Infect Dis Ther (2018) 7:197–217 https://doi.org/10.1007/s40121-018-0198-x REVIEW Delaﬂoxacin: Place in Therapy and Review of Microbiologic, Clinical and Pharmacologic Properties . . . Sarah C. J. Jorgensen Nicholas J. Mercuro Susan L. Davis Michael J. Rybak Received: February 20, 2018 / Published online: March 31, 2018 The Author(s) 2018 other zwitterionic ﬂuoroquinolones, which ABSTRACT tend to lose antibacterial potency under acidic conditions, and may be particularly advanta- Delaﬂoxacin (formerly WQ-3034, ABT492, RX- geous against methicillin-resistant Staphylococ- 3341) is a novel ﬂuoroquinolone chemically cus aureus, for which the signiﬁcance of the distinct from currently marketed ﬂuoro- intracellular mode of survival is increasingly quinolones with the absence of a protonat- being recognized. Delaﬂoxacin is also unique in able substituent conferring a weakly acidic its balanced target enzyme inhibition, a prop- character to the molecule. This property results erty that likely explains the very low frequen- in increased intracellular penetration and cies of spontaneous mutations in vitro. enhanced bactericidal activity under acidic Delaﬂoxacin recently received US Food and conditions that characterize the infectious Drug Administration approval for the treatment milieu at a number of sites. The enhanced of acute bacterial skin and skin structure infec- potency and penetration in low pH environ- tions and is currently being evaluated in a phase ments contrast what has been observed for 3 trial among patients with community-ac- Enhanced content To view enhanced content for this quired pneumonia. In the current era of a article go to https://doi.org/10.6084/m9.ﬁgshare.59992 heightened awareness pertaining to collateral ecologic damage, safety issues and antimicro- bial stewardship principles, it is critical to S. C. J. Jorgensen N. J. Mercuro S. L. Davis describe the unique properties of delaﬂoxacin M. J. Rybak (&) Anti-Infective Research Laboratory, Eugene and deﬁne its potential role in therapy. The Applebaum College of Pharmacy and Health purpose of this article is to review available data Sciences, Wayne State University, Detroit, MI, USA pertaining to delaﬂoxacin’s biochemistry, e-mail: firstname.lastname@example.org pharmacokinetic/pharmacodynamics charac- N. J. Mercuro S. L. Davis teristics, in vitro activity and potential for Department of Pharmacy Services, Henry Ford resistance selection as well as current progress in Hospital, Detroit, MI, USA clinical trials to ultimately assist clinicians in M. J. Rybak selecting patients who will beneﬁt most from Division of Infectious Diseases, Department of the distinctive properties of this agent. Medicine, School of Medicine, Wayne State University, Detroit, MI, USA M. J. Rybak Keywords: Acute bacterial skin and skin Department of Pharmacy Services, Detroit Medical structure infection; Antimicrobial stewardship; Center, Detroit, MI, USA 198 Infect Dis Ther (2018) 7:197–217 Delaﬂoxacin; Fluoroquinolone; Methicillin- clinicians in selecting patients most likely to resistant Staphylococcus aureus beneﬁt from the distinctive properties of this agent. INTRODUCTION Compliance with Ethics Guidelines Fluoroquinolones are among the most com- This article is based on previously conducted monly prescribed antibiotics, accounting for 23 studies and does not contain any studies with million and 3.8 million oral and injectable pre- human participants or animals performed by scriptions in the US in 2011, respectively [1, 2]. any of the authors. Attractive features of this class include their favorable pharmacokinetic (PK) properties, Data Sources broad spectrum of activity and clinical efﬁcacy for a wide range of commonly encountered Literature searches of MEDLINE (1946 to July infections . However, paralleling the wide- 2017) and EMBASE (1974 to July 2017) were spread use of ﬂuoroquinolones has been an conducted using the search terms ‘‘ABT-492,’’ alarming increase in the prevalence of ﬂuoro- ‘‘WQ-3034,’’ ‘‘RX-3341’’ and ‘‘delaﬂoxacin.’’ quinolone resistance among clinically relevant Results were limited to articles available in pathogens, underscoring the critical need to English. Additional citations were identiﬁed consider antimicrobial stewardship principles from the references of relevant literature. Cur- when deﬁning the place in therapy of novel rent trials focusing on delaﬂoxacin were iden- agents to ensure their utility is not short lived tiﬁed from clinicaltrials.gov. FDA review [4, 5]. documents for the ABSSSI indication were also Delaﬂoxacin (formerly WQ-3034, ABT492, examined. Lastly, data were obtained from RX-3341), a novel dual-targeting anionic ﬂuo- conference proceedings and published roquinolone with useful in vitro activity against abstracts. methicillin-resistant Staphylococcus aureus (MRSA), recently received US Food and Drug Administration (FDA) approval for the treat- CHEMISTRY AND MECHANISM ment of acute bacterial skin and skin structure OF ACTION infections (ABSSSIs) and is currently being evaluated in a phase 3 trial for the treatment of The ﬂuoroquinolone class of antibiotics exerts community-acquired pneumonia (CAP) . antimicrobial activity by inhibiting the two key Fluoroquinolones have not traditionally been enzymes, DNA gyrase and topoisomerase IV, among the ﬁrst-line options for ABSSSI; how- which are essential for replication . Although ever, delaﬂoxacin’s unique structural and all ﬂuoroquinolones in clinical use are active chemical characteristics, which result in against both enzymes, they differ in relative enhanced potency and intracellular penetration inhibitory potency, with DNA gyrase as the under acidic conditions, suggest it has the more sensitive target among gram-negative potential to ﬁll a distinctive therapeutic niche bacteria and topoisomerase IV as the preferen- for certain difﬁcult-to-treat infections . Fur- tial target among gram-positive pathogens . thermore, its dual targeting mechanism may Delaﬂoxacin demonstrates more balanced serve to limit the emergence of resistance . activity against both enzymes . In theory, The purpose of this article is to critically review equipotent enzyme inhibition should serve to available data pertaining to delaﬂoxacin’s bio- limit resistance selection since double muta- chemistry, pharmacokinetic/pharmacodynam- tions are relatively rare genetic events . ics (PK/PD) characteristics, in vitro activity and Delaﬂoxacin demonstrates minimum inhi- potential for resistance selection as well as cur- bitory concentrations (MICs) that are consis- rent progress in clinical trials to ultimately tently three- to ﬁve-fold lower than comparator delineate future research priorities and assist Infect Dis Ther (2018) 7:197–217 199 ﬂuoroquinolones against gram-positive organ- abscess ﬂuid, decubitis ulcers, epithelial lining isms. This is thought to be derived in part from ﬂuid and phagolysosomes of infected cells), its greater afﬁnity for DNA gyrase compared delaﬂoxacin exists predominantly in the neutral with other ﬂuoroquinolones. Because DNA form, which favors uptake by both eukaryotic gyrase acts ahead of the replication fork to cells and bacteria . This is accompanied by remove positive supercoils, it inhibits DNA increased activity against both extra- and replication more rapidly than the interaction intracellular pathogens, in particular S. aureus, with topoisomerase IV, which acts behind it and contrasts what has been observed for other and, as noted, is the