Drug Evaluation
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Finafloxacin for the treatment of urinary tract infections Riccardo Bartoletti†, Tommaso Cai, Giampaolo Perletti, Florian ME Wagenlehner & Truls E Bjerklund Johansen
1.
Introduction
2.
Evidence acquisition
3.
Overview of the market
4.
Introduction to the compound
5.
Conclusion
6.
Expert opinion
†
Department of Experimental and Clinical Medicine, University of Florence, Italy
Introduction: In the past decade, the indiscriminate use of fluoroquinolones in the prophylaxis and treatment of urinary tract infections (UTIs) has led to an increase of antibiotic resistance patterns. Finafloxacin is a new generation fluoroquinolone with interesting preclinical characteristics and pH-related efficacy. Areas covered: This review summarizes finafloxacin’s safety profile and prospectively evaluates its specific use in the treatment of UTIs. This article was based on a Medline English literature search. Expert opinion: In vitro and in vivo studies have shown that finafloxacin expresses its full antibacterial activity in acidic environments and is able to exert significant bactericidal effects in difficult-to-treat infections. Finafloxacin has a broad antibacterial spectrum and efficient pharmacokinetic absorption. Moreover, it undergoes extensive tissue distribution, resulting in good antibacterial activity for daily dosages from 400 to 800 mg. This novel compound has also been successfully tested on biofilm-related Escherichia coli. Finafloxacin has demonstrated a good safety and tolerability profile in humans when administered orally or intravenously and is thus an interesting compound for the treatment of UTIs. However, further prospective randomized clinical trials will be necessary to confirm these preliminary results before definitive conclusions can be made. Keywords: antibiotic resistance, antibiotic treatment, fluoroquinolones, urinary tract infection Expert Opin. Investig. Drugs (2015) 24(7):957-963
1.
Introduction
Urinary tract infections (UTIs) are among the most frequent causes of medical consultations and fluoroquinolones are still considered among the first choice treatments for these conditions [1]. Furthermore, these compounds are frequently administered for antibacterial prophylaxis prior to urological procedures such as prostate biopsy or cystoscopy, with conflicting results due to the specific antibiotic resistance patterns reported in different countries and communities [1]. Uncomplicated UTIs are predominantly caused by Escherichia coli strains. Other Enterobacteriaceae, in association with Staphylococcus spp. or Enterococcus spp., are frequently involved in nosocomial UTIs and are often complicated by coexisting favorable conditions such as urinary obstruction, stones and/or indwelling catheters [1]. Fluoroquinolones remain one of the favorite treatments for urologists, due to the high urinary concentration found in many members of this family, and to their broad spectrum of antibacterial activity [1]. Nevertheless, most part of the fluoroquinolones family seems to be unable to exert significant effects on strains difficult to treat such as methicillinresistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus Epidermidis (MRSE) and ciprofloxacin-resistant staphylococci. Aim of the present review is to determine the possible role of finafloxacin, a novel fluoroquinolone particularly efficient in acidic environments, in the treatment of UTIs, also in the case of selected species microorganisms and difficult-to-treat infections. 10.1517/13543784.2015.1052401 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of Administration Chemical Structure
Finafloxacin II Treatment of urinary tract infections DNA topoisomerase IV inhibitor Oral O F
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H
2.
N CN
O
Pivotal trial
OH
N
NH
O
H
4.
[6]
Evidence acquisition
We performed a search of the English language literature from 2008 through January 2015 with use of the Medline computerized database of the US National Library of Medicine [2]. The Google Scholar database has also been used [3]. The Medline search has been carried-out by using Medical Subject Headings and free text terms as follows: ‘finafloxacin’ and ‘urinary tract infections’ (exploded) were combined with the terms: ‘treatment’ and ‘therapy’. Abstracts were not considered when full articles focusing on the same studies were available. Overlapping experiments have not been included because they were considered as redundant. From an initial literature search with finafloxacin unique citation, a total of 10 extended papers and 7 abstracts were selected for the present review. The Prisma Statement was used to perform an accurate research checklist and report. 3.
Overview of the market
The use of quinolones was introduced in the urological clinical practice more than 50 years ago. Since then, new generations of fluoroquinolone molecules have been developed and their characteristics have been improved not only by including a fluorine atom at the C-6 position, which increased the antibacterial potency, but also by broadening the antibacterial spectrum of activity. Second-generation fluoroquinolones such as ciprofloxacin and norfloxacin were found to be active on Gram-negative bacterial strains, with ciprofloxacin also being active against Pseudomonas aeruginosa. Ofloxacin and levofloxacin were also found to be active against some atypical pathogens such as Mycoplasma pneumoniae, Legionella pneumophila and Chlamydia trachomatis. Third-generation fluoroquinolones such as moxifloxacin were used preferentially for pulmonary infections generated by Gram-positive bacterial strains -- usually resistant to the previous generation compounds -- and to treat infections caused by anaerobes. The last generation of fluoroquinolones 958
that includes prulifloxacin and trovafloxacin is characterized by an increased activity against anaerobic and atypical pathogens and also against Gram-positive bacteria, compared to firstand second-generation fluoroquinolones [4-6]. Fluoroquinolone bactericidal activity includes a direct inhibition of bacterial DNA synthesis as a result of interference with two bacterial enzymes, gyrase (topoisomerase II) and DNA topoisomerase IV. Despite the existence of two different receptors, most second- and third-generation fluoroquinolones have a higher affinity for one of the two enzymes, facilitating development of bacterial resistance. New-generation fluoroquinolones tend to bind both enzymes, possibly making the emergence of resistance more difficult [2].
