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Antimicrob Agents Chemother. 2016 October; 60(10): 6381–6385.
Published online 2016 September 23. Prepublished online 2016 July 25. doi:  10.1128/AAC.00941-16
PMCID: PMC5038254

In Vitro Activity of Delafloxacin Tested against Isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis

Abstract

Delafloxacin, an investigational anionic fluoroquinolone, is active against a broad range of Gram-positive and Gram-negative bacteria. In this study, 200 Streptococcus pneumoniae (plus 30 levofloxacin-resistant isolates), 200 Haemophilus influenzae, and 100 Moraxella catarrhalis isolates selected primarily from the United States (2014) were tested against delafloxacin and comparator agents. Delafloxacin was the most potent agent tested. MIC50 and MIC90 values against all S. pneumoniae isolates were 0.008 and 0.015 μg/ml. Delafloxacin susceptibility was not affected by β-lactamase status against H. influenzae and M. catarrhalis.

TEXT

Delafloxacin is an investigational anionic fluoroquinolone antibacterial currently in phase III development for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) (NCT01811732 and NCT01984684). Unlike other quinolones, which usually have a binding preference for DNA gyrase or topoisomerase IV, delafloxacin is equally potent against both enzymes (1). This dual targeting is believed to help reduce the selection of resistant mutants in vitro (1). Additionally, the anionic structure of delafloxacin may enhance its potency in acidic environments, which may be characteristic of the milieu at an infection site (2).

(This work was presented in part in abstract form at the joint Interscience Conference of Antimicrobial Agents and Chemotherapy [ICAAC] and International Congress of Chemotherapy and Infection [ICC] 2015 meeting.)

Delafloxacin is active against a broad range of Gram-positive and Gram-negative bacteria, including anaerobes and atypical bacteria (Chlamydia and Mycoplasma) (1, 3,8). It is highly active against pathogens that are found in skin and soft tissue infections, including fluoroquinolone-resistant staphylococci, methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, β-hemolytic streptococci, enteric bacteria, Pseudomonas aeruginosa, and anaerobes (1, 3, 5, 7). Delafloxacin is also active against bacteria associated with respiratory tract infections (RTI; hospital and community acquired), including activity against fluoroquinolone-resistant Streptococcus pneumoniae (1, 3,6, 8).

Two hundred S. pneumoniae isolates (plus 30 isolates selected for levofloxacin resistance), 200 Haemophilus influenzae isolates, and 100 Moraxella catarrhalis isolates were selected for this study, primarily from United States medical centers from the SENTRY surveillance platform. These isolates were collected from January through December 2014. MIC values were determined for S. pneumoniae and H. influenzae according to the broth microdilution method described in CLSI document M07-A10 (9); broth microdilution methods used for M. catarrhalis were as described in CLSI document M45-Ed3 (10). Dry-form panels (Thermo Fisher Scientific, Cleveland, OH, USA) to test S. pneumoniae and frozen-form panels (JMI Laboratories) to test delafloxacin, levofloxacin, and ciprofloxacin against H. influenzae and M. catarrhalis isolates were used and consisted of three media types: cation-adjusted Mueller-Hinton broth (CA-MHB), CA-MHB plus 2.5% to 5.0% lysed horse blood, and Haemophilus test medium. Quality control ranges and interpretive criteria used for the comparator compounds were those published in CLSI document M100-S26 and by EUCAST (11, 12).

Delafloxacin was 128-fold (MIC50) and 64-fold (MIC90) more active than levofloxacin against all S. pneumoniae isolates (Table 1). The delafloxacin MIC50 and MIC90 values for S. pneumoniae were 0.008 and 0.015 μg/ml, respectively, with the highest MIC value at 0.12 μg/ml (Table 1). The MIC50 and MIC90 values for delafloxacin (0.008 and 0.015 μg/ml) and levofloxacin (1 and 1 μg/ml) were unchanged for multidrug-resistant (MDR; nonsusceptible to at least two of penicillin, ceftriaxone, levofloxacin, tetracycline, trimethoprim-sulfamethoxazole, and erythromycin) isolates and the penicillin-susceptible, -intermediate, and -resistant subsets of S. pneumoniae (Table 1). Delafloxacin and levofloxacin retained activity against nine ceftriaxone-nonsusceptible isolates (Table 1). MIC values for delafloxacin were increased 16- to 32-fold (MIC50 and MIC90, 0.12 and 0.5 μg/ml) relative to the general population of S. pneumoniae when tested against levofloxacin-resistant S. pneumoniae.

