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Activity of omadacycline tested against Enterobacteriaceae causing urinary tract infections from a global surveillance program (2014)
Accepted Manuscript Activity of Omadacycline Tested against Enterobacteriaceae Causing Urinary Tract Infections from a Global Surveillance Program (2014)
M.A. Pfaller, P.R. Rhomberg, M.D. Huband, R.K. Flamm PII: DOI: Reference:
S0732-8893(18)30036-1 doi:10.1016/j.diagmicrobio.2018.01.019 DMB 14523
To appear in: Received date: Revised date: Accepted date:
15 August 2017 22 January 2018 24 January 2018
Please cite this article as: M.A. Pfaller, P.R. Rhomberg, M.D. Huband, R.K. Flamm , Activity of Omadacycline Tested against Enterobacteriaceae Causing Urinary Tract Infections from a Global Surveillance Program (2014). The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Dmb(2018), doi:10.1016/j.diagmicrobio.2018.01.019
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ACCEPTED MANUSCRIPT Activity of Omadacycline Tested against Enterobacteriaceae Causing Urinary Tract Infections from a Global Surveillance Program (2014)
a,b*
M.D. Huband
a
a
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R.K. Flamm
a
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P.R. Rhomberg
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M.A. Pfaller
a
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JMI Laboratories, North Liberty, Iowa, USA b
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M
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University of Iowa, Iowa City, Iowa, USA
Michael A. Pfaller, M.D.
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Contact Information:
JMI Laboratories
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345 Beaver Kreek Ctr, Ste A North Liberty, Iowa, 52317, USA
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Phone: 319-665-3370 Fax: 319-665-3371 [email protected]
ACCEPTED MANUSCRIPT Abstract Omadacycline is an aminomethylcycline with in vitro activity against many gram-negative pathogens. Omadacycline and comparators were tested against Enterobacteriaceae from urinary tract infections (UTI) selected from a 2014 global surveillance program and compared to results of isolates from 2010 surveillance. The omadacycline MIC50/90 for Enterobacteriaceae collected during 2014 was 2/≥8 µg/mL
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(1/4 µg/mL minus Proteus, Providencia, and Morganella spp.). The MIC50/90 for E. coli was 1/2 µg/mL,
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similar to that in 2010 (MIC50/90, 0.5/2 µg/mL). The MICs for 91.7% of Klebsiella spp. isolates in 2014
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(89.7%, 2010) were ≤4 µg/mL. In 2010 and 2014, a total of 100.0% and 95.8% of ESBL screen-positive (SP) phenotype E. coli and 73.9% and 75.0% of ESBL SP Klebsiella spp., respectively, exhibited MIC
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values at ≤4 µg/mL. Omadacycline was active against UTI-causing Enterobacteriaceae isolates from NA
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and EU. Further study of omadacycline to treat UTI caused by Enterobacteriaceae may be indicated.
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Key words: urinary tract infections; omadacycline; Enterobacteriaceae
ACCEPTED MANUSCRIPT 1
Introduction
Urinary tract infections (UTI) commonly occur in the community and health care settings (Gupta, et al., 2011; Hooton, et al., 2010; Kobayashi, et al., 2016; Magill, et al., 2014). UTI is a leading diagnosis that results in antibiotics prescribed for women seeking ambulatory care and is the fourth most common health care-associated infection (HAI) (Gupta, et al., 2011; Hooton, et al., 2010; Magill, et al., 2014). The
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vast majority of these infections are treated empirically with antibiotics, resulting in intense selection
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pressure for developing antibacterial resistance (Kobayashi, et al., 2016). In the hospital and long term
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care settings, catheter-associated bacteriuria comprises a large reservoir of antibiotic-resistant organisms that contributes to the problem of cross-infection and frequently triggers inappropriate antibiotic use
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(Hooton, et al., 2010). Studies have demonstrated considerable geographic variation in resistance rates among gram-negative bacteria (GNB) causing UTIs (Kahlmeter & Eco.Sens, 2003; Sanchez, et al., 2012;
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Zhanel, et al., 2006).