Introduction to the compound
New-generation fluoroquinolones include finafloxacin, a compound still undergoing evaluation of its clinical efficacy in the frame of randomized clinical trials. Finafloxacin is a novel 8-cyano-fluoroquinolone whose optimal antibacterial activity occurs at slightly acidic pH values in contrast to other fluoroquinolones. Moreover, finafloxacin is one of the most potent inhibitors of Escherichia coli gyrase and topoisomerase IV, exhibiting a comparatively high level of activity against both bacterial enzymes [7]. These features might render finafloxacin particularly suitable for the treatment of UTIs. The aim of this review is to focus on the effects of finafloxacin in the treatment of UTIs and to evaluate its safety profile on the basis of published available evidence (Box 1). Chemistry, structure--pharmacodynamics and structure--pharmacokinetics relationship
4.1
In addition to the 3-carboxylate and 4-carbonyl substituents, essential to ensure the binding of the drug to its target (the bacterial DNA--DNA gyrase complex), the quinoline backbone of finafloxacin contains two basic elements in common with a number of other quinolone antibacterial agents: a fluorine atom at position C-6 and a lipophilic cyclopropyl group at position N-1 (Box 1). The chemical structure of finafloxacin was drawn with the SketchEl software [8]. Whereas the fluorine substituent is known to enhance the penetration of the drug into bacterial cells and to improve drug potency when compared to non-fluorinated quinolone antibacterials [5], the cyclopropyl group can establish a strong hydrophobic interaction with the grove of bacterial DNA, within the DNA--topoisomerase binding complex [9], and is responsible for the large distribution volume (DV) and for the high bioavailability (F) of fluoroquinolones [10,11] (finafloxacin DV: 435 l; F: > 90%, after a single 800 mg oral dose) [6]. Small amino-substituents placed at the C-5 position of fluoroquinolones may confer increased activity against Gram-positive pathogens [12], but are responsible at the same time for severe side effects, like phototoxicity and QT interval prolongation via blockage of rapidly inactivating rectifier IKr currents, resulting in increased susceptibility to ventricular polymorphic
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Finafloxacin
tachycardias (torsades de pointes) [13,14]. Finafloxacin has no substituent at the C-5 position, to the advantage of the safety profile of the drug. Consistently, Patel et al. have reported that administration of increasing oral doses of finafloxacin up to 800 mg/day for up to 1 week to healthy volunteers did not result in prolongation of the corrected QT interval in the electrocardiogram [10]. Cyclic substituents at position C-7 play an important role in determining the pharmacokinetic and pharmacodynamic profiles of a fluoroquinolone. Lipophilic, bulky C-7 residues are known to increase the half-life and CNS penetration of these drugs [9,11,12]. For example, moxifloxacin is a fluoroquinolone characterized by a long plasma half-life (about 12 h), also due to its octahydro-6-h-pyrrolo pyridine C-7 substituent. This residue is similar in terms of bulkiness to the hexahydropyrrolo (1,4) oxazine of finafloxacin, which has a t1/2 of 10.5 h, measured after administration of a single 800 mg tablet [10]. Extended half-life allows once-daily oral dosing of the drug. Furthermore, bulky C-7 substituents are also known to decrease the selection of resistant mutants and to extend the antibacterial spectrum by increasing the anti-Gram-positive and anti-anaerobe activities of the fluoroquinolone [15]. Notably, the activity against anaerobic pathogens is also enhanced by the presence of substituents at the C-8 position [11,12]. However, this improved pharmacodynamic feature is associated with increased phototoxicity -- especially when halogens are used as C-8 substituents -- and cardiotoxicity, albeit to a lesser extent. Finafloxacin is substituted in position C-8 by a cyano-group. The partition coefficient logarithm of finafloxacin decreases together with the pH of water (logPoct/pH1: -1.7; antilog = 0.02), compared to neutral pH (logPoct/pH7: -0.6; antilog = 0.25) [16]. This indicates that the hydrophilicity of the drug is higher in an acidic medium. Thus, if the urinary (namely, the pre-urine) milieu is acidic, the drug will be less reabsorbed at the tubular level in the kidneys, thus being increasingly available at the site of infection, that is, in the renal pelvis, ureters and bladder. “In vitro” and “in vivo” studies Finafloxacin is characterized by a broad-spectrum antibacterial activity that is enhanced over a pH range of 5.0 -- 6.5, compared with neutral and basic values [17]. Dalhoff et al. demonstrated significant differences between the kill rates and times needed for reduction of viable microorganism counts in a study evaluating the effects of finafloxacin and ciprofloxacin in artificial medium at different pH values (pH 7.2 and pH 5.8, respectively) using different bacterial strains [18]. The absolute drug concentration for finafloxacin was always the same, whereas ciprofloxacin concentrations were from twice as high to 128 times higher in synthetic urine than in cation-adjusted Mueller-Hinton broth at pH 7.2, depending on the bacterial strains tested [18]. The absolute kill rates for both fluoroquinolones were comparable despite the differences between their absolute concentrations to obtain comparative results. A comparison of normalized kill 4.2
rates demonstrated that finafloxacin is more active than ciprofloxacin against S. aureus, E. coli, E. coli wild-type and comparable to ciprofloxacin in Enterococcus faecalis at pH 7.2 [18]. The normalized kill rates for finafloxacin are up to 47 times higher than those of ciprofloxacin for all four strains grown at pH 5.8 [18]. Similarly, Stubbings et al. investigated the effects of finafloxacin over pH values ranging between 4.8 and 7.4, in order to better define the optimal conditions for activity against 445 isolates belonging to 19 different bacterial species with comparable results [19]. Thauvin-Eliopoulos and Eliopoulos found that increased concentrations of urinary magnesium induced a proportional increase in the MICs of any commercially available fluoroquinolone for various bacterial species [20]. The reduced bactericidal and bacteriostatic effects of fluoroquinolones in urine can also be related to the low pH normally present in this medium. Other antibiotic classes such as aminoglycosides and trimethoprim also show lower antibacterial activity in acidic urine [21-23]. The b-lactams are also less active in an acidic milieu, due to the increase of drug hydrolysis by b-lactamases. This has a negative effect on the bactericidal activity of these agents, which however retain their bacteriostatic effects [24]. Emrich et al. compared the effects of finafloxacin with other fluoroquinolones such as ciprofloxacin, levofloxacin and moxifloxacin