Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

ABSTRACT

Introduction: In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach.

Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included.

Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram-positive infections, especially if co-infection with other pathogens is suspected. This is because of the very low MIC of the agent for Gram-positive (including MRSA) and anaerobic bacteria and because of the wide spectrum of activity against Gram-negative organisms. For these interesting microbiological and PK/PD characteristics we expect future uses of this drug in other indications such as diabetic foot infection, osteomyelitis, prosthetic joint infections, abdominal infections and central nervous system infections.

KEYWORDS:

• Delafloxacin
• fluoroquinolones
• methicillin-resistant Staphylococcus aureus
• pharmacokinetic
• skin and skin structure infection

1. Introduction

Skin and skin structure infections (SSSIs) represent one of the most common infectious causes of referral to the emergency department and of hospital admissions. The Infectious Diseases Society of America classified skin and soft tissue infections (SSTIs) into uncomplicated (uSSTIs) and complicated (cSSTIs) on the basis of the extent of the infection and the need for surgical intervention [1].

In 2013, the Food and Drug Administration (FDA) added in the regulatory procedures of new antibacterials for SSTIs the definition of acute bacterial skin and skin structure infections (ABSSSIs). ABSSSI is defined as a bacterial infection of the skin with a lesion size area of at least 75 cm². Early assessment of clinical response (represented by a ≥20% reduction in lesion size at 48–72 h compared with baseline) was introduced as a new primary end point [2].

The expansion of aging population with comorbidities contributes to the increase in incidence [3]. In the USA, visits for uncomplicated SSTIs (uSSTIs) almost doubled between 1993 and 2005 (from 1.35% to 2.98%, p < 0.001) [4] and hospital admission increased by 30% between 2000 and 2004 [5].

The increasing role of methicillin-resistant Staphylococcus aureus (MRSA) as a causative pathogen is a major concern for clinicians, both in the hospital and in the outpatient settings [6]. The progressive increase in methicillin resistance during the last decades introduced additional therapeutic challenges, leading to high rates of inadequate antibiotic treatment and significant increases in morbidity, mortality, and overall health-care costs [7,8]. In Europe, the percentage of S. aureus isolates that are methicillin resistant shows significant country variation, ranging from 0.9% in the Netherlands to 56.0% in Romania; an overall decrease in incidence has been reported in the last years, with population-weighted mean percentage for MRSA declining from 18.6% in 2011 to 17.4% in 2014 [9]. In recent years, MRSA has progressively spread among outpatients affected by multiple comorbidities or reporting frequent access to health-care facilities. Community-acquired (CA)-MRSA is characterized by peculiar epidemiology, clinical features, and genetic characteristics; this pathogen is typically involved in the development of epidemic and recurrent episodes of acute bacterial SSTIs in young and healthy patients. CA-MRSA infections in the USA are now generalized although they were initially recognized as being more common in closed communities such as military establishments, prisons, and among athletes [10]. Delafloxacin represents one of the new therapeutic options for the treatment of SSSIs, when coverage of MRSA is required in the empirical or targeted approach.

2. Overview of the market

Despite its poor diffusion in skin and skin structures, vancomycin is still considered the standard therapy for cSSSIs caused by MRSA. Vancomycin efficacy, however, has been recently questioned because of the progressive increase in vancomycin minimum inhibitory concentrations (MICs) in MRSA, and the choice of an alternative molecule is suggested when vancomycin MIC is greater than 1 µg/mL [11]. A number of new therapeutic options have recently been marketed or will be available in the near future for the treatment of cSSTIs caused by MRSA, including strains with increased vancomycin MICs. Oxazolidinones (linezolid and tedizolid) are available in both intravenous (IV) and oral formulation and are therefore suitable for sequential therapy. Other compounds of new generation (daptomycin, telavancin, tigecycline, and ceftaroline) are for IV use only and require hospitalization in most cases. New lipoglycopeptides as dalbavancin and oritavancin are characterized by a long half-life and can reduce the need for hospitalization, but the antimicrobial spectrum is limited to gram-positive pathogens. Pros and cons of new antimicrobials for the treatment of complicated SSSIs are listed in Table 1.

Table 1. Pros and cons of new and old antimicrobials for complicated skin and skin structure infections.