Although trimethoprim-sulfamethoxazole and nitrofurantoin are recommended for empiric treatment of
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uncomplicated cystitis (Gupta, et al., 2011), the fluoroquinolones are the most frequently prescribed
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agents for treating UTIs in the United States (U.S.) (Kobayashi, et al., 2016). This extensive use of fluoroquinolones is associated with an increase in fluoroquinolone-resistant uropathogens, including
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fluoroquinolone-resistant Escherichia coli (Sanchez, et al., 2012). In addition, resistance rates of >20% in the U.S. and Europe (EU) to ampicillin and trimethoprim-sulfamethoxazole have been reported for GNB
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uropathogens (Kahlmeter & Eco.Sens, 2003; Sanchez, et al., 2012; Zhanel, et al., 2006). The microbial spectrum of uncomplicated cystitis and pyelonephritis consists mainly (75-95%) of E. coli
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with occasional species of other Enterobacteriaceae such as Klebsiella pneumoniae and Proteus mirabilis (Gupta, et al., 2011; Kobayashi, et al., 2016). Other GNB (eg, Pseudomonas aeruginosa) and grampositive cocci (GPC; methicillin-resistant Staphylococcus aureus [MRSA] and enterococci) are common in more complicated catheter-associated infections, but are rarely isolated in uncomplicated UTIs (Gupta, et al., 2011; Hooton, et al., 2010). Due to varying resistance profiles of E. coli strains causing UTIs, a specific recommendation for empiric therapy may not always be suitable for all regions. Thus, an understanding of local antimicrobial resistance patterns of E. coli and other uropathogens must be considered in empirical antibiotic selection (Gupta, et al., 2011; Kobayashi, et al., 2016).
ACCEPTED MANUSCRIPT Given a trend among uropathogens toward increasing resistance for most antibiotics (Kahlmeter & Eco.Sens, 2003; Sanchez, et al., 2012), prospective resistance surveillance at the regional, local, or health care system level is critical for optimal empiric antibacterial selection. Most agents used for UTI empirical treatment lack established resistance thresholds, above which an antimicrobial agent should not be considered for empiric therapy. Two exceptions, however, are the fluoroquinolones and trimethoprim-
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sulfamethoxazole, for which 10% and 20% resistance have been considered as thresholds for treatment
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of pyelonephritis and cystitis, respectively (Gupta, et al., 2011). These findings underscore the continued
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importance of antibiotic resistance surveillance and the need to assess the potential impact of newly introduced and novel antibacterial agents targeting specific resistance phenotypes (Perez & Villegas,
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2015; van Duin & Bonomo, 2016).
Omadacycline is a semisynthetic derivative of minocycline and the first member of the novel class of
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aminomethylcyclines (Draper, et al., 2014; Honeyman, et al., 2015; Macone, et al., 2014). Similar to the older tetracyclines (doxycycline, minocycline, and tetracycline), omadacycline binds to the 30S ribosomal
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subunit of target GPC and GNB that results in protein synthesis inhibition (Draper, et al., 2014;
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Honeyman, et al., 2015; Roberts, 2003). Notably, omadacycline remains active in bacterial strains expressing ribosomal protection or efflux tetracycline-resistance genes (Honeyman, et al., 2015; Macone,
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et al., 2014; Villano, et al., 2016). Omadacycline also maintains its activity against difficult-to-treat pathogens such as MRSA, vancomycin-resistant enterococci (VRE), and Enterobacteriaceae strains that
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produce a wide array of extended-spectrum β-lactamases (ESBLs) and carbapenemases (CRE) in addition to multidrug-resistant (MDR; resistant to ≥3 classes of agents) strains of Acinetobacter spp. and
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Stenotrophomonas maltophilia (Villano, et al., 2016). Omadacycline has been shown to be non-inferior to linezolid in a Phase 2 study of the treatment of acute bacterial skin and skin structure infections (ABSSI) (Noel, et al., 2012). Phase 3 studies for treatment of ABSSI and community-acquired bacterial pneumonia (CABP) are ongoing (Villano, et al., 2016). A Phase 1B study in uncomplicated urinary tract infections (UTIs) reported positive top-line pharmacokinetic proof-of-principle data in November 2016 (Paratek Pharmaceuticals, data on file). In the present study, we evaluated the in vitro activity of omadacycline and comparator agents tested by Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution methods against
ACCEPTED MANUSCRIPT Enterobacteriaceae isolates causing UTIs in North America (NA) and EU in the 2014 SENTRY Surveillance Program compared to data collected in the 2010 SENTRY Surveillance Program. Evaluations of E. coli and K. pneumoniae resistant subsets are included in the analysis.