under different pH conditions against a set of isogenic E. coli strains [25]. A significant negative impact of pH on fluoroquinolone activity as well as the enhanced efficacy of finafloxacin at low pH values (MICs 2- to 16-fold lower than other fluoroquinolones tested) was confirmed, demonstrating that finafloxacin could be considered a fluoroquinolone optimally acting in an acidic milieu [21]. Finafloxacin is also active against anaerobic pathogens, as shown by Genzel et al. on a large number of Bacteroides fragilis and Clostridium difficile strains [26]. Ladel et al. tested finafloxacin in vivo on mice models with difficult-to-treat infections, in comparison with other fluoroquinolones [27]. Bacterial inocula were administered by different routes: intraperitoneal, oral, via implantation of colonized catheters, via thigh intramuscular injection and via direct injection into the kidneys, bladder, granuloma pouch or abscess [27]. The end points of the study were the survival rate at 3 -- 5 days or the reduction of bacterial counts. Finafloxacin showed enhanced antibacterial activity compared to other fluoroquinolones in these models, suggesting that the pH profile of this drug may be considered as an advantage in treating severe bacterial infections expressing an acidic milieu [27]. However, the activity of this drug against pathogens generating an alkaline milieu due to their high urease activity (e.g., Proteus mirabilis) should be further investigated. Finafloxacin in vitro activity against S. aureus, MRSA, MRSE and ciprofloxacin-resistant staphylococci
4.3
Recent epidemiological investigations underline the increasing prevalence of UTIs generated by Gram-positive bacteria,
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and particularly by S. aureus [1]. This evidence seems to be more abundant in the case of complicated UTIs [1]. Idelevich et al. investigated the effects of finafloxacin, compared to other fluoroquinolones, against Staphylococcus strains displaying normal and small colony variants (SCV) [28]. They found a descending order of activity with moxifloxacin>finafloxacin>levofloxacin>ciprofloxacin at pH 7.2, but a significantly higher activity of finafloxacin at lower pH values [28]. Overall, ciprofloxacin MIC50 and MIC90 values were higher for SCV strains at any pH condition. Similarly Garcia et al. confirmed both the lower activity of ciprofloxacin (increased MICs) for Staphylococcus SCV compared to the normal phenotype in favor of other fluoroquinolones or finafloxacin at normal or low pH respectively [29]. Lemaire et al. investigated the activity of finafloxacin against a panel of ciprofloxacin-susceptible and -resistant S. aureus isolates and studied its accumulation by THP-1 human macrophages and the activity toward susceptible extracellular and intracellular S. aureus at neutral and acidic pH [30]. They found that finafloxacin accumulated less than ciprofloxacin in THP-1 cells, but the situation was reversed by exposure of cells to acidic pH [30]. Limited information is still available concerning the effect of finafloxacin against MRSA. Morrissey et al. demonstrated that finafloxacin activity against MRSA, MRSE and ciprofloxacin-resistant staphylococci was much better than that of other fluoroquinolones tested such as ciprofloxacin, levofloxacin and moxifloxacin [31]. Idelevich et al. confirmed a good activity of finafloxacin at low pH also for MRSA pairs and coagulase negative strains, but the clinical relevance of this observation has to be clarified and further confirmed in future prospective clinical studies, due to the lack of interpretative criteria on finafloxacin [28]. Pharmacokinetics, bactericidal activity and safety profile in humans
4.4
Pharmacokinetics and safety profiles of finafloxacin have been investigated by Patel et al. on a series of 95 healthy volunteers of both sexes, 18 of whom received placebo tablets [10]. The volunteers’ body mass index ranged between 20.1 and 27.9 kg/m2. Single escalating oral doses were 25, 50, 100, 200, 400 and 800 mg. Multiple escalating oral doses were 150, 300, 600 and 800 mg, with each dose given once daily for 7 days. Each group consisted of eight volunteers, two of whom received placebo in a double-blind manner. Tablet formulations contained 50 mg of finafloxacin-free base. A series of blood samples were collected for plasma finafloxacin concentration measurements before dosing and at different times after administration. Finafloxacin was well absorbed, rapidly generating maximum plasma concentrations, similar to other fluoroquinolones (Cmax: 11.1 mg/l; tmax: 0.88 h, after a single oral 800 mg dose), with a half-life of ~ 10 h [10]. About one-third of the dose was excreted unchanged in the urine. Renal elimination was a saturable process leading to normalization 960
for dosages of ‡ 400 mg. Adverse events were considered to mirror those of other fluoroquinolones, including hypoglycemia and neurotoxic effects in a small fraction of subjects. Notably, adverse events were also reported among subjects treated with placebo tablets [10]. Wagenlehner et al. obtained similar results by investigating six healthy volunteers after the administration of 200 and 800 mg single-dose finafloxacin [32]. Urinary bactericidal titers (UBT) were determined for a reference strain and for nine selected uropathogens at the pH of native, acidified and alkalinized urine. The median urinary concentrations were 69.3 mg/l (0 -- 2 h) and 150 mg/l (4 -- 8 h) after 200 and 800 mg finafloxacin, respectively. Median UBTs were in general agreement with MICs of strains and urinary pH values. UBTs in alkaline urines were significantly lower than those in native or acidic urine, except for E. faecalis. The median UBT for E. faecalis were similar in acidic and alkaline urine following both the 200 and the 800 mg doses, with a slightly increased activity in the acidic environment. Finafloxacin was well tolerated by all volunteers and no serious adverse events occurred during the study. There were no significant changes in the results from laboratory tests on blood and urine [32]. Similarly Luckermann et al. investigated the safety and tolerability of single and multiple escalating doses (from 200 to 1000 mg) of finafloxacin intravenously administered in 58 healthy subjects. They found no relevant changes in the laboratory safety tests assessment and recorded light adverse events in 35 subjects. The systemic exposure of finafloxacin increased in a dose-dependent manner. They concluded that finafloxacin single and multiple doses intravenously administered were well tolerated [33]. The role of finafloxacin in the treatment of bacteria endowed in mucus layer or in biofilms was also investigated by Goh et al. Finafloxacin showed bactericidal activity against adherent and planktonic E. coli, as demonstrated by a reduction of the exposed population to a greater extent than equivalent concentrations of the comparator fluoroquinolones ciprofloxacin and levofloxacin [34].
5.