preferential target of com- agents (ﬂuoroquinolones, macrolides, amino- parator ﬂuoroquinolones . Delafoxacin’s glycosides), which lose antibacterial potency increased potency against gram-positive bacte- under acidic conditions . Delaﬂoxacin MICs ria is also related to its speciﬁc shape, size and against a diverse range of gram-negative and - polarity . Distinguishing structural charac- positive organisms decrease four- to seven-fold teristics include the presence of a sizable sub- as pH in the surrounding media is reduced from stituted heteroaromatic ring at N1, the absence 7.2 to 5.5 . The reduction in MICs are most of a basic group at C7 and weak polarity deﬁned pronounced among gram-positive bacteria . by the chlorine atom at C8 (Fig. 1). The heteroaromatic ring at N1 increases the solvent- MICROBIOLOGY accessible surface area, and collaboration between this large substituent and the weakly The in vitro activity of delaﬂoxacin and com- polar group at C8 is thought to inﬂuence parator ﬂuoroquinolones against a diverse range potency against quinolone-resistant gram-posi- of gram-positive and -negative bacteria are pre- tive bacteria . It is hypothesized that this C8 sented in Tables 1 and 2. Minimum inhibitory substitution could also reduce second-step concentration (MIC , range) values are repre- resistance development in S. aureus [13, 14]. The sentative of pooled data from studies conducted absence of a basic group at C7 gives delaﬂoxacin with delaﬂoxacin with preference for studies an anionic character at neutral pH . This conducted using isolates collected within the latter characteristic is unlike the majority of last 5 years [16, 17]. Standard MIC determina- other ﬂuoroquinolones, which exist as zwitte- tion methods are conducted under neutral pH rions at physiologic pH . Under the acidic conditions, and these values may give a con- conditions that characterize the local environ- servative estimate of delaﬂoxacin activity under ment at many infection sites (urinary tract, acidic physiologic conditions. Among contemporary S. aureus isolates (MSSA and MRSA), delaﬂoxacin MIC values 50/90 were B 0.004/0.25 mg/l, respectively [18–20]. For a number of bacterial species, including S. aureus, delaﬂoxacin MICs were bimodal (0.002–0.003 and 0.06–4 mg/l), presumably because of existing ﬂuoroquinolone resistance within the population . Applying the FDA S. aureus delaﬂoxacin susceptibility MIC break- point of 0.25 mg/l to the cumulative MIC values from a diverse collection of contemporary iso- lates from US and European medical centers yields susceptibility rates of 98.7% and 88.0% for MSSA and MRSA, respectively [6, 19]. The corresponding levoﬂoxacin susceptibility rates were 89.8% and 30%, respectively . Fig. 1 Chemical structure of delaﬂoxacin 200 Infect Dis Ther (2018) 7:197–217 Table 1 In vitro activity (MIC, mg/l) of delaﬂoxacin and comparators against aerobic gram-positive bacteria. Adapted from references [18–20, 23] Organism Phenotype Delaﬂoxacin Levoﬂoxacin Moxiﬂoxacin MIC Range MIC Range MIC Range 90 90 90 Staphylococcus aureus All 0.25 B 0.004 to 4 [ 4 B 0.12 to [ 4 MSSA 0.015 B 0.004 to 4 2 B 0.12 to [ 4 MRSA 0.5 B 0.004 to 4 [4 B 0.12 to [ 4 Coagulase-negative All 0.5 B 0.004 to 2 1 B 0.12 Staphylococci to [ 4 MSCoNS 0.03 B 0.004 to 1 4 B 0.12 to [ 4 MRCoNS 1 B 0.004 to 2 [ 4 B 0.12 to [ 4 Enterococcus faecalis All 1 B 0.004 to 2 [ 4 0.25 to [ 4 VSE 1 B 0.004 to 2 [ 4 0.25 to [ 4 VRE 1 B 0.008 to 2 [ 4 [ 4 Enterococcus faecium All [ 4 0.008 to [ 4 [ 4 0.5 to [ 4 VSE [ 4 0.008 to [ 4 [ 4 [ 4 VRE [ 4 [ 4 [ 4 [ 4 Streptococcus pneumoniae All 0.03 B 0.004 to 1 0.5 to [40.25 B 0.12 to 4 0.25 PSSP 0.03 B 0.004 to 1 0.5 to 1 0.03 PISP 0.015 0.008 to 0.15 1 0.5 to 1 PRSP 0.03 0.008 to 0.03 1 0.5 to 1 0.25 B 0.12 to 0.25 MDR 0.015 B 0.004 to 1 0.5 to [40.25 B 0.12 to 4 0.12 Ceftriaxone non- NR B 0.004 to NR 1 to 2 B 0.12 to susceptible 0.015 0.25 Levoﬂoxacin resistant 0.5 0.015 to 1 32 2 to 32 4 0.25 to [ 4 Streptococcus pyogenes 0.015 B 0.004 to 1 0.25 0.25 B 0.12 to 0.03 to [ 4 0.5 Infect Dis Ther (2018) 7:197–217 201 Table 1 continued Organism Phenotype Delaﬂoxacin Levoﬂoxacin Moxiﬂoxacin MIC Range MIC Range MIC Range 90 90 90 Streptococcus agalactiae 0.03 B 0.004 to 1 0.25 0.25 B 0.12 0.5 to [ 4 to [ 4 Streptococcus dysgalaciae 0.015 B 0.004 to 1 0.25 0.25 B 0.12 to 0.03 to [ 4 0.25 Viridans group 0.06 B 0.004 to 2 2 B 0.12 0.25 B 0.12 to 4 Streptococci to [ 4 Streptococcus anignosus 0.015 0.008 to 0.5 0.5 group 0.015 Streptococcus mitis group 0.06 0.03 to 0.06 2 1 to 2 Listeria monocytogenes 0.12 0.06 to 0.12 1 1 MIC minimum inhibitory concentration, MRCoNS methicillin-resistant coagulase-negative staphylococcus, MRSA methicillin-resistant Staphylococcus aureus, MSCoNS methicillin-susceptible coagulase-negative staphylococcus, MSSA methicillin-susceptible Staphylococcus aureus, NA not applicable, NR not reported, PISP penicillin-intermediate Streptococcus pneumoniae, PRSP, penicillin-resistant Streptococcus pneumoniae, PSSP penicillin-susceptible Streptococcus pneumoniae, VRE vancomycin-resistant enterococcus, VSE vancomycin-susceptible enterococcus McCurdy et al. recently evaluated the activ- three (0.4%) levoﬂoxacin-resistant MRSA iso- ity of delaﬂoxacin against a global collection of lates had MIC values above the current dela- S. aureus isolates (n = 687) from skin and skin ﬂoxacin S. aureus breakpoint . structure infections, of which 34% demon- Delaﬂoxacin also demonstrated potent strated the levoﬂoxacin-resistant phenotype activity against S. pneumoniae, and, similar to . Among levoﬂoxacin-susceptible strains, earlier respiratory ﬂuoroquinolones, its activity delaﬂoxacin showed excellent in vitro activity, extends to strains displaying penicillin-resistant and MIC values were not affected by the or ceftriaxone non-susceptible phenotypes methicillin-resistant phenotype (MIC [19–22]. In a 2014 surveillance study, all Euro- 0.008 mg/l for both MSSA and MRSA). Dela- pean and 98% of US S. pneumoniae isolates were ﬂoxacin maintained increased activity against inhibited by delaﬂoxacin B 0.03 mg/l . levoﬂoxacin-resistant MSSA and MRSA isolates; These values are similar to those obtained in a however, the MIC values were increased bacterial respiratory surveillance program con- 32-fold (0.25 mg/l) compared with levoﬂoxacin- ducted 12 years earlier throughout Canada susceptible strains , which does raise ques- (CROSS), suggesting that delaﬂoxacin, like tions pertaining to the risk of selecting resistant other respiratory ﬂuoroquinolones but in con- mutants during treatment, particularly in high trast to ciproﬂoxacin, has maintained its inoculum S. aureus infections. Resistance selec- potency against S. pneumoniae despite the tion studies have indeed demonstrated fewer selective pressure of ﬂuoroquinolone use during passages are required to select mutants with the intervening period . Approximately 1% increased MICs among ﬂuoroquinolone-resis- of isolates in the US/European surveillance tant S. aureus strains compared with sensitive study displayed a levoﬂoxacin-resistant strains . In the study by McCurdy et al., only 202 Infect Dis Ther (2018) 7:197–217 Table 2 In vitro activity (MIC, mg/l) of delaﬂoxacin and comparators against aerobic gram-negative bacteria. Adapted from references [11, 18–20, 23, 24] Organism Phenotype Delaﬂoxacin Levoﬂoxacin Ciproﬂoxacin MIC Range MIC Range MIC Range 90 90 90 Escherichia coli All 4 B 0.004 [ 4 B 0.12 [ 4 B 0.03 to [ 4 to [ 4 to [ 4 ESBL [ 4 0.008 [ 4 B 0.12 [ 4 B 0.03 to [ 4 to [ 4 to [ 4 Klebsiella pneumoniae All [ 4 0.015 [ 4 B 0.12 to [ 4 to [ 4 ESBL [40.06to [ 4 [ 4 B 0.12 to [ 4 Klebseilla oxytoca 0.12 0.03 to 1 B 0.12 B 0.12 to 0.06 B 0.03 1 to [ 4 Proteus mirabilis All 2 0.015 [ 4 B 0.12 [ 4 B 0.03 to [ 4 to [ 4 to [ 4 ESBL [42to [ 4 [ 4 [ 4 Enterobacter spp. 1 B0.004 0.5 B 0.12 0.25 B 0.03 to [ 4 to [ 4 to [ 4 Citrobacter spp. 2 0.008 0.5 B 0.12 0.5 B 0.03 to [ 4 to [ 4 to [ 4 Serratia spp. 2 0.03 to [41 B 0.12 1 B 0.03 to [ 4 to [ 4 Providencia spp. 0.12 0.008 to 0.5 0.25 0.12 to 0.25 Morganella morganii 40.12to4 [ 4 B 0.12 to [ 4 Proteus spp. Indole-positive 4 0.008 [ 4 B 0.12 [ 4 B 0.03 to [ 4 to [ 4 to [ 4 Salmonella spp. 0.06 0.008 to 0.5 0.06 0.015 to 1 0.015 0.002 to 0.25 Shigella spp. NR 0.002 to NR 0.004 to 0.008 0.015 Pseudomonas aeruginosa [ 4 0.015 [ 4 B 0.12 [4 B 0.03 to [ 4 to [ 4 to [ 4 Acinetobacter baumannii–A. [ 4 0.015 [ 4 B 0.12 [4 0.06 calcoaceticus to [ 4 to [ 4 to [ 4 Infect Dis Ther (2018) 7:197–217 203 Table 2 continued Organism Phenotype Delaﬂoxacin Levoﬂoxacin Ciproﬂoxacin MIC Range MIC Range MIC Range 90 90 90 Burkholder cepacia Ciproﬂoxacin NR 0.25 NR 1 NR 1 susceptible Ciproﬂoxacin 16 0.25 to 16 [ 128 2 to [ 128 [ 128 2 to [ 128 resistant Haemophilus inﬂuenza 0.004 B 0.001 to 0.03 0.008 0.015 0.004 0.25 to [ 2 to [ 2 Moraxella catarrhalis 0.008 0.004 to 0.06 0.03 to 0.06 0.015 to 0.015 0.12 0.06 Neisseria gonorrhea 0.06 0.125 16 0.004 to [ 16 ESBL extended-spectrum beta-lactamase, MIC minimum inhibitory concentration, NA not applicable, NR not reported phenotype (MIC [ 4 mg/l), and all were inhib- range of contemporary aerobic gram-negative ited by delaﬂoxacin B 0.25 mg/l . bacteria is presented in Table 2. As shown, Delaﬂoxacin is also very active against gram- delaﬂoxacin MIC values for E. coli and Kleb- negative respiratory pathogens. Haemophilus siella pneumoniae exceed the clinical breakpoint inﬂuenzae and Moraxella catarrhalis MIC values of B 0.25 mg/l by 16-fold and [ 16-fold, were B 0.004 and 0.008 mg/l, respectively . respectively [19, 20]. The levoﬂoxacin-resistant Due to the paucity of clinical data pertaining to phenotype was observed in approximately 30% outcomes with the use of delaﬂoxacin for the and 20% of isolates, respectively, in these treatment of respiratory tract infections at this studies [19, 20]. In the surveillance study by time, the clinical breakpoints for these three Pfaller et al., delaﬂoxacin susceptibility rates pathogens have not yet been established. among US E. coli and K. pneumoniae isolates The MIC value of contemporary Enterococ- were 65% and 78%, respectively . Among cus faecalis isolates from both clinical and isolates with the ESBL phenotype, susceptibility surveillance studies was 1 mg/l with a range rates were just 17.3% and 5.7%, respectively of B 0.004 to 2 mg/l (Table 1)[18–20, 23]. . Against Enterobacter spp., delaﬂoxacin Among levoﬂoxacin-resistant E. faecalis isolates, appears less active than levoﬂoxacin. Dela- delaﬂoxacin’s MIC values were 0.25 and ﬂoxacin demonstrated more potent activity 50/90 8 mg/l, respectively . In the absence of against K. oxytoca with MIC values of 0.12 mg/ clinical efﬁcacy or PK/PD studies conducted l[19, 20]. As shown in Table 2, delaﬂoxacin with E. faecalis, the interpretive breakpoint activity against Pseudomonas aeruginosa (MIC 50/ of B 0.12 mg/l was established by the FDA, 0.25/4 mg/l; 65% susceptible) is similar to which is many fold lower than the observed comparator anti-pseudomonal ﬂuoro- MIC values . As shown in Table 1, dela- quinolones [19, 20]. ﬂoxacin is not expected to have useful activity Clinical experience with the indicated gram- against E. faecium (MIC [ 4 mg/l) [19, 20]. negative pathogens has been very limited with The in vitro activity of delaﬂoxacin and ﬂu- most non-surveillance isolates cultured from oroquinolone comparators against a broad poly-microbial infections in ABSSSI studies 204 Infect Dis Ther (2018) 7:197–217 [18, 20]. If the use of delaﬂoxacin is contem- interpreting the ﬁndings because isolates were plated for infections in which gram-negative collected nearly 15 years ago, and in the inter- bacilli are common pathogens, additional clin- vening period ﬂuoroquinolone resistance ical data are needed to better determine how among key anaerobic bacteria has increased MIC values measured by standard methods signiﬁcantly [16, 29]. More recent US surveil- should inform treatment decisions. lance data testing isolates collected during 2010 Delaﬂoxacin has shown excellent in vitro to 2012 have shown much lower susceptibility activity against Neisseria gonorrheae including rates for moxiﬂoxacin against key anaerobic ciproﬂoxacin-resistant and multidrug-resistant species [16, 29]. Although the potential for (MDR) strains (Table 2). Against a panel of cross-resistance among anaerobic species for N. gonorrheae clinical isolates collected from delaﬂoxacin and other ﬂuoroquinolones has medical centers across the US during 2012 to not been explored, high levels of cross-resis- 2015, including 67.5% with the ciproﬂoxacin- tance have been documented between earlier resistant phenotype, the delaﬂoxacin MIC ﬂuoroquinolones. value was 0.125 mg/l . Lessons from the past More contemporary data pertaining to dela- however have shown that ﬁndings from in vitro ﬂoxacin’s activity against Clostridium difﬁcile studies may not be entirely predictive of clinical has been presented. Vernon et al. investigated outcomes for N. gonorrheae infection . the in vitro activity of delaﬂoxacin and com- Unfortunately, a phase 3 trial comparing a sin- parator agents against prevalent C. difﬁcile gle oral dose of delaﬂoxacin (900 mg) to ceftri- ribotypes (RTs) . Delaﬂoxacin’s geometric axone for the treatment of uncomplicated mean (GM) MIC overall was 0.37 mg/l. Large gonorrhea (NCT02015637) was terminated differences in activity were observed for isolates early in 2015 for reasons of insufﬁcient efﬁcacy belonging to the hypervirulent RT027 com- following an independent interim review . pared with non-RT027 (GM MIC 4.0, 0.13 mg/l, The in vitro activity of delaﬂoxacin against respectively), suggesting delaﬂoxacin shares in Mycobacterium tuberculosis and M. avium was the universal ﬂuoroquinolone class resistance in evaluated in a single study . Delaﬂoxacin this troublesome strain . was more efﬁcacious than levoﬂoxacin at inhibiting intracellular macrophage growth of PHARMACOKINETICS M. tuberculosis. It is hypothesized that this observation may be related to improved deliv- The PK properties of delaﬂoxacin have been ery of delaﬂoxacin to the phagosomes of MM6- evaluated in phase 1 and 3 studies utilizing M/s that engulf bacteria. Additionally, the single and multiple ascending doses ranging potentiation of delaﬂoxacin’s antimicrobial from 300 to 1200 mg (IV) and 50 to 1600 mg activity under the acidic conditions that are (oral) [31–33]. As shown in Table 3, at steady characteristic of the macrophage phagosomes state, delaﬂoxacin, administered as 300 mg IV that engulf mycobacterial pathogens may be every 12 h, achieves a maximum serum con- particularly advantageous . Further support centration (C ) of 9.29 mg/l and total expo- max for delaﬂoxacin’s ability to accumulate and sure (AUC from 0 to 12 h, AUC ) of 23.4 mg h/l. exert antibacterial activity within mammalian The bioavailability of the tablet formulation is cells comes from demonstrations of its activity 59%, which is lower than that of other ﬂuoro- against