Materials and Methods
2.1
Organism collection
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A total of 151 Enterobacteriaceae that were identified as urinary tract isolates from patients in medical
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centers in EU and 150 from NA (2014 global surveillance; n=301) were selected for susceptibility testing. These organisms were chosen to represent approximate percentages of Enterobacteriaceae species in
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the complete collection of UTI (2014). Organisms (number) included Citrobacter amalonaticus (1), C. freundii (11), C. koseri (8), Enterobacter aerogenes (7), E. cloacae (16), Escherichia coli (138), Klebsiella
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oxytoca (8), K. pneumoniae (52), Morganella morganii (14), Proteus mirabilis (22), P. vulgaris (7), Providencia rettgeri (6), P. stuartii (5), and Serratia marcescens (6).
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Susceptibility results for 2014 isolates were compared to the results of 826 UTI isolates of
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Enterobacteriaceae from EU and NA medical centers in 2010. The 2010 organism collection contained Citrobacter freundii (5), C. koseri (3), Enterobacter aerogenes (12), E. asburiae (1), E. cloacae (23),
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unspeciated Enterobacter (1), Escherichia coli (543), Klebsiella oxytoca (32), K. pneumoniae (123), Morganella morganii (8), Proteus mirabilis (50), P. vulgaris (3), Providencia rettgeri (1), P. stuartii (1),
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unspeciated Providencia (4), unspeciated Salmonella (1), and Serratia marcescens (15). Among the 1,127 isolates tested from 2010 and 2014, 253 (22.4%) were from inpatients, 789 (70.0%) were from
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outpatients, and 85 (7.6%) were not designated as inpatient or outpatient in origin. All isolates were identified to the species level at each participating medical center and confirmed by the monitoring laboratory (JMI Laboratories, North Liberty, Iowa, USA) using the VITEK 2 System (bioMérieux, Hazelwood, Missouri, USA) or matrix-assisted laser desorption ionization-time of flight mass spectrometry (Bruker, Billerica, Massachusetts, USA), when necessary. 2.2
Susceptibility testing
Omadacycline and comparators was tested in dry-form panels in 2010 (omadacycline range, 0.015-32 µg/mL). and panels with fresh frozen medium made at JMI Laboratories (North Liberty, Iowa, USA) for
ACCEPTED MANUSCRIPT testing 2014 isolates (omadacycline range, 0.008-8 µg/mL). Comparator agents were selected to represent agents that may be used to treat both uncomplicated and complicated UTI (Gupta et al, 2011; Hooton et al, 2010). Upon receipt of the panels at the monitoring laboratory (JMI Laboratories) each batch of panels was tested against the appropriate CLSI quality control (QC) organisms in triplicate, and all MIC values were within the established testing range (CLSI, 2015, 2016). In the validation process for
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the dry-form panels, we have performed studies that show that the essential agreement (+/- 1 dil) with
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reference panels (frozen/fresh) was 99.7% (data not shown). E. coli and K. pneumoniae were grouped as
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“ESBL SP phenotype” based on the CLSI screening criteria for potential ESBL production—ie, ceftazidime, ceftriaxone, and/or aztreonam MIC values of ≥2 µg/mL (CLSI, 2016). Concurrent QC testing
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was also performed to assure proper test conditions and procedures and all values were within published ranges (CLSI, 2015, 2016). The QC strains tested were Escherichia coli ATCC 25922 and Pseudomonas
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aeruginosa ATCC 27853 (CLSI, 2016). CLSI (CLSI, 2015, 2016) interpretive criteria were used.