Conclusion
Finafloxacin is a new-generation fluoroquinolone particularly efficient in acidic environments, thus prospectively suitable in the treatment of UTIs. The effects of finafloxacin have already been demonstrated in ex vivo and in vivo studies and its safety proven in preliminary studies on humans. Finafloxacin has not yet been included into a specific fluoroquinolone “generation”. Its placement in the fourth generation is advisable due to its structural similarity with moxifloxacin and the good activity exerted on anaerobic bacteria. Further randomized controlled comparative studies are necessary to determine the efficacy of finafloxacin on different bacterial strains in patients with simple or complicated UTIs.
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Finafloxacin
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6.
Expert opinion
UTIs are common diseases in the outpatient as well as in the institutional healthcare settings, and are responsible for a large part of antibiotic administrations [1]. Most of the pathogens involved in the genesis and development of UTI are prone to develop antibiotic resistance in relation to the inadequate use of these compounds for empirical treatments by physicians, to careless self-administration by patients, and to the diffusion of resistant strains in the environment [1]. Other relevant factors determining the onset of resistance are the suboptimal drug dosing and the timing of administration of antibacterial agents [1]. Fluoroquinolones are still considered to be among the treatments of choice in recurrent UTI episodes as well as in the antibacterial prophylaxis prior to various surgical procedures like prostate biopsy [1]. The Global Prevalence Study of Infections in Urology recently demonstrated that ~ 90% of patients undergoing transrectal ultrasound-guided prostate biopsy had previously received antibiotic prophylaxis with fluoroquinolones independently from the single community resistance rates and the prevalence of previous urinary infection episodes [35]. Steensels et al. showed that the use of fluoroquinolones in the 6 months before prostate biopsy and the presence of chronic prostatitis were associated with fecal carriage of fluoroquinoloneresistant E. coli strains [36]. Additionally, the raising prevalence of infections caused by Gram-positive bacteria limits the current use of these compounds, directing urologists toward the use of other antibacterial agents, with an even higher risk of developing resistance. New strategies such as optimization of the antibiotic treatment schedule and timing, as well as antibiotic stewardship policies in regard to decreased antibiotic consumption should be adopted in daily clinical practice [37]. New fluoroquinolones represent a new frontier in the treatment of UTIs. These compounds are candidates to be Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Grabe M, Bartoletti R, Bjerklund-Johansen TE, et al. Guidelines in Urological Infections. European Association of Urology Ed. EAU Guidelines volume; 2014 Database of the US National Library of Medicine (Medline). Available from: http://www.ncbi.nlm.nih.gov/pubmed
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included in the armamentarium against multidrug-resistant pathogens. Due to its enhanced activity in a slightly acidic medium such as the urine, finafloxacin shows favorable characteristics for the therapeutic management of UTIs. Moreover the drug is less reabsorbed at the tubular level in the kidneys, thus being increasingly available at the site of infection in the urinary tract. Preclinical studies have provided encouraging results not only in the control of pathogens commonly related to UTIs, but also in case of relatively less frequent or “difficult-to-treat” bacterial strains and biofilm-associated bacteria. Moreover, whereas its antibacterial activity at neutral pH matches that of other quinolones in clinical practice, it is expected to exceed this activity in tissues and body fluids acidified by infection or inflammation processes [10]. In fact, finafloxacin exhibits broad-spectrum antibacterial activity that is enhanced over a pH range of 5.0 -- 6.5. On the other hand, ciprofloxacin, levofloxacin and moxifloxacin exhibit significantly reduced activity at slightly acidic pH (5.0 -- 6.5) [25]. It is expected that the results of ongoing prospective doubleblind randomized clinical trials will further extend our knowledge about this promising novel compound.
Declaration of interest FME Wagenlehner is consultant of Merlion Company and principal investigator in the clinical Phase II trial on finafloxacin in the treatment of complicated UTI/pyelonephritis. The other 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.
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Idelevich EA, Krigeskorte A, Stubbings W, et al. Comparative in vitro activity of finafloxacin against staphylococci displaying normal and small colony variant phenotypes. J Antimicrob Chemother 2011;66:2809-13 The author of the paper investigated on the effects of finafloxacin on small colony variant staphylococci.
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Morrissey I, Hawser S, Vente A, Dalhoff A. Efficacy of the investigational fluoroquinolone finafloxacin against resistant staphylococci as compared to ciprofloxacin, levofloxacin and moxifloxacin (abstr. P1669). 24th ECCMID, Barcelona Spain; 2014 This is the first report regarding the effects and safety of finafloxacin against methicillin-resistant staphylococci.
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Wagenlehner FM, Wagenlehner CM, Blenk B, et al. Urinary pharmacokinetics and bactericidal activity of finafloxacin (200 and 800 mg.) in healthy volunteers receiving a single oral dose. Chemotherapy 2011;57:97-107 This paper describes the first significant study on finafloxacin pharmacokinetics and activity in human healthy volunteers. Luckermann M, Mooney L, Patel H, et al. A phase I study to determine safety, tolerability and pharmacokinetics (PK) of intravenous doses of finafloxacin HCl (FIN) in healthy subjects (A-1960). 52nd ICAAC 2012; S.Francisco USA; 2012 This is the first report regarding the safety and pharmacokinetics of finafloxacin administered intravenously.
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Goh CY, Goh F, Stubbings W, et al. Bactericidal activity of finafloxacin against difficult to kill growth forms for Escherichia coli ( AbstractF1-2042). 48th ICAAC, Washington;2008
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Wagenlehner FM, van Oostrum E, Tenke P, et al. Infective complications after prostate biopsy: outcome of the Global Prevalence Study of Infections in Urology (GPIU) 2010 and 2011, a prospective multinational multicentre prostate biopsy study. Eur Urol 2013;63:521527 This study indicates that men who previously underwent prostate biopsies and treated with fluoroquinolonebased antibiotic prophylaxis, presented positive urine culture due to the presence of resistant bacteria.