Drug	Pros	Cons
Delafloxacin	● Broad spectrum of activity ● Bactericidal activity ● Anti-biofilm activity ● Improved activity in acid mediums ● Oral formulation allows treatment of outpatients and early oral switch ● Good tolerability profile ● Few drug interactions	● Twice-daily administration ● Risk of tendinopathy and tendon rupture ● Risk of arthropathy
Daptomycin	● Rapid bactericidal activity ● Anti-biofilm activity ● Good tolerability profile ● Low drug interactions	● Only intravenous ● Spectrum limited to gram positives ● Dosage not well established
Tigecycline	● Broad spectrum of activity ● Good tissue penetration	● Only intravenous ● Twice-daily administration ● Frequent nausea ● FDA black box warning
Linezolid	● Oral formulation allows treatment of outpatients and early oral switch ● Good penetration in the tissue (skin and bone)	● Spectrum limited to gram positives ● Drug–drug interactions ● Important adverse effects ● Twice-daily administration
Tedizolid	● Oral formulation allows treatment of outpatients and early oral switch ● Good penetration in the tissue (skin and bone) ● Once-daily administration ● Few drug interactions ● Low myelotoxicity	● Spectrum limited to gram positives
Dalbavancin	● Once-weekly administration ● Single injection for skin infections ● Good penetration into cortical bone and articular tissues ● Good tolerability profile	● Spectrum limited to Gram positives ● Only intravenous
Oritavancin	● Single-dose treatment ● Good tolerability profile ● Bactericidal	● Spectrum limited to gram positives ● Only intravenous
Ceftaroline	● Broad-spectrum activity ● Good tolerability profile	● Only intravenous ● Twice-daily administration

Adapted from Bassetti et al., 2017 [42].

3. Introduction to the compound and chemistry

Unlike other quinolones, delafloxacin lacks a strongly basic group at the C-7 position in the chemical structure, a property that confers to the molecule a weak acid character (Box 1). Specifically, in the presence of a slightly acidic environment (pH ≤5.5), the molecule is uncharged, the calculated pKa of the carboxylic function being 5.6. Moreover, compared with other molecules of the same class, delafloxacin presents a hetero-aromatic substitution at N-1 that contributes to a larger molecular surface and shows a chlorine at C-8 position that exerts a strongly electron-withdrawing effect on the aromatic ring [13]. Thanks to its chemical characteristics, the antibacterial potency of delafloxacin in environments with a low pH is greatly enhanced.

Since delafloxacin has a double mechanism of action, targeting both DNA gyrase and topoisomerase IV, the risk for selection of resistant microbial strains is considered very low [14]. The broad spectrum of activity and the efficacy against pathogens involved in SSSIs have been described in details in a recent review [15].

4. Pharmacokinetics

The pharmacokinetic profile of delafloxacin was studied in three phase I clinical trials [16]. The first was a double-blind, randomized, single ascending-dose study in which delafloxacin at the 1-h IV dosages of 300, 450, 600, 750, 900, and 1200 mg was infused to adult healthy volunteers (52 active and 10 placebo). Pharmacokinetic analysis revealed that in the dose range studied (from 300 to 1200 mg), the C_max increased proportionally to dose, whereas area under the concentration–time curve (AUC) increased more than proportional to dose. Time to maximum plasma concentration (T_max) was reported to be of 1.0 h among all of the tested dosages. Systemic clearance (CL) and volume of distribution (Vd) ranged between 7.59 and 12.53 L/h and between 30.2 and 38.50 L, respectively. The contribution of renal clearance to systemic clearance was estimated to range between 32.1% and 39.7%. Moreover, it appeared that renal clearance may decrease with increasing delafloxacin dose.

The degree of drug accumulation following multiple doses was assessed in a randomized, double-blind, placebo-controlled study involving 12 healthy volunteers with dosing regimen of 300 mg every 12 h intravenously. No appreciable accumulation of delafloxacin was observed when comparing drug exposure at day 1 and day 14 (mean accumulation ratio of 1.09).