Results
3.1
Activity of omadacycline against Enterobacteriaceae
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MIC distributions for all Enterobacteriaceae combined data from EU and NA medical centers are shown in
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Table 1. ESBL SP phenotype strains of E. coli and Klebsiella spp. accounted for 17.4% and 26.7% of isolates, respectively, in the 2014 collection compared to 8.8% and 14.8%, respectively, in the 2010
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collection (Table 1). The MIC50/90 values for all Enterobacteriaceae and for ESBL SP phenotype E. coli in 2010 were 1/4 µg/mL (Table 1). Overall, the omadacycline MIC values for the 2010 isolates were ≤4
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µg/mL for 99.6% of E. coli and 89.7% of Klebsiella spp. ESBL SP phenotype strains of Klebsiella spp. from 2010 were less susceptible to omadacycline (MIC50/90, 2/≥8 µg/mL) than ESBL SP phenotype E. coli (MIC50/90, 1/4 µg/mL). For the 2014 isolates, the omadacycline MIC50/90 values were 2/≥8 µg/mL overall for Enterobacteriaceae and were 1/4 µg/mL for ESBL SP phenotype E. coli and 4/≥8 µg/mL for Klebsiella spp. (Table 1). The majority of Enterobacteriaceae isolates for which MIC values were ≥8 µg/mL in 2010 (56/82, 68.3%) and 2014 (51/60, 85.0% were either Proteus, Providencia or Morganella spp., all of which are intrinsically resistant to tetracyclines and tend to have higher MIC values for omadacycline than either
ACCEPTED MANUSCRIPT E. coli or Klebsiella spp. (Villano, et al., 2016). The MIC50/90 values for Enterobacteriaceae minus Proteus, Providencia, and Morganella spp. were 1/2 µg/mL in 2010 and 1/4 µg/mL in 2014 (data not shown). In 2014, the frequency of ESBL SP phenotype strains of E. coli and Klebsiella spp. was higher among EU isolates (20.3% and 48.3%, respectively) than NA isolates (13.6% and 6.5%, respectively) (Table 1). Omadacycline MIC90 values tended to be higher for EU isolates of E. coli and Klebsiella spp. than for NA
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isolates (eg, in 2014, 1/2 µg/mL [NA/EU], and 4/≥8 µg/mL, respectively) (Table 1). Among the 5 isolates
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of Klebsiella spp. in 2014 (all K. pneumoniae; 2 from NA and 3 from EU [all from different medical
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centers]) for which MIC values were > 4 µg/mL, 4 exhibited an ESBL SP phenotype and an ESBL (3 CTX-M group 1) or MBL (1 VIM)) genotype; all 5 were resistant to tetracycline and doxycycline (data not
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shown). ESBL SP phenotype strains of E. coli from EU and NA (2014) showed comparable susceptibility with 93.8% and 100.0%, respectively, inhibited by ≤4 µg/mL of omadacycline (Table 1). Omadacycline
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was considerably less active against EU and NA strains of ESBL SP phenotype Klebsiella spp. (collected in 2014) with 78.6% and 50.0%, respectively, inhibited by ≤4 µg/mL. Susceptibility of EU and NA Enterobacteriaceae isolates to comparator agents
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All Enterobacteriaceae isolates (minus Proteus, Providencia and Morganella spp.) from NA and EU demonstrated high susceptibility for tigecycline (100.0/99.8% [NA/EU]), aztreonam (91.9/84.8%
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[NA/EU]), ceftazidime (93.1/88.1% [NA/EU]), ceftriaxone (90.6/82.4% [NA/EU]), gentamicin (92.9/87.9% [NA/EU]), and imipenem (99.8/98.9% [NA/EU]) (Table 2). All comparator agents were slightly more
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active against Enterobacteriaceae isolates from NA versus those from EU, although the activity of most of these agents was suboptimal in both regions (Table 2). Resistance to doxycycline, tetracycline,
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levofloxacin, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole all exceeded 15%, suggesting that these agents may not be reliable for use as empiric therapy (Table 2). All E. coli isolates from both regions were susceptible to tigecycline and imipenem (Table 2). The least active agents from both regions were doxycycline, tetracycline, levofloxacin, and trimethoprimsulfamethoxazole. Among the ESBL SP phenotype isolates of E. coli only tigecycline, imipenem and gentamicin were active against more than 50% of isolates. Although Klebsiella spp. isolates from NA and EU were highly susceptible to tigecycline (100.0/98.8% susceptible [NA/EU]) and imipenem (99.3/96.3% susceptible [NA/EU]), the EU isolates were considerably