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Steensels D, Slabbaert K, De Wever L, et al. Fluoroquinolone-resistant E. coli in intestinal flora of patients undergoing transrectal ultrasound-guided prostate biopsy-should we reassess our practices for antibiotic prophylaxis? Clin Microbiol Infect 2012;18(6):575-81
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Wagenlehner FM, Bartoletti R, Cek M, et al. Antibiotic stewardship: a call for action by the urologic community. Eur Urol 2013;64:358-60
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Affiliation
Riccardo Bartoletti†1 MD, Tommaso Cai2, Giampaolo Perletti3,4, Florian ME Wagenlehner5 & Truls E Bjerklund Johansen6 † Author for correspondence 1 University of Florence, Department of Experimental and Clinical Medicine, 4-50139 Florence, Italy, E-mail: [email protected] 2 Urology Unit, S.Chiara Regional Hospital, Trento, Italy 3 University of Insubria, Biomedical Research Division, Department of Theoretical and Applied Sciences, Varese, Italy 4 University of Ghent, Department of Basic Medical Sciences, Belgium 5 Justus-Liebig University, Clinic for Urology, Pediatric Urology and Andrology, Giessen, Germany 6 Oslo University Hospital, Department of Urology, Oslo, Norway
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Finafloxacin for the treatment of urinary tract infections Riccardo Bartoletti†, Tommaso Cai, Giampaolo Perletti, Florian ME Wagenlehner & Truls E Bjerklund Johansen
1.
Introduction
2.
Evidence acquisition
3.
Overview of the market
4.
Introduction to the compound
5.
Conclusion
6.
Expert opinion
†
Department of Experimental and Clinical Medicine, University of Florence, Italy
Introduction: In the past decade, the indiscriminate use of fluoroquinolones in the prophylaxis and treatment of urinary tract infections (UTIs) has led to an increase of antibiotic resistance patterns. Finafloxacin is a new generation fluoroquinolone with interesting preclinical characteristics and pH-related efficacy. Areas covered: This review summarizes finafloxacin’s safety profile and prospectively evaluates its specific use in the treatment of UTIs. This article was based on a Medline English literature search. Expert opinion: In vitro and in vivo studies have shown that finafloxacin expresses its full antibacterial activity in acidic environments and is able to exert significant bactericidal effects in difficult-to-treat infections. Finafloxacin has a broad antibacterial spectrum and efficient pharmacokinetic absorption. Moreover, it undergoes extensive tissue distribution, resulting in good antibacterial activity for daily dosages from 400 to 800 mg. This novel compound has also been successfully tested on biofilm-related Escherichia coli. Finafloxacin has demonstrated a good safety and tolerability profile in humans when administered orally or intravenously and is thus an interesting compound for the treatment of UTIs. However, further prospective randomized clinical trials will be necessary to confirm these preliminary results before definitive conclusions can be made. Keywords: antibiotic resistance, antibiotic treatment, fluoroquinolones, urinary tract infection Expert Opin. Investig. Drugs (2015) 24(7):957-963
1.
Introduction
Urinary tract infections (UTIs) are among the most frequent causes of medical consultations and fluoroquinolones are still considered among the first choice treatments for these conditions [1]. Furthermore, these compounds are frequently administered for antibacterial prophylaxis prior to urological procedures such as prostate biopsy or cystoscopy, with conflicting results due to the specific antibiotic resistance patterns reported in different countries and communities [1]. Uncomplicated UTIs are predominantly caused by Escherichia coli strains. Other Enterobacteriaceae, in association with Staphylococcus spp. or Enterococcus spp., are frequently involved in nosocomial UTIs and are often complicated by coexisting favorable conditions such as urinary obstruction, stones and/or indwelling catheters [1]. Fluoroquinolones remain one of the favorite treatments for urologists, due to the high urinary concentration found in many members of this family, and to their broad spectrum of antibacterial activity [1]. Nevertheless, most part of the fluoroquinolones family seems to be unable to exert significant effects on strains difficult to treat such as methicillinresistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus Epidermidis (MRSE) and ciprofloxacin-resistant staphylococci. Aim of the present review is to determine the possible role of finafloxacin, a novel fluoroquinolone particularly efficient in acidic environments, in the treatment of UTIs, also in the case of selected species microorganisms and difficult-to-treat infections. 10.1517/13543784.2015.1052401 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of Administration Chemical Structure
Finafloxacin II Treatment of urinary tract infections DNA topoisomerase IV inhibitor Oral O F
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H
2.
N CN
O
Pivotal trial
OH
N
NH
O
H
4.
[6]
Evidence acquisition
We performed a search of the English language literature from 2008 through January 2015 with use of the Medline computerized database of the US National Library of Medicine [2]. The Google Scholar database has also been used [3]. The Medline search has been carried-out by using Medical Subject Headings and free text terms as follows: ‘finafloxacin’ and ‘urinary tract infections’ (exploded) were combined with the terms: ‘treatment’ and ‘therapy’. Abstracts were not considered when full articles focusing on the same studies were available. Overlapping experiments have not been included because they were considered as redundant. From an initial literature search with finafloxacin unique citation, a total of 10 extended papers and 7 abstracts were selected for the present review. The Prisma Statement was used to perform an accurate research checklist and report. 3.
Overview of the market
The use of quinolones was introduced in the urological clinical practice more than 50 years ago. Since then, new generations of fluoroquinolone molecules have been developed and their characteristics have been improved not only by including a fluorine atom at the C-6 position, which increased the antibacterial potency, but also by broadening the antibacterial spectrum of activity. Second-generation fluoroquinolones such as ciprofloxacin and norfloxacin were found to be active on Gram-negative bacterial strains, with ciprofloxacin also being active against Pseudomonas aeruginosa. Ofloxacin and levofloxacin were also found to be active against some atypical pathogens such as Mycoplasma pneumoniae, Legionella pneumophila and Chlamydia trachomatis. Third-generation fluoroquinolones such as moxifloxacin were used preferentially for pulmonary infections generated by Gram-positive bacterial strains -- usually resistant to the previous generation compounds -- and to treat infections caused by anaerobes. The last generation of fluoroquinolones 958
that includes prulifloxacin and trovafloxacin is characterized by an increased activity against anaerobic and atypical pathogens and also against Gram-positive bacteria, compared to firstand second-generation fluoroquinolones [4-6]. Fluoroquinolone bactericidal activity includes a direct inhibition of bacterial DNA synthesis as a result of interference with two bacterial enzymes, gyrase (topoisomerase II) and DNA topoisomerase IV. Despite the existence of two different receptors, most second- and third-generation fluoroquinolones have a higher affinity for one of the two enzymes, facilitating development of bacterial resistance. New-generation fluoroquinolones tend to bind both enzymes, possibly making the emergence of resistance more difficult [2].