The third investigation was a two-period, two-sequence crossover study conducted in 55 healthy volunteers to assess the bioequivalence between a single 450-mg oral dose and a single 300-mg IV dose. The results showed mean absolute bioavailability of 58.8% and drug exposure that was equivalent in terms of AUC_0-∞, but not in terms of C_max. The geometric least square mean ratio (90% confidence interval) was 0.8768 (range, 0.8356–0.9200) and 0.5516 (range, 0.5150–0.5908) for AUC_0-∞ and C_max, respectively.

The rates and routes of excretion of delafloxacin were investigated in an open-label, phase I clinical trial which including six healthy male volunteers after the administration of a single 300-mg IV dose of [¹⁴C]-delafloxacin. The findings showed that urinary excretion accounted for 65.7 ± 4.97% of the total radioactive dose, while the fecal elimination accounted for 28.5 ± 4.92% of the radioactivity at 144 h. Delafloxacin accounted for 69.7% of the recovered dose (41.2% urine and 28.5% feces), while the glucuronide (delafloxacin main circulating metabolite eliminated exclusively in the urine) accounted for 20.4% of the recovered dose. In addition to these major components, other three glucuronide conjugates and a di-hydroxyl compound were also recovered in urine and feces, though none of them was greater than 1% of the total excreted radioactivity. Additionally, the study confirmed that the main pharmacokinetic parameters were similar to those found in the aforementioned studies. Drug half-life was 2.35 h [17]. The pharmacokinetic parameters of delafloxacin (parent compound) and of other fluoroquinolones used in SSTIs are reported in Table 2.

Table 2. Summary of pharmacokinetic parameters after single-dose fluoroquinolones.

	Dose (mg)	Cmax (mg/L)	tmax (min)	Vd (L/kg)	Pb (%)	CL (L/h)	t1/2β (h)	AUC0-∞ (mgh/L)	Fos (%)	fe (%)	Ref.
Levofloxacin	500 PO	5.2	78 ± 30	1.3^a	30	10.5^b	6.5	47.7		69	[18]
	500 IV	6.3		1.2		9.4	6.6	55.3		61	[18]
Moxifloxacin	400 PO	2.5	120	3.1^c	45	11.6^b	15.6	29.8	86.2	19.3	[19]
	400 IV	3.6		2.1		11.6	15.4	34.6		22.1	[19]
Delafloxacin	450 PO	6.12	49		84			24.2	58.8		[16]
	300 IV	8.98	60	0.43		12.53	2.35	24.8		38.9	[17]

^a V_β/F.

^b CL/F.

^c V_ss/F.

AUC_0−∞: area under the concentration–time curve to infinity; CL: total body clearance; C_max: peak plasma concentration; F_os: oral bioavailability; f_e: fraction of unchanged drug excreted in the urine; IV: intravenous; OS: oral; P_b: protein binding; t_1/2β: elimination half-life; t_max: time to peak plasma concentration; V_d: volume of distribution; V_ss: volume of distribution at steady state; V_β: volume of distribution determined during the β-elimination phase.

Delafloxacin primarily binds to albumin. Delafloxacin human plasma protein binding was determined by equilibrium dialysis and was approximately 84%. The plasma protein binding of delafloxacin is not significantly affected by renal impairment [20].

The effect of food, sex, and age on the pharmacokinetics of delafloxacin was studied in two phase I clinical trials. Delafloxacin bioavailability was investigated in fed versus fasted condition among 30 healthy volunteers after administration of a single 900-mg oral dose. Pharmacokinetic assessments were conducted under the following three conditions: after at least 10 h of fasting (controls, n = 10), 30 min before (n = 10), and 2 h after (n = 10) a standardized high-fat breakfast. C_max showed a 20.5% decrease in fed conditions, whereas total exposure in terms of AUC_0-∞ was unaffected. Therefore, it was concluded that delafloxacin could be orally administered at the same dosage regardless of food intake. As far as the effect of sex and age is concerned, a double-blind, placebo-controlled study was conducted in young and elderly men and women after a single 250-mg dose. The findings showed that the pharmacokinetic parameters were comparable in men and women, whereas significantly higher C_max and AUC_0-∞ were observed in the elderly compared to younger adults. This was possibly due to a lower creatinine clearance in elderly individuals [21].