ACCEPTED MANUSCRIPT less susceptible to all other comparators than the NA isolates (Table 2). Specifically, less than 70% of EU isolates of Klebsiella spp. were susceptible to doxycycline, tetracycline, amoxicillin-clavulanate, aztreonam, ceftriaxone, and trimethoprim-sulfamethoxazole, whereas all were active against more than 80% of NA isolates. Only tigecycline (100.0/100.0% susceptible [NA/EU]) and imipenem (88.9/90.0% susceptible [NA/EU]) were active against ESBL SP phenotype isolates of Klebsiella spp. None of the
Conclusions
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comparator agents tested were active against more than 50% of isolates from either region (Table 2).
In the present survey, we examined the in vitro susceptibility profiles of 1,127 UTI isolates of
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Enterobacteriaceae from EU and NA medical centers for the years 2010 and 2014. Overall, we found higher rates of ESBL SP phenotype E. coli and Klebsiella spp. among EU isolates versus those from NA
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(Table 1). Enterobacteriaceae isolates from EU were less susceptible to omadacycline and all comparators than the NA isolates.
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Data from the present survey document the in vitro activity of omadacycline against GNB uropathogens
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from a global survey. Overall, the broadest coverage of tested pathogens was observed with imipenem and tigecycline (Table 2). Omadacycline was active against ESBL SP phenotype strains of E. coli but was
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less active against ESBL SP phenotype Klebsiella spp. Tigecycline and imipenem were the most active agents against Enterobacteriaceae, including ESBL SP phenotype strains.
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These data build on those reported by previous investigators (Almer, et al., 2004; Flamm, et al., 2016; Harnett, et al., 2004; Nilius, et al., 2003; Remy, et al., 2012) and indicate that omadacycline merits further
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study in treating cUTI in which mixed GPC and GNB infections may occur and pathogens resistant to older antimicrobials are common.
ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS This study at JMI Laboratories was supported by Paratek Pharmaceuticals (King of Prussia, Pennsylvania), and JMI Laboratories received compensation fees for services in relation to preparing the manuscript, which was funded by Paratek.
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FUNDING
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JMI Laboratories contracted to perform services in 2016 for Achaogen, Actelion, Allecra Therapeutics,
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Allergan, AmpliPhi Biosciences, API, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer AG, BD, Biomodels, Cardeas Pharma Corp., CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc.,
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CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Debiopharm Group, Dipexium Pharmaceuticals, Inc., Duke, Entasis Therapeutics, Inc., Fortress Biotech, Fox Chase Chemical Diversity Center, Inc.,
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Geom Therapeutics, Inc., GSK, Laboratory Specialists, Inc., Medpace, Melinta Therapeutics, Inc., Merck & Co., Micromyx, MicuRx Pharmaceuticals, Inc., Motif Bio, N8 Medical, Inc., Nabriva Therapeutics, Inc.,
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Nexcida Therapeutics, Inc., Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synlogic, TenNor Therapeutics, TGV Therapeutics,
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The Medicines Company, Theravance Biopharma, ThermoFisher Scientific, VenatoRx Pharmaceuticals,
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Inc., Wockhardt, Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.