Introduction to the compound
New-generation fluoroquinolones include finafloxacin, a compound still undergoing evaluation of its clinical efficacy in the frame of randomized clinical trials. Finafloxacin is a novel 8-cyano-fluoroquinolone whose optimal antibacterial activity occurs at slightly acidic pH values in contrast to other fluoroquinolones. Moreover, finafloxacin is one of the most potent inhibitors of Escherichia coli gyrase and topoisomerase IV, exhibiting a comparatively high level of activity against both bacterial enzymes [7]. These features might render finafloxacin particularly suitable for the treatment of UTIs. The aim of this review is to focus on the effects of finafloxacin in the treatment of UTIs and to evaluate its safety profile on the basis of published available evidence (Box 1). Chemistry, structure--pharmacodynamics and structure--pharmacokinetics relationship
4.1
In addition to the 3-carboxylate and 4-carbonyl substituents, essential to ensure the binding of the drug to its target (the bacterial DNA--DNA gyrase complex), the quinoline backbone of finafloxacin contains two basic elements in common with a number of other quinolone antibacterial agents: a fluorine atom at position C-6 and a lipophilic cyclopropyl group at position N-1 (Box 1). The chemical structure of finafloxacin was drawn with the SketchEl software [8]. Whereas the fluorine substituent is known to enhance the penetration of the drug into bacterial cells and to improve drug potency when compared to non-fluorinated quinolone antibacterials [5], the cyclopropyl group can establish a strong hydrophobic interaction with the grove of bacterial DNA, within the DNA--topoisomerase binding complex [9], and is responsible for the large distribution volume (DV) and for the high bioavailability (F) of fluoroquinolones [10,11] (finafloxacin DV: 435 l; F: > 90%, after a single 800 mg oral dose) [6]. Small amino-substituents placed at the C-5 position of fluoroquinolones may confer increased activity against Gram-positive pathogens [12], but are responsible at the same time for severe side effects, like phototoxicity and QT interval prolongation via blockage of rapidly inactivating rectifier IKr currents, resulting in increased susceptibility to ventricular polymorphic
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Finafloxacin
tachycardias (torsades de pointes) [13,14]. Finafloxacin has no substituent at the C-5 position, to the advantage of the safety profile of the drug. Consistently, Patel et al. have reported that administration of increasing oral doses of finafloxacin up to 800 mg/day for up to 1 week to healthy volunteers did not result in prolongation of the corrected QT interval in the electrocardiogram [10]. Cyclic substituents at position C-7 play an important role in determining the pharmacokinetic and pharmacodynamic profiles of a fluoroquinolone. Lipophilic, bulky C-7 residues are known to increase the half-life and CNS penetration of these drugs [9,11,12]. For example, moxifloxacin is a fluoroquinolone characterized by a long plasma half-life (about 12 h), also due to its octahydro-6-h-pyrrolo pyridine C-7 substituent. This residue is similar in terms of bulkiness to the hexahydropyrrolo (1,4) oxazine of finafloxacin, which has a t1/2 of 10.5 h, measured after administration of a single 800 mg tablet [10]. Extended half-life allows once-daily oral dosing of the drug. Furthermore, bulky C-7 substituents are also known to decrease the selection of resistant mutants and to extend the antibacterial spectrum by increasing the anti-Gram-positive and anti-anaerobe activities of the fluoroquinolone [15]. Notably, the activity against anaerobic pathogens is also enhanced by the presence of substituents at the C-8 position [11,12]. However, this improved pharmacodynamic feature is associated with increased phototoxicity -- especially when halogens are used as C-8 substituents -- and cardiotoxicity, albeit to a lesser extent. Finafloxacin is substituted in position C-8 by a cyano-group. The partition coefficient logarithm of finafloxacin decreases together with the pH of water (logPoct/pH1: -1.7; antilog = 0.02), compared to neutral pH (logPoct/pH7: -0.6; antilog = 0.25) [16]. This indicates that the hydrophilicity of the drug is higher in an acidic medium. Thus, if the urinary (namely, the pre-urine) milieu is acidic, the drug will be less reabsorbed at the tubular level in the kidneys, thus being increasingly available at the site of infection, that is, in the renal pelvis, ureters and bladder. “In vitro” and “in vivo” studies Finafloxacin is characterized by a broad-spectrum antibacterial activity that is enhanced over a pH range of 5.0 -- 6.5, compared with neutral and basic values [17]. Dalhoff et al. demonstrated significant differences between the kill rates and times needed for reduction of viable microorganism counts in a study evaluating the effects of finafloxacin and ciprofloxacin in artificial medium at different pH values (pH 7.2 and pH 5.8, respectively) using different bacterial strains [18]. The absolute drug concentration for finafloxacin was always the same, whereas ciprofloxacin concentrations were from twice as high to 128 times higher in synthetic urine than in cation-adjusted Mueller-Hinton broth at pH 7.2, depending on the bacterial strains tested [18]. The absolute kill rates for both fluoroquinolones were comparable despite the differences between their absolute concentrations to obtain comparative results. A comparison of normalized kill 4.2
rates demonstrated that finafloxacin is more active than ciprofloxacin against S. aureus, E. coli, E. coli wild-type and comparable to ciprofloxacin in Enterococcus faecalis at pH 7.2 [18]. The normalized kill rates for finafloxacin are up to 47 times higher than those of ciprofloxacin for all four strains grown at pH 5.8 [18]. Similarly, Stubbings et al. investigated the effects of finafloxacin over pH values ranging between 4.8 and 7.4, in order to better define the optimal conditions for activity against 445 isolates belonging to 19 different bacterial species with comparable results [19]. Thauvin-Eliopoulos and Eliopoulos found that increased concentrations of urinary magnesium induced a proportional increase in the MICs of any commercially available fluoroquinolone for various bacterial species [20]. The reduced bactericidal and bacteriostatic effects of fluoroquinolones in urine can also be related to the low pH normally present in this medium. Other antibiotic classes such as aminoglycosides and trimethoprim also show lower antibacterial activity in acidic urine [21-23]. The b-lactams are also less active in an acidic milieu, due to the increase of drug hydrolysis by b-lactamases. This has a negative effect on the bactericidal activity of these agents, which however retain their bacteriostatic effects [24]. Emrich et al. compared the effects of finafloxacin with other fluoroquinolones such as ciprofloxacin, levofloxacin and moxifloxacin