Renal failure significantly affected delafloxacin CL among patients with mild (estimated glomerular filtration rate, (eGFR) of 62.8 ± 7.8 mL/min/1.73 m²), moderate (eGFR of 38.6 ± 4.9 mL/min/1.73 m²), and severe (eGFR of 22.3 ± 6.2 mL/min/1.73 m²) renal impairment. As drug CL approximately halved in patients with severe renal disease compared to subjects with normal renal function (eGFR of 91.9 ± 11.4 mL/min/1.73 m²), a dosage reduction to 200 mg every 12 h is recommended only for the IV route of administration when in presence of severe renal impairment [22].

The pharmacokinetic of delafloxacin was investigated also in patients with hepatic impairment. In a phase I, open-label single 300-mgIV dose study, 18 patients were homogeneously divided into three groups according to their Child–Pugh classification system score of hepatic impairment (group A, mild; group B, moderate; and group C, severe) and were matched 1:1 to healthy controls. Mean delafloxacin AUC_0-∞, C_max, CL, and Vd were similar between groups of patients and matched controls, leading to the conclusion that dose adjustment of delafloxacin was not needed in the presence of hepatic impairment [23].

As far as the potential for drug–drug interaction of delafloxacin is concerned, in vitro studies conducted with human liver microsomes excluded any inhibitory effects of delafloxacin on hepatic enzymes. Nonetheless, a mild induction on CYP3A4 enzymes was observed. On this basis, a phase I study was conducted in 22 healthy subjects to investigate the clinical relevance of this observation. Two doses of midazolam (at day 1 and day 8), a well-known metabolic probe of CYP3A4, were administered in the absence (day 1) and after 6 days of delafloxacin coadministration (450 mg every 12 h). The AUCs_24h of both midazolam and its metabolite, hydroxymidazolam, did not differ between day 1 and day 8, suggesting that no clinically meaningful induction of delafloxacin on CYP3A4 was present [24]. A summary of pharmacokinetic parameters of main fluoroquinolones is displayed in Table 2.

5. Pharmacodynamics

Pharmacokinetic/pharmacodynamic (PK/PD) targets of delafloxacin have been determined by two experimental animal studies conducted in neutropenic murine lung infection models. Similarly to other fluoroquinolones, the fAUC/MIC ratio was the pharmacodynamic determinant of efficacy. However, the magnitude of this PK/PD index associated with 1-log kill of bacterial burden was different in relation to the investigated pathogen. Lepak et al. [25] found a median fAUC/MIC ratio of 7.92 vs. four different strains of S. aureus (one methicillin-susceptible Staphylococcus aureus, (MSSA) and three MRSA); 3.36 vs. four strains of Streptococcus pneumoniae (two penicillin-susceptible and two penicillin-resistant); and 55.2 in four strains of Klebsiella pneumoniae (three of which extended spectrum beta-lactamase, (ESBL)-positive). In contrast, Thabit et al. [26] found a median fAUC/MIC of 0.4 vs. two strains of MSSA, 24.7 vs. two strains of MRSA, 31.8 vs. five strains of S. pneumoniae, and 9.6 vs. two strains of K. pneumoniae. Moreover, results from a Monte Carlo simulation conducted using MRSA skin and wound infections data confirmed an excellent attainment of the pharmacodynamic target of efficacy also in this context [27].

As these PK/PD data are very preliminary and heterogeneous, they are insufficient to draw definitive conclusion about the AUC/MIC values of delafloxacin both for gram positives and for gram negatives. However, it might be speculated that these thresholds could be attained with the dosages of 300 mg every 12 h intravenously or 450 mg every 12 h orally.

