al., 2019). According to previous studies, delafloxacin has less probability of interaction with other drugs (Pullman et al., 2017). The occurrence of the discontinuation of drug study for adverse effects is lower for delafloxacin than its comparators (Lan et al., 2019).

Conclusion

Delafloxacin, the fourth generation antibiotic exerts a wide array of activity against a variety of microorganisms such as P. aeruginosa, K. pneumoniae, S. pneumoniae, E. coli, MRSA, etc. Oral 450 mg and IV 300 mg dose of delafloxacin is available in the market. The unique structural features make delafloxacin special among other fluoroquinolones. The weak acidic property of delafloxacin enhances its activity at the infection site where pH is acidic. In most of the cases, the potency of delafloxacin is higher than its comparators. Delafloxacin targets both DNA gyrase and topoisomerase IV enzymes that makes it more effective on a variety of microorganisms. Delafloxacin exhibits a good pharmacokinetic profile and less adverse effects than its comparators.

Acknowledgments

None.

Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of the manuscript.

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