under different pH conditions against a set of isogenic E. coli strains [25]. A significant negative impact of pH on fluoroquinolone activity as well as the enhanced efficacy of finafloxacin at low pH values (MICs 2- to 16-fold lower than other fluoroquinolones tested) was confirmed, demonstrating that finafloxacin could be considered a fluoroquinolone optimally acting in an acidic milieu [21]. Finafloxacin is also active against anaerobic pathogens, as shown by Genzel et al. on a large number of Bacteroides fragilis and Clostridium difficile strains [26]. Ladel et al. tested finafloxacin in vivo on mice models with difficult-to-treat infections, in comparison with other fluoroquinolones [27]. Bacterial inocula were administered by different routes: intraperitoneal, oral, via implantation of colonized catheters, via thigh intramuscular injection and via direct injection into the kidneys, bladder, granuloma pouch or abscess [27]. The end points of the study were the survival rate at 3 -- 5 days or the reduction of bacterial counts. Finafloxacin showed enhanced antibacterial activity compared to other fluoroquinolones in these models, suggesting that the pH profile of this drug may be considered as an advantage in treating severe bacterial infections expressing an acidic milieu [27]. However, the activity of this drug against pathogens generating an alkaline milieu due to their high urease activity (e.g., Proteus mirabilis) should be further investigated. Finafloxacin in vitro activity against S. aureus, MRSA, MRSE and ciprofloxacin-resistant staphylococci
4.3
Recent epidemiological investigations underline the increasing prevalence of UTIs generated by Gram-positive bacteria,
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and particularly by S. aureus [1]. This evidence seems to be more abundant in the case of complicated UTIs [1]. Idelevich et al. investigated the effects of finafloxacin, compared to other fluoroquinolones, against Staphylococcus strains displaying normal and small colony variants (SCV) [28]. They found a descending order of activity with moxifloxacin>finafloxacin>levofloxacin>ciprofloxacin at pH 7.2, but a significantly higher activity of finafloxacin at lower pH values [28]. Overall, ciprofloxacin MIC50 and MIC90 values were higher for SCV strains at any pH condition. Similarly Garcia et al. confirmed both the lower activity of ciprofloxacin (increased MICs) for Staphylococcus SCV compared to the normal phenotype in favor of other fluoroquinolones or finafloxacin at normal or low pH respectively [29]. Lemaire et al. investigated the activity of finafloxacin against a panel of ciprofloxacin-susceptible and -resistant S. aureus isolates and studied its accumulation by THP-1 human macrophages and the activity toward susceptible extracellular and intracellular S. aureus at neutral and acidic pH [30]. They found that finafloxacin accumulated less than ciprofloxacin in THP-1 cells, but the situation was reversed by exposure of cells to acidic pH [30]. Limited information is still available concerning the effect of finafloxacin against MRSA. Morrissey et al. demonstrated that finafloxacin activity against MRSA, MRSE and ciprofloxacin-resistant staphylococci was much better than that of other fluoroquinolones tested such as ciprofloxacin, levofloxacin and moxifloxacin [31]. Idelevich et al. confirmed a good activity of finafloxacin at low pH also for MRSA pairs and coagulase negative strains, but the clinical relevance of this observation has to be clarified and further confirmed in future prospective clinical studies, due to the lack of interpretative criteria on finafloxacin [28]. Pharmacokinetics, bactericidal activity and safety profile in humans
4.4
Pharmacokinetics and safety profiles of finafloxacin have been investigated by Patel et al. on a series of 95 healthy volunteers of both sexes, 18 of whom received placebo tablets [10]. The volunteers’ body mass index ranged between 20.1 and 27.9 kg/m2. Single escalating oral doses were 25, 50, 100, 200, 400 and 800 mg. Multiple escalating oral doses were 150, 300, 600 and 800 mg, with each dose given once daily for 7 days. Each group consisted of eight volunteers, two of whom received placebo in a double-blind manner. Tablet formulations contained 50 mg of finafloxacin-free base. A series of blood samples were collected for plasma finafloxacin concentration measurements before dosing and at different times after administration. Finafloxacin was well absorbed, rapidly generating maximum plasma concentrations, similar to other fluoroquinolones (Cmax: 11.1 mg/l; tmax: 0.88 h, after a single oral 800 mg dose), with a half-life of ~ 10 h [10]. About one-third of the dose was excreted unchanged in the urine. Renal elimination was a saturable process leading to normalization 960
for dosages of ‡ 400 mg. Adverse events were considered to mirror those of other fluoroquinolones, including hypoglycemia and neurotoxic effects in a small fraction of subjects. Notably, adverse events were also reported among subjects treated with placebo tablets [10]. Wagenlehner et al. obtained similar results by investigating six healthy volunteers after the administration of 200 and 800 mg single-dose finafloxacin [32]. Urinary bactericidal titers (UBT) were determined for a reference strain and for nine selected uropathogens at the pH of native, acidified and alkalinized urine. The median urinary concentrations were 69.3 mg/l (0 -- 2 h) and 150 mg/l (4 -- 8 h) after 200 and 800 mg finafloxacin, respectively. Median UBTs were in general agreement with MICs of strains and urinary pH values. UBTs in alkaline urines were significantly lower than those in native or acidic urine, except for E. faecalis. The median UBT for E. faecalis were similar in acidic and alkaline urine following both the 200 and the 800 mg doses, with a slightly increased activity in the acidic environment. Finafloxacin was well tolerated by all volunteers and no serious adverse events occurred during the study. There were no significant changes in the results from laboratory tests on blood and urine [32]. Similarly Luckermann et al. investigated the safety and tolerability of single and multiple escalating doses (from 200 to 1000 mg) of finafloxacin intravenously administered in 58 healthy subjects. They found no relevant changes in the laboratory safety tests assessment and recorded light adverse events in 35 subjects. The systemic exposure of finafloxacin increased in a dose-dependent manner. They concluded that finafloxacin single and multiple doses intravenously administered were well tolerated [33]. The role of finafloxacin in the treatment of bacteria endowed in mucus layer or in biofilms was also investigated by Goh et al. Finafloxacin showed bactericidal activity against adherent and planktonic E. coli, as demonstrated by a reduction of the exposed population to a greater extent than equivalent concentrations of the comparator fluoroquinolones ciprofloxacin and levofloxacin [34].