6. Clinical efficacy

Regarding ABSSSIs, a phase II double-blind study compared two doses of delafloxacin (300 and 450 mg b.i.d. intravenously) with tigecycline (100 mg intravenously as a loading dose followed by 50 mg b.i.d.) in 150 adult patients with cellulitis (36%), abscesses (33%), and wound infections (31%). The length of treatment was 5–14 days. S. aureus was the predominant pathogen (86.5% of cases; approximately 70% of strains were MRSA; among these, 63% were resistant to levofloxacin). MIC₉₀ value in S. aureus group was 0.06 µg/mL for delafloxacin, 0.12 µg/mL for tigecycline, 4 µg/mL for levofloxacin, and 8 µg/mL for ciprofloxacin. In the clinically evaluable population, cure rate was 94.3% in the delafloxacin 300 mg b.i.d. group, 92.5% in the delafloxacin 450 mg b.i.d. group, and 91.2% in the tigecycline group [28]. A second phase II trial was conducted in a population of 256 adult patients with ABSSSI (45% cellulitis, 28.5% abscesses, 25% wound infection, and 1.5% burns). In the group of patients with a positive culture, the predominant pathogen was S. aureus and MRSA accounted for 67% of the strains. The aim of the study was the evaluation of the efficacy of delafloxacin (300 mg IV b.i.d.) compared to linezolid (600 mg IV b.i.d.) and vancomycin (15 mg/kg IV b.i.d.). MIC₉₀ values for delafloxacin, linezolid, and vancomycin were 0.12, 2, and 0.5 μg/mL, respectively. Delafloxacin achieved the highest cure rate (70.4%): the difference in cure rates was statistically significant compared to vancomycin (54.1%, p = 0.03) but not to linezolid (64.9%). This result has probably been affected by the good performance of delafloxacin in the obese patients group (defined by a body mass index of ≥30 kg/m²; 78.8% delafloxacin vs. 58.8% linezolid vs. 48.8% vancomycin, p < 0.05). In the group of patients with MRSA infections, clinical cure rates were comparable in the three arms of treatment. Delafloxacin, linezolid, and vancomycin achieved the secondary end point (the reduction of at least 20% in lesion erythema at 48–72 h) in 74.4%, 73.3%, and 68.4% of cases, respectively [29].

Delafloxacin has recently completed two phase III studies, together known as PROCEED, for the treatment of ABSSSI caused by a heterogeneous group of pathogens, including MRSA: study RX-3341-302-NCT01811732 [30], with 660 patients involved, and study RX-3341–303-NCT01984684 [31], with 860 patients involved. In both studies, delafloxacin was given 300 mg IV q12h. In one of the studies, after six doses of IV delafloxacin, patients had a mandated switch to delafloxacin 450 mg oral q12h. Delafloxacin, compared to the combination of vancomycin plus aztreonam, demonstrated non-inferiority in reducing lesion size at the primary infection site at 48–72 h. As required by the European Medicines Agency, delafloxacin also showed non-inferiority compared to vancomycin in the study’s secondary end points, including investigator assessment of signs and symptoms of infection at the follow-up visit. In the second phase III PROCEED study, RX-3341-303, delafloxacin was tested as an IV-to-oral monotherapy regimen. On 19 June 2017, delafloxacin was approved by the US FDA for the treatment of ABSSI.

7. Safety, tolerability, and toxicity

No significant safety concerns for delafloxacin have emerged so far. In the phase II trial on cSSSIs comparing two doses of delafloxacin and tigecycline, IV formulation of delafloxacin at the dose of 300 mg b.i.d. did not cause remarkable signs and symptoms related to drug toxicity [28]. Mild gastrointestinal events (mostly nausea) were considerably higher in the tigecycline and in the high-dose (450 mg b.i.d.) IV delafloxacin arms. A total of five patients, two in the delafloxacin 450 mg b.i.d. arm and three in the tigecycline arm, abandoned the study because of adverse events; seven patients experienced one or more serious adverse events, but none of them was thought to be related to the study drug. A decrease in glucose plasma levels (with one case of hypoglycemia) was detected in several patients of the two delafloxacin groups, an adverse reaction that is linked to this antibiotic class. However, this finding has not been confirmed by other phase II or phase III trials, and there is no warning/precaution regarding glucose in the final label.

In the study comparing delafloxacin to linezolid and vancomycin, the group that received delafloxacin experienced the highest number of adverse events, nausea being the most frequent. In two patients, one in the delafloxacin group and one in the vancomycin group, an elevation of the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels was detected, probably related to the drug. No cases of hypoglycemia were reported [29].