TABLE 1
Activity of delafloxacin and comparator antimicrobial agents tested against isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis

Delafloxacin was 8-fold more potent than the next most potent agent, i.e., ceftaroline (MIC90, 0.12 μg/ml; 100.0% susceptible), against S. pneumoniae (Table 1). Susceptibilities to erythromycin (52.5% susceptible), trimethoprim-sulfamethoxazole (75.5% susceptible), tetracycline (81.0% susceptible), and meropenem (86.0% susceptible) were compromised (Table 1). Against penicillin-resistant isolates, delafloxacin was 16-fold more active than the next potent comparator, i.e., ceftaroline (MIC90, 0.015 versus 0.25 μg/ml) (Table 1). Susceptibilities for most antimicrobials were generally decreased among penicillin-resistant isolates compared to those of the general population, with the exception of the fluoroquinolones and ceftaroline. For example, susceptibilities to erythromycin, trimethoprim-sulfamethoxazole, and ceftriaxone were 7.7%, 15.4%, and 53.8%, respectively (Table 1). The highest MIC for delafloxacin was 16-fold lower than that for the most potent comparator, i.e., moxifloxacin (0.015 versus 0.25 μg/ml), and 32-fold lower than that for ceftaroline (0.015 versus 0.5 μg/ml) against ceftriaxone-nonsusceptible S. pneumoniae (Table 1). The fluoroquinolones (levofloxacin and moxifloxacin) and ceftaroline retained activity (100.0% susceptible) against ceftriaxone-nonsusceptible S. pneumoniae; however, many of the other antimicrobials showed decreased activity compared to the normal population. Ceftaroline (MIC90, 0.12 μg/ml; 100.0% susceptible) demonstrated the most potent activity against levofloxacin-resistant S. pneumoniae, followed by delafloxacin (MIC90, 0.5 μg/ml), meropenem (MIC90, 1 μg/ml; 66.7% susceptible), and ceftriaxone (MIC90, 2 μg/ml; 83.3% susceptible). Limited activity with moxifloxacin was noted (MIC90, 4 μg/ml; 20.0% susceptible).

The MIC50 and MIC90 values for delafloxacin against H. influenzae were ≤0.001 and 0.004 μg/ml (highest MIC value at 0.25 μg/ml) (Table 1). For levofloxacin, the MIC50 and MIC90 values were 0.015 and 0.03 μg/ml; however, two isolates were not susceptible (MIC, >2 μg/ml) (Table 1). The activities of delafloxacin and levofloxacin against H. influenzae were unaffected by β-lactamase status (data not shown). Both delafloxacin and levofloxacin were active against M. catarrhalis, although delafloxacin was 8-fold more active than levofloxacin (Table 1).

Delafloxacin was the most potent agent tested against H. influenzae (Table 1). The MIC90 (0.004 μg/ml) was 4-fold and 8-fold lower than those for ciprofloxacin and levofloxacin, respectively (Table 1). Ciprofloxacin and levofloxacin susceptibilities were 99.0%, and all isolates were susceptible to ceftaroline, ceftazidime, and meropenem (Table 1). Tetracycline (93.8% versus 100.0% for β-lactamase-negative isolates) and trimethoprim-sulfamethoxazole (62.5% versus 65.8%) susceptibilities were lower for the β-lactamase-positive isolates (data not shown). Delafloxacin was the most potent agent tested against M. catarrhalis, exhibiting an MIC90 (0.008 μg/ml) that was 8-fold lower than those for ciprofloxacin and levofloxacin (Table 1). All isolates were susceptible to amoxicillin-clavulanate, ceftazidime, ciprofloxacin, levofloxacin, and tetracycline (Table 1).