Chlamydia spp., an obligate intracellular quinolones such as levoﬂoxacin and moxi- pathogen, with MICs ranging from 0.03 to ﬂoxacin (99% and 92%, respectively; Table 3); 0.06 mg/l . however, the AUC of delaﬂoxacin 450 mg Few studies have evaluated the activity of administered orally (20.6 mg h/l) is comparable delaﬂoxacin against clinically relevant anaero- to that achieved with a labeled IV dose of bic organisms [11, 28]. Potent activity was 300 mg [6, 32–34]. Both the IV and oral for- demonstrated against Bacteroides fragilis in par- mulations demonstrate approximate dose pro- ticular in one study, with an MIC value of portional increases in exposure following single 0.125 mg/l . Caution is advised when Infect Dis Ther (2018) 7:197–217 205 Table 3 Pharmacokinetic parameters of delaﬂoxacin and comparator ﬂuoroquinolones. Adapted from references [6, 33–35] Parameter Delaﬂoxacin IV Delaﬂoxacin PO Levoﬂoxacin PO Ciproﬂoxacin PO Moxiﬂoxacin PO (300 mg, every (450 mg, every (750 mg, every (500 mg, every (400 mg, every 12 h) 12 h) 24 h) 12 h) 12 h) a a V (l) 35–48 100 84–189 119–189 C (mg/l) 9.29 7.45 8.6 3.0 4.5 max fC (mg/l) 1.49 1.19 5.3–6.5 1.8–2.4 2.25–3.15 max AUC 30.8 23.4 90.7 13.7 48 0–s (mg h/l) fAUC 4.93 3.74 56.2–68.9 8.2–11.0 24–33.6 0–s (mg h/l) AUC (mg h/ 61.6 46.8 90.7 27.4 48 l) fAUC (mg h/ 9.86 7.48 56.2–68.9 16.4–22.0 24–33.6 l) Protein binding 84% 24–38% 20–40% 30–50% T (h) 3.7 4.2–8.5 8.8 4–6 10–14 1/2 Elimination 64.5%:28.4% 50.2%:47.7% 87%:4% 57%:20–35% 20%:25% (urine:feces) Oral N/A 58.8% 99% 70% 92% bioavailability Metabolism Glucuronidation Limited? Oxidation? Sulfation, glucuronidation V volume of distribution, C peak serum concentration, fC free peak concentration, AUC area under the curve d max max 0–s over the dosing interval, fAUC free area under the curve over the dosing interval, AUC area under the curve over 24 h, 0-s 24 fAUC free area under the curve over 24 h, T half- life 24 1/2 Based on a 70-kg adult After a single dose No signiﬁcant circulating metabolites doses ranging up to 1200 and 1600 mg, respec- Delaﬂoxacin volumes of distribution have tively [32, 33]. The C is reduced 20%, and ranged from 35 to 48 l across studies. Protein max the time to C (T ) is doubled when dela- binding (primarily to albumin) is approximately max max ﬂoxacin tablets are administered with food 84% (Table 3)[6, 33–35]. Delaﬂoxacin shares compared with the fasting state. However, total the ﬂuoroquinolone class characteristic of high delaﬂoxacin exposure (AUC ) is similar when pulmonary distribution with a 13:1 mean pen- administered with or without food; thus, PK etration ratio into the epithelial lining ﬂuid vs. changes secondary to food intake around the free plasma concentration . Data pertaining time of dosing are not expected to affect clinical to the distribution characteristics of dela- outcomes [32, 33]. ﬂoxacin in other tissues have not been reported at this time. 206 Infect Dis Ther (2018) 7:197–217 Delaﬂoxacin is primarily metabolized adjustment of the oral formulation for patients through glucuronidation, with oxidative meta- with severe renal impairment is not recom- bolism accounting for approximately 1% of the mended. Currently, there are no explicit labeled administered dose, suggesting a low potential recommendations for dosing in patients main- for drug interactions. The predominant route of tained on HD. Twenty percent of the drug is elimination is renal (50–65%) with the remain- removed during a 4-h HD session . der of elimination occurring in the feces as The PK proﬁle of delaﬂoxacin has been unchanged drug. Delaﬂoxacin’s half-life was evaluated in subjects with varying degrees of 3.7 h following a single IV 300 mg dose and hepatic impairment. Total AUC values were ranged from 4.2 to 8.5 h following multiple oral similar in patients with normal, mild and doses [6, 33, 37]. moderate hepatic function. Higher PK variabil- PK parameters of delaﬂoxacin have been ity was observed in patients with severe hepatic examined in patients with varying degrees of impairment, and total exposure was increased renal impairment . Delaﬂoxacin exposure approximately 40% compared with controls. has consistently been shown to increase with These differences are unlikely to be clinically decreasing renal function; however, clinically important, and dosage adjustment in this pop- important differences are not apparent until the ulation is not recommended . estimated glomerular ﬁltration rate (eGFR) as calculated using the Modiﬁcation of Diet in PHARMACODYNAMICS Renal Disease equation (MDRD) is under 30 ml/ min/1.73 m . The AUC increased 1.8-fold in Similar to other ﬂuoroquinolones, delaﬂoxacin patients with severe renal impairment (eGFR exhibits concentration-dependent antimicro- 15–29 ml/min/1.73 m ) following a single bial activity, and the unbound drug AUC over 300 mg IV dose. The corresponding fold chan- 24 h divided by the MIC of the pathogen ges in total exposure among patients with end- (fAUC /MIC) is the PK/PD parameter most stage renal disease (ESRD) when delaﬂoxacin closely associated with delaﬂoxacin activity was administered before and after hemodialysis [33, 38]. The PD target value for delaﬂoxacin (HD) were 2.1 and 2.6, respectively. Decreased against S. aureus was determined in a series of plasma protein binding has also been observed experiments using the murine neutropenic in subjects with severe renal impairment and thigh infection model . Animals were inoc- ESRD (80% and 75%, respectively). Based on ulated with 10 CFU of MSSA or MRSA pos- population PK simulations, an adjusted dose of sessing delaﬂoxacin MICs ranging from 0.004 to 200 mg IV every 12 h is recommended for 0.006 mg/l and 0.016 to 0.8 mg/l, respectively. patients with severe renal impairment [6, 33]. Delaﬂoxacin (1.25 to 320 mg/kg) was adminis- The lower dose also reduces the risk for adverse tered as a single dose, and the bacterial burden renal effects secondary to sulfobutylether-beta- was determined 24 h after dosing. The median cyclodextrin (SBECD, an excipient in the IV fAUC /MIC ratios associated with net bacterial formulation) accumulation . stasis and a 1-log CFU reduction were 9.3 and Decreasing renal function does not appear to 14.3, respectively. Utilizing a murine lung greatly impact the exposure of delaﬂoxacin infection model for collection of MSSA and tablets; drug exposure was 1.5-fold higher in MRSA isolates with MICs ranging from 0.004 to subjects with severe renal impairment following 0.008 mg/l, Andes et al. documented substan- oral administration (450 mg) compared with tially lower median target ratios (stasis 1.74 and subjects with normal renal function. A dosing 1-log CFU reduction 7.92) . Similarly, the regimen of 450 mg IV every 12 h produced median fAUC /MIC ratio of delaﬂoxacin to exposures in patients with normal renal func- achieve either stasis or 1-log CFU reduction in tion similar to those achieved in patients with a neutropenic murine lung model by Thabit severe renal impairment that were administered et al. utilizing MSSA isolates (MIC the 450-mg oral dose, and tolerability was 0.002–0.52 mg/l) was 0.4 . However, the acceptable at these exposures . Thus, dosage Infect Dis Ther (2018) 7:197–217 207 corresponding target ratios for MRSA isolates however. The penetration of delaﬂoxacin with baseline MICs of 0.25–1 mg/l were mark- within the bioﬁlm was observed to range from edly higher in this study (stasis 8.1 and 1-log 0.62% to 51.8% and was generally greater in