5.
Conclusion
Finafloxacin is a new-generation fluoroquinolone particularly efficient in acidic environments, thus prospectively suitable in the treatment of UTIs. The effects of finafloxacin have already been demonstrated in ex vivo and in vivo studies and its safety proven in preliminary studies on humans. Finafloxacin has not yet been included into a specific fluoroquinolone “generation”. Its placement in the fourth generation is advisable due to its structural similarity with moxifloxacin and the good activity exerted on anaerobic bacteria. Further randomized controlled comparative studies are necessary to determine the efficacy of finafloxacin on different bacterial strains in patients with simple or complicated UTIs.
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Finafloxacin
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6.
Expert opinion
UTIs are common diseases in the outpatient as well as in the institutional healthcare settings, and are responsible for a large part of antibiotic administrations [1]. Most of the pathogens involved in the genesis and development of UTI are prone to develop antibiotic resistance in relation to the inadequate use of these compounds for empirical treatments by physicians, to careless self-administration by patients, and to the diffusion of resistant strains in the environment [1]. Other relevant factors determining the onset of resistance are the suboptimal drug dosing and the timing of administration of antibacterial agents [1]. Fluoroquinolones are still considered to be among the treatments of choice in recurrent UTI episodes as well as in the antibacterial prophylaxis prior to various surgical procedures like prostate biopsy [1]. The Global Prevalence Study of Infections in Urology recently demonstrated that ~ 90% of patients undergoing transrectal ultrasound-guided prostate biopsy had previously received antibiotic prophylaxis with fluoroquinolones independently from the single community resistance rates and the prevalence of previous urinary infection episodes [35]. Steensels et al. showed that the use of fluoroquinolones in the 6 months before prostate biopsy and the presence of chronic prostatitis were associated with fecal carriage of fluoroquinoloneresistant E. coli strains [36]. Additionally, the raising prevalence of infections caused by Gram-positive bacteria limits the current use of these compounds, directing urologists toward the use of other antibacterial agents, with an even higher risk of developing resistance. New strategies such as optimization of the antibiotic treatment schedule and timing, as well as antibiotic stewardship policies in regard to decreased antibiotic consumption should be adopted in daily clinical practice [37]. New fluoroquinolones represent a new frontier in the treatment of UTIs. These compounds are candidates to be Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Grabe M, Bartoletti R, Bjerklund-Johansen TE, et al. Guidelines in Urological Infections. European Association of Urology Ed. EAU Guidelines volume; 2014 Database of the US National Library of Medicine (Medline). Available from: http://www.ncbi.nlm.nih.gov/pubmed
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included in the armamentarium against multidrug-resistant pathogens. Due to its enhanced activity in a slightly acidic medium such as the urine, finafloxacin shows favorable characteristics for the therapeutic management of UTIs. Moreover the drug is less reabsorbed at the tubular level in the kidneys, thus being increasingly available at the site of infection in the urinary tract. Preclinical studies have provided encouraging results not only in the control of pathogens commonly related to UTIs, but also in case of relatively less frequent or “difficult-to-treat” bacterial strains and biofilm-associated bacteria. Moreover, whereas its antibacterial activity at neutral pH matches that of other quinolones in clinical practice, it is expected to exceed this activity in tissues and body fluids acidified by infection or inflammation processes [10]. In fact, finafloxacin exhibits broad-spectrum antibacterial activity that is enhanced over a pH range of 5.0 -- 6.5. On the other hand, ciprofloxacin, levofloxacin and moxifloxacin exhibit significantly reduced activity at slightly acidic pH (5.0 -- 6.5) [25]. It is expected that the results of ongoing prospective doubleblind randomized clinical trials will further extend our knowledge about this promising novel compound.
Declaration of interest FME Wagenlehner is consultant of Merlion Company and principal investigator in the clinical Phase II trial on finafloxacin in the treatment of complicated UTI/pyelonephritis. The other 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.
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Morrissey I, Hawser S, Vente A, Dalhoff A. Efficacy of the investigational fluoroquinolone finafloxacin against resistant staphylococci as compared to ciprofloxacin, levofloxacin and moxifloxacin (abstr. P1669). 24th ECCMID, Barcelona Spain; 2014 This is the first report regarding the effects and safety of finafloxacin against methicillin-resistant staphylococci.
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Wagenlehner FM, Wagenlehner CM, Blenk B, et al. Urinary pharmacokinetics and bactericidal activity of finafloxacin (200 and 800 mg.) in healthy volunteers receiving a single oral dose. Chemotherapy 2011;57:97-107 This paper describes the first significant study on finafloxacin pharmacokinetics and activity in human healthy volunteers. Luckermann M, Mooney L, Patel H, et al. A phase I study to determine safety, tolerability and pharmacokinetics (PK) of intravenous doses of finafloxacin HCl (FIN) in healthy subjects (A-1960). 52nd ICAAC 2012; S.Francisco USA; 2012 This is the first report regarding the safety and pharmacokinetics of finafloxacin administered intravenously.
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Affiliation
Riccardo Bartoletti†1 MD, Tommaso Cai2, Giampaolo Perletti3,4, Florian ME Wagenlehner5 & Truls E Bjerklund Johansen6 † Author for correspondence 1 University of Florence, Department of Experimental and Clinical Medicine, 4-50139 Florence, Italy, E-mail: [email protected] 2 Urology Unit, S.Chiara Regional Hospital, Trento, Italy 3 University of Insubria, Biomedical Research Division, Department of Theoretical and Applied Sciences, Varese, Italy 4 University of Ghent, Department of Basic Medical Sciences, Belgium 5 Justus-Liebig University, Clinic for Urology, Pediatric Urology and Andrology, Giessen, Germany 6 Oslo University Hospital, Department of Urology, Oslo, Norway
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