Delafloxacin showed good tolerance in the phase III studies with 0.8% of withdrawals because of adverse events related to treatment [30,31]. In the phase III studies against vancomycin/aztreonam, the overall adverse event rate was comparable between groups [32,33]

Only one case of diarrhea due to Clostridium difficile has been reported in clinical trials so far (in a patient who had received other antibiotics prior to entering the trial), which could partly be attributable to the in vitro activity of delafloxacin against this pathogen, with low MICs (<0.015 μg/mL) [34]. Similarly, no adverse events at the level of the tendons, muscles, joints, nerves, and central nervous system have been recorded. In a randomized study conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval, the absence of a clinically meaningful increase in the QTc interval was demonstrated [35]. In a phase I study, no clinically significant phototoxicity potential was assessed for delafloxacin compared to lomefloxacin, at any wavelength tested [36]

8. Drug–drug interactions

Delafloxacin is not expected to give significant drug–drug interaction concerns. This agent does not show any clinically significant effects on cytochrome P450 enzymes and was not an inhibitor of any major hepatic or renal drug transporter. The major route of excretion is renal; about 40% of a delafloxacin dose is apparently cleared unchanged by the liver or conjugated as glucuronide metabolites by the liver [23]. A recent study evaluating the effects of delafloxacin on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A substrate, showed that delafloxacin did not produce significant changes in midazolam pharmacokinetics [24]. The low potential for drug–drug interactions makes delafloxacin a promising compound in the treatment of infections in patients receiving specific drugs such as calcineurin inhibitors, metabolic inducers, antiretroviral agents, and so on.

9. Dosing routes

Delafloxacin is administered twice daily with equivalence in exposure obtained for 300 mg intravenously and 450 mg orally. Hoover et al. evaluated in a phase I study the safety of delafloxacin in individuals with several degrees of renal failure [37]. This resulted in a recommendation to reduce the delafloxacin IV dose to 200 mg b.i.d. for patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m²). No dose reduction of the oral drug in mild, moderate, and severe renal impairment has been recommended.

10. Conclusion

Delafloxacin has a broad-spectrum activity and the potential for sequential therapy from IV to oral route of administration, as both formulations exists.

Delafloxacin has shown excellent activity against both gram-positive bacteria (including MRSA) and gram-negative bacteria (especially quinolone-susceptible Escherichia coli, K. pneumoniae, and Pseudomonas aeruginosa), and it is also active against many anaerobes. Clinical studies have demonstrated non-inferiority of delafloxacin compared to tigecycline, linezolid, vancomycin, and the combination of vancomycin plus aztreonam in the treatment of ABSSSI. No significant safety concerns have emerged so far.

11. Expert opinion

An increasing number of therapeutic agents are included in the antibiotic pipeline for the treatment of ABSSSI. Among these, delafloxacin offers the additional advantages of a having wide spectrum of activity against both gram-positive and gram-negative bacteria and a favorable PK/PD profile. As other quinolones, delafloxacin is bactericidal, fat soluble, with excellent distribution volume, tissue affinity, bioavailability, and endovenous/oral correlation (~100%). Furthermore, delafloxacin offers the additional advantages of greater antibacterial activity and in vitro potency, especially against gram-positive organisms, including quinolone-resistant MRSA.

Quinolones do not all share the same metabolic routes. Delafloxacin is excreted as unchanged and as glucuronides in urine and also hepatically. Ciprofloxacin exhibits significant phase I hepatic metabolism, whereas delafloxacin metabolism is almost exclusively phase II glucuronidation. These features are additional considerations in the treatment choice, along with the expected pathogen(s), the infected site, and patient’s comorbidities. Several in vitro studies have demonstrated the low potential of delafloxacin for resistance selection if used in empirical regimens.

Delafloxacin is a promising candidate for the treatment of gram-positive infections, especially if coinfection with other pathogens is suspected. This is because of the very low MIC of the agent for gram-positive (including MRSA) and anaerobic bacteria, keeping a good profile against gram-negative organisms.

Skin and soft tissue infections represent an ideal setting for its use. However, considering the promising microbiological and pharmacological features of the drug, further research should address the usefulness of the drug for other sites of infections, such as osteomyelitis, mediastinitis, prosthetic joint infections, abdominal infections, central nervous system infections, and respiratory tract infections. The use of delafloxacin in these settings is currently under investigation or off-label.