CFU reduction 24.7) and more closely aligned bioﬁlms with lower pH values . to those generally quoted for ﬂuoroquinolones Renal abscesses involving S. aureus are chal- against gram-positive cocci (fAUC /MIC C 25) lenging to treat with currently available agents [36, 38]. Thus, it appears that PK/PD targets for because of the presence of a large proportion of delaﬂoxacin may differ between stains, pheno- bacteria in the stationary phase of growth, and types and site of infection. the local environment is usually characterized Similar experiments were also conducted to by low pH values . Ding et al. investigated the determine the threshold fAUC /MIC ratios comparative activity of delaﬂoxacin and moxi- associated with efﬁcacy against E. coli and P. ﬂoxacin against renal abscesses formed by a aeruginosa. Findings indicated mean fAUC / community-associated MRSA strain (MW2) in a MIC targets for bacterial stasis and a 1-log CFU murine model of systemic infection . Both reduction for E. coli were 14.5 and 26.2, delaﬂoxacin and moxiﬂoxacin reduced the respectively, while the corresponding fAUC / bacterial load in renal abscesses compared with MIC targets for P. aeruginosa were 3.8 and 5.0, controls. The reduction of the bacterial burden respectively. by delaﬂoxacin was signiﬁcantly greater than Staphylococcus aureus is frequently associated that by moxiﬂoxacin . with bioﬁlm-related infections, which are par- Delaﬂoxacin has also demonstrated ticularly difﬁcult to treat because antibiotics increased activity against gram-negative patho- tend to be much less active against bacteria gens under acidic experimental conditions. So embedded in bioﬁlm compared with those in et al. examined the effect of urine matrix and its the planktonic state . The increased potency varying pH on the activity of delaﬂoxacin and of delaﬂoxacin under acidic conditions may be ciproﬂoxacin against 16 MDR urogenic E. coli particularly advantageous in this setting . and K. pneumoniae . All isolates were resis- Utilizing an in vitro PD model of mature S. tant to both ciproﬂoxacin (MIC 32 to [ 64 mg/ aureus bioﬁlms, Bauer et al. reported that dela- l) and delaﬂoxacin (MIC 2–16 mg/l) at baseline ﬂoxacin reduced both MSSA and MRSA bioﬁlm when measured in standard media. Similar to viability by at least 50% at clinically achievable results obtained for delaﬂoxacin against gram- concentrations . Delaﬂoxacin, oxacillin positive pathogens tested under acidic experi- (MSSA) and daptomycin were the most efﬁca- mental conditions , delaﬂoxacin MICs cious among a panel of nine anti-staphylococ- decreased by 1–3 doubling dilutions in 53% and cal agents. The interpretation of these ﬁndings 68% of observations for E. coli and K. pneumo- is somewhat hampered by the use of reference S. niae, respectively, when MIC testing was per- aureus strains displaying MICs that are 4- formed in acidic urine. By contrast, MICs for (MSSA) and 125-fold (MRSA) lower than MIC ciproﬂoxacin remained relatively unchanged values documented in contemporary surveil- across the range of pH values tested . Even lance studies . with the maximal MIC reductions when using In a second bioﬁlm study using MSSA and urine as the test media, most isolates would MRSA with a broader range of delaﬂoxacin MIC continue to demonstrate MICs far above the values (0.004–0.125 mg/l), delaﬂoxacin dis- current delaﬂoxacin Enterobacteriaceae inter- played potent activity at clinically achievable pretive breakpoint of B 0.25 mg/l; thus, the concentrations against ﬁve of the seven isolates clinical implications of this study as relates to tested . Investigators did not account for the potential utility of delaﬂoxacin in the delaﬂoxacin protein binding (84%) when con- treatment of MDR Enterobacteriaceae are not sidering achievable C values in vivo entirely clear [6, 44]. max 208 Infect Dis Ther (2018) 7:197–217 the parent strain were characterized by both RESISTANCE previously described and novel mutations in gryA and gyrB. Two variant isolates, both with Resistance to ﬂuoroquinolones most commonly MICs of 4 mg/l and selected from a parent strain involves step-wise chromosomal mutations in with pre-existing gyrA and grlA mutations, the quinolone resistance-determining regions showed no changes in the QRDR or the norA (QRDR) of DNA gyrase (gyrA) and/or topoiso- sequence and its surrounding regulatory merase IV (parC/grlA). Overexpression of efﬂux regions, suggesting delaﬂoxacin resistance may pumps and decreased uptake secondary to arise through previously uncharacterized reduced expression of outer membrane porins mechanisms . may also contribute to chromosomal resistance [9, 45]. Finally, plasmid-mediated ﬂuoro- quinolone resistance is an emerging concern . CLINICAL EFFICACY Delaﬂoxacin maintains clinically useful activity against a range of bacteria displaying The clinical efﬁcacy of delaﬂoxacin has been the quinolone-resistant phenotype secondary to evaluated in phase 2 and phase 3 studies among single and double mutations in the QRDR as patients with ABSSSI as well as phase 2 studies well as efﬂux pump expression. The ability of among patients with acute exacerbation of delaﬂoxacin to select for spontaneous muta- chronic obstructive pulmonary disease and CAP tions within the QRDR or efﬂux pump gene loci [47–52]. in vitro has been investigated in a number of The ﬁrst clinical study to evaluate dela- studies using both naı¨ve strains and those with ﬂoxacin in the treatment of ABSSSIs was a phase pre-existing mutations. Remy et al. conducted a 2 randomized, double-blind, multicenter, dose- series of spontaneous resistance selection ranging comparative study . Adults with experiments using four strains of S. aureus, three wound infection, abscess or cellulitis were of which carried pre-existing mutations in the enrolled from 14 centers in the US; patients QRDR . The observed resistance frequencies (n = 150) were randomized to delaﬂoxacin 300 -9 -9 were low (6.0 9 10 to \ 9.5 9 10 ) for dela- or 450 mg, each administered IV, every 12 h or ﬂoxacin at two times the baseline MIC and tigecycline 100 mg IV once, followed by 50 mg similar to those demonstrated for moxiﬂoxacin IV, every 12 h for 5–14 days . S. aureus . The resistance frequencies of both drugs comprised nearly 90% of gram-positive patho- were substantially less than that of levoﬂoxacin. gens, and methicillin-resistance was detected in Notably, no delaﬂoxacin-resistant strains could 71%. Clinical cure rates and microbiologic be isolated from the strain that had no pre-ex- eradication rates exceeded 90% in all treatment isting QRDR mutations . The minimum pro- groups with no between-group differences. tective concentration in the present study Kingsley et al. performed the second phase 2 ranged from one to four times the initial MIC ABSSSI multicenter, randomized, double-blind for all quinolones tested. Delaﬂoxacin-resistant trial evaluating delaﬂoxacin (300 mg) versus mutants maintained their reduced susceptibility linezolid (600 mg) and vancomycin (15 mg/kg, following passage in drug-free media for 7 days, actual body weight; maximum 1250 mg; target suggesting a stable phenotype [8, 46]. trough 15–20 mg/l), each administered IV twice Whole-genome sequencing characterized the daily for 5–14 days . The addition of blinded nature of the mutations of the resultant vari- aztreonam was permitted for patients with ants. Delaﬂoxacin-selected variants with MIC gram-negative infections randomized to line- shifts B 4-fold of the parent