In a bacterial respiratory surveillance program conducted from 1997 to 2002 throughout Canada (CROSS), the delafloxacin MIC50 and MIC90 values were 0.008 and 0.015 μg/ml when tested against 6,991 isolates of S. pneumoniae (13). These values were similar for delafloxacin when it was tested against 389 penicillin-resistant strains (MIC50 and MIC90, 0.015 and 0.015 μg/ml) (13). The MIC50 and MIC90 values for delafloxacin tested against 200 contemporary S. pneumoniae isolates from the United States in this study were also 0.008 and 0.015 μg/ml, respectively, and the MIC90 for delafloxacin tested against penicillin-resistant isolates matched that of the CROSS study. This indicates that delafloxacin maintained its potency despite the selective pressure of fluoroquinolone use in the intervening decade. In a study of the comparative activity of delafloxacin against Gram-positive and Gram-negative pathogens, Harnett et al. (5) demonstrated that the MIC50 and MIC90 values for delafloxacin tested against H. influenzae were both 0.001 μg/ml, and the MIC50 and MIC90 values for delafloxacin against M. catarrhalis were both 0.008 μg/ml. The data from our current study are consistent with the highly potent nature of the activity of delafloxacin, with MIC50 and MIC90 values of ≤0.001 and 0.004 µg/ml against H. influenzae and ≤0.008 and ≤0.008 µg/ml against M. catarrhalis.

Overall, delafloxacin was the most potent compound tested against S. pneumoniae, H. influenzae, and M. catarrhalis in our study. It was active against penicillin-resistant, ceftriaxone-nonsusceptible, and levofloxacin-resistant subsets of S. pneumoniae. Although delafloxacin demonstrated potent activity against levofloxacin-resistant organisms, MIC values were increased compared to those in wild-type organisms. The MIC50 and MIC90 values were 0.008 and 0.015 μg/ml against the collection of 200 S. pneumoniae and 0.12 and 0.5 μg/ml against 30 levofloxacin-resistant isolates, which is a 16- to 32-fold increase. This level of cross-resistance suggests some overlap in the binding targets of DNA gyrase and topoisomerase IV. The potent activity of delafloxacin against pathogens frequently associated with community-acquired pneumonia (S. pneumoniae, H. influenzae, and M. catarrhalis), including those that are MDR, indicates that further study in community-acquired bacterial pneumonia is warranted.

ACKNOWLEDGMENTS

We thank J. Oberholser and M. Janechek for the preparation of the manuscript and the JMI staff members for scientific assistance in performing the study.

This study was funded under a service agreement with Melinta Therapeutics, Inc.

JMI Laboratories, Inc., received research and educational grants in 2014 to 2015 from Achaogen, Actavis, Actelion, Allergan, American Proficiency Institute (API), AmpliPhi, Anacor, Astellas, AstraZeneca, Basilea, Bayer, BD, Cardeas, Cellceutix, CEM-102 Pharmaceuticals, Cempra, Cerexa, Cidara, CorMedix, Cubist, Debiopharm, Dipexium, Dong Wha, Durata, Enteris, Exela, Forest Research Institute, Furiex, Genentech, GSK, Helperby, ICPD, Janssen, Lannett, Longitude, Medpace, Meiji Seika Kasha, Melinta, Merck, Motif, Nabriva, Novartis, Paratek, Pfizer, Pocared, PTC Therapeutics, Rempex, Roche, Salvat, Scynexis, Seachaid, Shionogi, Tetraphase, The Medicines Co., Theravance, Thermo Fisher, VenatoRX, Vertex, Wockhardt, Zavante, and some other corporations.

Some JMI employees are advisors/consultants for Allergan, Astellas, Cubist, Pfizer, Cempra, and Theravance.

Funding Statement

This study was funded under a service agreement with Melinta Therapeutics, Inc.

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