The excellent performance in the treatment of ABSSSI is partly due to the weak acidity of delafloxacin, which enhances its antibacterial potency in environments with a low pH (i.e. skin and cutaneous abscesses). In acidic milieus (pH 5.5–6.5), the MIC of delafloxacin against different bacteria is reduced. These features make delafloxacin a promising candidate for the salvage treatment of Helicobacter pylori, which showed in vitro susceptibility to the drug [34].

Fluoroquinolones have been extensively used for the treatment of osteomyelitis and prosthetic joint infections for their good penetration into the bone tissue. Studies on patients undergoing hip or knee arthroplasty showed that levofloxacin and moxifloxacin bone concentrations exceed 50% of the plasma concentrations and were higher than the MICs of the pathogens involved in the infection [38–40]. Moreover, in implant-related infections, the antimicrobial diffusion into the biofilm plays a fundamental role in achieving eradication: within the biofilm, pathogens are protected from the attack of the host defense mechanisms and from antibiotics, and in this protected environment, the organisms can thrive and develop resistance. Data on activity of delafloxacin on biofilm production of S. aureus have already demonstrated how its performance at clinically achievable concentration is comparable with that of daptomycin, by reducing bacterial viability by >50% and biofilm thickness in both MSSA and MRSA. Among the antistaphylococcal agents with activity against the biofilm, delafloxacin and daptomycin appear to be the most effective, with a superior performance of delafloxacin on MRSA strains [41].

For the aforementioned features of presumptive good diffusion within the bone and the MRSA biofilm, delafloxacin is a good candidate for targeted therapy of osteoarticular infections, given its oral bioavailability.

Delafloxacin appears to be particularly promising for the empirical treatment of diabetic foot infections. This subset of SSSIs is characterized by a wide range of potential pathogens, including highly resistant strains such as MRSA, and by poor blood supply. Ischemic conditions make this an acidic environment. Delafloxacin has a high tissue affinity, a wide-spectrum and improved performance in acidic environments, making this an ideal candidate for the treatment of diabetic foot infections.

Sequential therapy from IV to oral is possible with delafloxacin, as both formulations exist. This strategy allows shorter permanence in wards and earlier discharges. In hospital patients with complicated MRSA skin and soft tissue infections, early switch to oral treatment and early discharge are safe and cost-effective as long as the patient is clinically stable and tolerates oral fluids and diet. Nathwani et al. argued that more than one-third of European patients hospitalized for MRSA cSSTI could be eligible for early switch and early discharge. This would result in substantial reductions in hospitalization for IV treatment, with potential savings of €2000 per early discharge-eligible patient. In this view, delafloxacin represents an exciting opportunity [12]. Anyway, we wish to point out that there may be less expensive oral alternatives to delafloxacin for step-down therapy for discharge.

In conclusion, delafloxacin is a very promising option for the treatment of infections caused by multidrug-resistant pathogens. In the context of ABSSSIs, this compound represents an attractive therapeutic option in both community and nosocomial settings. Despite the evidence of a good safety profile in clinical studies, long-term follow-up is needed as the occurrence of rare but serious side effects has been a reason in the past for the abandonment or withdrawal of many other compounds within this class.

Box 1. Drug summary.

(Adapted from Bassetti M et al, 2015 [15])
Drug name	Delafloxacin
Phase	III
Indication	Acute bacterial skin and skin structure infections
Pharmacology description/mechanism of action	Inhibition of DNA gyrase and topoisomerase IV activity
Route of administration	Injectable/oral
Chemical structure
Pivotal trials	NCT01811732 [30], NCT01984684 [31]

Article highlights

• Delafloxacin is a new compound in the class of quinolones, currently in Phase III of clinical development for the treatment of skin and skin structure infections

• Unlike other quinolones, delafloxacin lacks a strongly basic group at the C-7 position in the chemical structure, resulting in weak acidity and improved activity in acidic environments

• Delafloxacin shows very low MICs for Gram-positive (including MRSA) and anaerobic bacteria and a wide spectrum of activity against Gram-negative organisms

• Delafloxacin shows a favorable pharmacokinetic/pharmacodynamic profile, with low potential for drug-drug interactions

• Further research should address the usefulness of the drug for other sites of infections

This box summarizes key points contained in the article.

Declaration of interest

M Bassetti declares relationships with Menarini and Angelini. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper is not funded.