strain showed no zolid or vancomycin. In total, 256 patients genetic changes in the QRDR or the norA loci, comprised the intention-to-treat population which encodes for the predominant ﬂuoro- (ITT). S. aureus was the most frequently isolated quinolone efﬂux pump in S. aureus. Mutant organism with 67% of strains displaying the strains with delaﬂoxacin MICs C 8-fold those of methicillin-resistant phenotype . Cure rates Infect Dis Ther (2018) 7:197–217 209 at the follow-up time point (day 14) were 70.4% doses except for patients with an eGFR 15–29 ml/ in the delaﬂoxacin group compared with 64.9% min who were to receive delaﬂoxacin 200 mg IV in the linezolid group (P = 0.496 vs. dela- every 12 h for all doses [51, 52]. If gram-negative ﬂoxacin) and 54.1% in the vancomycin group pathogens were not isolated on the baseline (P = 0.031 vs. delaﬂoxacin). The higher cure culture, aztreonam was discontinued. No similar rate in the delaﬂoxacin vs. vancomycin group de-escalation to targeted therapy occurred for appeared to be driven by patients with a body patients in the delaﬂoxacin arms. Patients with mass index (BMI) C 30 kg/m (78.8% vs. 48.8%; infections involving prosthetic material or asso- P = 0.009). Among the microbiologically ciated with human/animal bites, osteomyelitis, evaluable population (n = 125), presumed or decubitus ulcer, diabetic foot ulcer, septic documented eradication rates were similar arthritis, necrotizing fasciitis or burns cover- between groups and ranged from 80.8% to ing C 10% of the body surface area were not eli- 88.2% . gible for enrollment. Other key exclusion criteria There are several limitations to these studies included severe underlying comorbidity (liver that deserve comment. Importantly, as phase 2 disease, end-stage renal disease, cardiac disease, trials, they were not designed with a formal pre- malignancy), history of seizure disorder and speciﬁed hypothesis or powered for any infer- pregnancy or lactation. The primary endpoint in ential statistical testing. Both trials included a the two studies was C 20% reduction in lesion relatively small number of patients and, as a size at 48–72 h in the ITT population. In study consequence, the range of bacterial pathogens 303, enrollment was expanded above the calcu- recovered was limited. Furthermore, patients lated sample size to enrich for a pre-speciﬁed most at risk for infection with a broader range of subgroup analysis by BMI [51, 52]. bacterial species (i.e., those who are immuno- In total, 660 and 850 patients were ran- compromised or have severe underlying domized in study 302 and 303, respectively. In comorbidity) and who therefore may stand to both studies, the majority of patients were beneﬁt from delaﬂoxacin’s expanded spectrum enrolled from US centers. The mean age of of activity, were excluded from the studies. The participants was approximately 46 and 50 years MRSA MICs for delaﬂoxacin were considerably in study 302 and 303, respectively. Few patients lower than has been observed in recent aged 65 years and older were enrolled (7% and surveillance studies [20, 47, 48]. All patients 20%, respectively). Approximately 80–90% of were enrolled from US centers, which raises the patients were Caucasian; African American question of whether the data are applicable patients were under-represented (7% and 20%). across geographic populations. Finally, Obese patients (BMI C 30 kg/m ) comprised although most patients were treated in the 32% and 40% of the study populations. Eight to outpatient setting, the efﬁcacy of the oral for- 13% of patients carried a diagnosis of diabetes, mulation of delaﬂoxacin was not evaluated. and approximately 1% had severely decreased To address these limitations as well as fulﬁll renal function (eGFR \ 30 ml/min). Bacteremia regulatory drug approval requirements, two was rare in both studies (2.3%, 2.2%) [51, 52]. phase 3 studies evaluating delaﬂoxacin for the The most prevalent pathogen isolated from treatment of adult patients with ABSSSIs were the infection site was S. aureus, which was initiated in 2013 (NCT01811732/RX-3341-302 identiﬁed in 66% and 58% of the microbiologic and NCT1984684/RX-3341-303, hereafter refer- ITT (MITT) patients in study 302 and 303, red to as study 302 and 303, respectively) [51, 52]. respectively. MRSA accounted for 52% and 36% Both were multicenter, randomized, double- of the S. aureus isolates, respectively [51, 52]. blind, non-inferiority studies comparing dela- Delaﬂoxacin was non-inferior to van- ﬂoxacin (300 mg) with vancomycin (15 mg/kg comycin plus aztreonam for the primary end- actual body weight) plus aztreonam (2 g), each point in both trials. Outcomes at the end of the administered IV, every 12 h for 5–14 days therapy time point (14 ± 1 day) were similar, [51, 52]. In study 303, a switch to oral dela- suggesting a sustained response to treatment in ﬂoxacin (450 mg) was mandated following six IV all groups. Importantly, outcomes at the later 210 Infect Dis Ther (2018) 7:197–217 time points in study 303 are supportive of oral larger number of patients and conducting for- delaﬂoxacin, which would have been initiated mal hypothesis testing, they did not expand following assessment of the primary outcome. knowledge of delaﬂoxacin’s performance Among the MITT population, per pathogen among patients at risk for a broader range of response rates were generally similar between pathogens. Key populations including the treatment groups across all pathogens. Overall, elderly, those with organ dysfunction, and 66% of MRSA isolates were levoﬂoxacin non- those with signiﬁcant underlying comorbidity susceptible . Among these isolates, the were either excluded or under-represented. delaﬂoxacin MIC value was 0.25 mg/l, and the Furthermore, although too few gram-negative eradication or presumed eradication rate was isolates were collected to allow for meaningful 98.6%. One MRSA isolate displayed an MIC of analysis, the high delaﬂoxacin MIC values dis- 4 mg/l, and double mutations in both gyrA and played among those that were obtained suggest parC were subsequently conﬁrmed. The micro- delaﬂoxacin may not be an ideal option when biologic response for the patient with this iso- these pathogens are suspected, although, as late was presumed eradicated based on clinical noted previously, MIC values determined by response. Approximately 15% of isolates recov- standard methods may underestimate in vivo ered were gram-negative. The predominant activity. gram-negative pathogens were K. pneumoniae The efﬁcacy of delaﬂoxacin has also been and E. coli. Levoﬂoxacin non-susceptibility was explored among patients with respiratory tract low among K. pneumoniae (2.2%), and most infections [49, 50]. Longcor et al. conducted a were susceptible to delaﬂoxacin (MIC 0.12/ phase 2, double-bind, randomized, dose-rang- 50/90 0.25 mg/l). Levoﬂoxacin non-susceptibility was ing study comparing three dose ranges of oral slightly higher among E. coli, and the dela- delaﬂoxacin (100, 200, 400 mg daily 9 5 days) ﬂoxacin MIC was 4 mg/l . to levoﬂoxacin (500 mg daily 9 7 days) in adult Subgroup analysis by age, sex, race and geo- outpatients diagnosed with ABECB . In graphic region were consistent with the overall total, 280 patients were randomized with a results; however, analysis is limited by the small mean age of 61 years. Clinical cure rates were number of patients in some subgroups, partic- similar in the four groups (69–79%), and no ularly those from regions outside of the US and dose-response trend was identiﬁed. Regarding African American patients [51, 52]. bacteriologic cure rates, however, outcomes In study 302, an exploratory post hoc anal- were improved among patients assigned to ysis by BMI category suggested a signiﬁcant delaﬂoxacin 400 mg compared with the lower improvement in cure rates at the long-term doses. In the phase 2 study evaluating the follow-up time point among obese patients clinical and bacteriologic outcomes with assigned to delaﬂoxacin compared with van- ascending delaﬂoxacin doses (100, 200 or comycin (71.7% vs. 57.5%; treatment difference 400 mg once daily for 7 day) among adult out- 14.2%, 95% CI 1.3% to 26.9%) [51, 52]. This patients with CAP (n = 309), clinical and bac- ﬁnding however was not subsequently con- teriologic cure rates were similar in the 200 and ﬁrmed in study 303, which, as noted previously, 400 mg groups and slightly lower for the was enriched with obese patients to allow for 100 mg group . formal statistical testing of this hypothesis. While the results of these studies are Among obese patients the cure rates at the late encouraging and appear to support a role for follow-up time point were similar (68.3% vs. delaﬂoxacin in the treatment of bacterial respi- 71.0%; treatment difference -2.7%, 95% ratory tract infections, further data from an CI - 11.5% to 6.0%). Information pertaining to ongoing phase 3 study comparing delaﬂoxacin vancomycin trough target attainment has not to moxiﬂoxacin or linezolid for the treatment been reported for the overall study populations CAP (NCT02679573) are required before or by BMI category [51, 52]. deﬁnitive conclusions pertaining to its efﬁcacy Although these studies addressed several for respiratory infections can be made. limitations of the phase 2 studies including a Infect Dis Ther (2018) 7:197–217 211 severity, and all other events were considered to ADVERSE EFFECTS be mild. Predisposing factors such as concomi- tant steroid use and renal disease were not pre- For many years, ﬂuoroquinolones were consid- sent in any of the affected patients . ered a safe and generally well-tolerated class of AEs involving the CNS have generally been antimicrobials . In recent decades, however, the second most commonly encountered form safety concerns have led to restrictions on the of ﬂuoroquinolone toxicity and include a broad use of ﬂuoroquinolones and, in some instances, variety of effects ranging from headaches and withdrawal of agents from the market [53, 54]. dizziness to acute psychosis to seizures . Recently, the FDA advisory committees on These effects are thought to occur secondary to antimicrobial drugs and drug safety concluded ﬂuoroquinolone blockade of GABA receptors that a risk vs. beneﬁt analysis did not support [53, 54]. In vitro experiments suggest that the the use of these agents in a number of uncom- delaﬂoxacin concentrations required to inhibit plicated infections, and labeling of all marketed GABA are many fold above those achieved ﬂuoroquinolones has been updated to include clinically . In line with these experimental stronger warnings pertaining to the risks serious observations, headache occurred in just 3% of adverse effects (AEs) such as tendon rupture, delaﬂoxacin-treated patients in pooled phase 3 peripheral neuropathy and central nervous sys- trials, and other CNS AEs were relatively rare tem (CNS) disturbances . Distinct differ- . No patients in the delaﬂoxacin arms of ences among ﬂuoroquinolones with regard to phase 3 studies experienced seizures or convul- their safety proﬁle can be predicted in part by sions . One patient who received a higher structural differences with structure-AE rela- than labeled dose of delaﬂoxacin (450 mg IV) tionships based on constituents at speciﬁc sites during a phase 2 study experienced a seizure on the quinolone nucleus . Delaﬂoxacin has . a number of unique structural characteristics, Structural differences at positions 1, 5 and 8 however, which present challenges when of the quinolone nucleus inﬂuence the photo- attempting to predict the potential for serious toxic potential . Fluoroquinolones with a AEs by this approach. halogen at position 8 of the nucleus along with As with all ﬂuoroquinolones, the most a bulky side chain are well known for their commonly reported AEs in phase 3 delaﬂoxacin associated phototoxicity . A methyl group at trials were gastrointestinal (GI) related (diarrhea position 5 may also contribute . Dela- 8%, nausea 8%) or mild CNS events . Data ﬂoxacin contains a chlorine at position 8 but from phase 1 and 2 studies indicate an associa- lacks a bulky side chain and contains no R5 tion between GI AEs and higher doses . substituent . A phase 1 study investigating There does not appear to be a clear ﬂuoro- the photosensitizing potential of delaﬂoxacin quinolone structure-GI AE relationship, but demonstrated ﬁndings similar to placebo with rather GI AEs are thought to be due to direct GI no evidence of phototoxicity in either the low irritation and/or indirect CNS effects . (200 mg) or high (400 mg) dose arms of dela- Tendinopathies are rare AEs associated with ﬂoxacin-treated subjects . By comparison, ﬂuoroquinolones . Although there has not more subjects assigned to the positive control been a widely accepted structural moiety asso- group (lomeﬂoxacin) exhibited both mild and ciated with tendinopathy, animal models sug- severe phototoxicity at various wavelengths. gest structural differences at position 7 may play Assessment of the hepatotoxic potential of a role with a methypiperadinyl group causing delaﬂoxacin is limited by the relatively small the highest number of tendon lesions . number of patients who have been exposed at Delaﬂoxacin is the only marketed ﬂuoro- this time. Although case reports of severe liver quinolone with a weakly acidic substituent at injury emerged soon after trovaﬂoxacin was this position . Three patients in pooled introduced into the clinic, it was not until phase 3 delaﬂoxacin trials reported tendonitis approximately 2.5 million courses of therapy . One event was graded as moderate in had been administered that the causal 212 Infect Dis Ther (2018) 7:197–217 relationship was deemed strong enough to a number of risk factors for CDAD besides warrant its removal from the market . The antibiotic exposure . frequency of clinically signiﬁcant elevations Fluoroquinolones are not known to com- ([ 5 times the upper limit of normal) of aspar- monly cause harmful effects on the kidneys; tate aminotransferase, alanine aminotransferase however, the vehicle used to deliver IV dela- and alkaline phosphatase was 0.3% or less ﬂoxacin, SBECD, may be problematic in across delaﬂoxacin groups in phase 3 trials, and patients with renal impairment . A reduced no clinically signiﬁcant elevations in bilirubin delaﬂoxacin dose (200 mg IV q12 h) is therefore occurred . These parameters may be poorly recommended in patients with an eGFR \ predictive of the potential for drug-induced 30 ml/min/1.73 m and a switch to oral dela- hepatotoxicity however. ﬂoxacin as soon as clinically indicated . The main area of interest relating to the To summarize, the available data have not cardiac toxicity of ﬂuoroquinolones is prolon- demonstrated signiﬁcant safety concerns for gation of the QTc interval . The mechanism delaﬂoxacin. However, as with all new antibi- by which this occurs is likely multifactorial, and otics, assessment of safety is limited by the an obvious structural moiety that increases the small number of healthy subjects and patients risk for QTc prolongation has not yet been to whom it has been administered. Exclusion identiﬁed . Studies of various ﬂuoro- criteria in completed phase 3 trials also limit the quinolones have shown a dose-dependent generalizability of safety ﬁndings to patients inhibition of the rapid-acting portion of the who may be more likely to receive this agent in delayed rectiﬁer potassium current, which is the clinic, i.e., those with pre-existing organ controlled by the human ether-a-go-go gene dysfunction and a higher degree of baseline (HERG) . Preclinical studies with dela- comorbidities. Nevertheless, the additional ﬂoxacin have found that it did not block HERG quasi-experimental data, which included posi- currents. In a phase 1 study delaﬂoxacin doses tive controls for two important class AEs, pho- up to three-fold higher than the currently totoxicity and QTc prolongation, are reassuring. labeled dose (900 mg) did not induce clinically meaningful changes in the QTc, while moxi- DRUG INTERACTIONS ﬂoxacin, which served as the positive control, produced predicted prolongation of the QTc Like other ﬂuoroquinolones, delaﬂoxacin forms interval [56, 61]. In phase 3 studies, no occur- insoluble chelation complexes with multivalent rences of drug-induced arrhythmias were cations in the GI tract resulting in a substantial reported . decrease in oral absorption of the antibiotic, Administration of ﬂuoroquinolones has and concomitant administration should be emerged as one of the most important risk fac- avoided . At clinically relevant concentra- tors for C. difﬁcile-associated diarrhea (CDAD) tions, delaﬂoxacin does not inhibit cytochrome caused by the hypervirulent RT027 strain . P450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, In early surveillance studies, delaﬂoxacin 2C19, 2D6, 2E1 or 3A4/5 . Delaﬂoxacin demonstrated potent activity against many demonstrated mild induction of CYP3A4 at anaerobic species . In particular, it showed clinically relevant concentrations in vitro; greater in vitro activity against C. difﬁcile than however, it did not affect the C and AUC max comparator ﬂuoroquinolones; however, activity values for midazolam (a sensitive CYP3A4 sub- against the RT027 strain was considerably lower strate) or its metabolite when administered to . The impact of delaﬂoxacin, of which healthy volunteers prior to midazolam admin- 35–50% is eliminated unchanged in the feces, istration . Delaﬂoxacin is a substrate of on bowel ﬂora is unknown at this time. Two breast cancer-related protein (BCRP) and a cases of CDAD were reported among patients potential substrate of P-glycoprotein . enrolled in the delaﬂoxacin arms of phase 2 and However, only modest increases in delaﬂoxacin 3 studies . Both patients were noted to have concentrations are anticipated when co- Infect Dis Ther (2018) 7:197–217 213 administered with BCRP or P-glycoprotein distinctive structural and chemical properties of inhibitors, and the clinical signiﬁcance is delaﬂoxacin may be harnessed to make it a expected to be minimal . The impact of particularly valuable addition to the antibiotic P-glycoprotein inducers, such as rifampicin, on armamentarium. Improving long-term out- delaﬂoxacin exposure has not been reported. comes in patients with bioﬁlm-associated infections is a critical unmet need, and dela- ﬂoxacin’s potent activity against S. aureus PLACE IN THERAPY embedded in bioﬁlm suggests a potential role in AND CONCLUSIONS this setting [41, 42]. Antibiotics that are capable of eradicating intracellular non-replicating per- ABSSSI is a popular market-entry indication for sister bacteria in bone, prosthetic device-asso- pharmaceutical companies developing new ciated infections and deep-seated abscesses are antimicrobials targeting MRSA [64–67]. Dela- clearly an unmet medical need, and dela- ﬂoxacin recently received FDA approval in this ﬂoxacin’s excellent intracellular penetration, setting based on registry studies showing it to be especially in the acidic conditions that are an effective and well-tolerated alternative . characteristic of these difﬁcult to treat infec- Notable advantages of delaﬂoxacin for the tions, points to another therapeutic niche . A treatment of ABSSSI include the availability of potent oral agent would be particularly desir- both parenteral and oral formulations, a low able in these settings because prolonged therapy potential for drug–drug interactions and reas- with IV antibiotics is often necessary but asso- suring clinical and experimental data pertaining ciated with tremendous expense, inconve- to key class-adverse effects such as cardiotoxic- nience and harmful effects associated with ity and phototoxicity. With the availability of a extended catheterization. The prospect of variety of new agents for the treatment of combination therapy with delaﬂoxacin and ABSSSI, it will be important to determine which rifampicin for these infections is intriguing, and agents are most suitable for speciﬁc patients on future research investigating the potential syn- the basis of coverage (broad versus narrow ergistic activity in bioﬁlm models would be spectrum), delivery (IV or PO) and potential for valuable. Delaﬂoxacin’s bactericidal activity adverse reactions and compliance (single versus and excellent pulmonary penetration  are multiple daily dosing). also suggestive of a promising role against Of particular concern, ﬂuoroquinolone use pneumonia. The diminishing pool of effective has been associated with increased rates of col- antibiotics for gonorrhea represents an urgent onization and infection with MRSA, ESBL-pro- public health threat . Although a single oral ducing Enterobacteriaceae and [5, 68–70] the dose of delaﬂoxacin was not sufﬁciently effec- hypervirulent C. difﬁcile RT027 strain [62, 70]. tive for uncomplicated gonorrhea infection, its Recent international guidelines for the treat- potent in vitro activity against this pathogen ment of a number of infectious diseases explic-  suggests that evaluations of alternative itly recognize the ecologic AEs of dosing schedules would be worthwhile. ﬂuoroquinolones as important factors in thera- Struggles with resistance will not cease with peutic decision-making and have called for the availability of new antibiotics, and we must more restricted use of these agents [71, 72]. As learn how to optimally use and not abuse antibiotic innovation continues to move for- promising new agents such as delaﬂoxacin. An ward, greater attention needs to be placed on oral antibiotic with in vitro activity against pinpointing unique properties of novel agents MRSA, Pseudomonas spp., anaerobes, and atypi- to assist in determining their speciﬁc therapeu- cal organisms will attract many prescribers, and tic niche with respect to areas of unmet medical antimicrobial stewards will be tasked with need while limiting collateral damage. implementing it appropriately into practice. As There are many important areas of unmet clinicians contemplate how to best incorporate need in the treatment of gram-positive infec- delaﬂoxacin into infectious disease treatment tions for which experimental data suggest the strategies, additional data pertaining to whether 214 Infect Dis Ther (2018) 7:197–217 the promising experimental data detailed in REFERENCES this review do indeed translate into improved outcomes for patient with difﬁcult to treat 1. US Food and Drug Administration. 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