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Draper, MP, Weir, S, Macone, A, Donatelli, J, Trieber, CA, Tanaka, SK, & Levy, SB (2014) Mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob Agents Chemother,
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Flamm, RK, Rhomberg, PR, Huband, MD, & Farrell, DJ (2016) In vitro activity of delafloxacin tested
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Noel, GJ, Draper, MP, Hait, H, Tanaka, SK, & Arbeit, RD (2012) A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of linezolid for treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother, 56: 5650-5654. Perez, F, & Villegas, MV (2015) The role of surveillance systems in confronting the global crisis of antibiotic-resistant bacteria. Curr Opin Infect Dis, 28: 375-383. Remy, JM, Tow-Keogh, CA, McConnell, TS, Dalton, JM, & Devito, JA (2012) Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: resistance selection and characterization. J Antimicrob Chemother, 67: 2814-2820.
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Noreddin, A, Low, DE, Karlowsky, JA, Group, N, & Hoban, DJ (2006) Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract
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ACCEPTED MANUSCRIPT Table 1. Cumulative frequency distribution of omadacycline MIC results for urinary tract isolates from Europe (EU) and North America (NA) MIC in µg/mL (cumulative %): Year
No. of Isolates
≤0.12
0.25
0.5
1
2
4
≥8
NA + EU
2014
301
--
2 (0.7)
66 (22.6)
78 (48.5)
67 (70.8)
28 (80.1)
60 (100.0)a
NA + EU
2010
826
--
49 (5.9)
279 (39.7)
199 (63.8)
170 (84.4)
47 (90.1)
82 (100.0)b
NA
2014
150
--
--
39 (26.0)
33 (48.0)
35 (71.3)
8 (76.7)
NA
2010
377
--
27 (7.2)
124 (40.1)
103 (67.4)
69 (85.7)
17 (90.2)
EU
2014
151
--
2 (1.3)
27 (19.2)
45 (49.0)
32 (70.2)
EU
2010
449
--
22 (4.9)
155 (39.4)
96 (60.8)
Organism Enterobacteriaceae
MIC50
T P
Escherichia coli NA+EU
2014
138
NA+EU
2010
543
NA
2014
59
NA
2010
224
EU
2014
EU
2010
--
E C
2 (1.4)
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D E
MIC90
T IP 2
≥8
R C
1
4
35 (100.0)
2
≥8
37 (100.0)
1
4
20 (83.4)
25 (100.0)
2
≥8
101 (83.3)
30 (90.0)
45 (100.0)
1
≥8
S U
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58 (43.5)
49 (79.0)
20 (93.5)
8 (99.3)
1 (100.0)
1
2
--
49 (9.0)
273 (59.3)
134 (84.0)
70 (96.9)
15 (99.6)
2 (100.0)
0.5
2
--
--
33 (55.9)
16 (83.1)
9 (98.3)
1 (100.0)
--
0.5
2
--
27 (12.1)
122 (66.5)
56 (91.5)
16 (98.7)
3 (100.0)
--
0.5
1
79
--
2 (2.5)
25 (34.2)
33 (75.9)
11 (89.9)
7 (98.7)
1 (100.0)
1
4
319
--
22 (6.9)
151 (54.2)
78 (78.7)
54 (95.6)
12 (99.4)
2 (100.0)
0.5
2
ACCEPTED MANUSCRIPT Escherichia coli ESBL SP phenotype NA+EU
2014
24
--
--
6 (25.0)
8 (58.3)
6 (83.3)
3 (95.8)
1 (100.0)
1
4
NA+EU
2010
48
--
--
15 (31.2)
10 (52.1)
18 (89.6)
5 (100.0)
--
1
4
NA
2014
8
--
--
2 (25.0)
4 (75.0)
1 (87.5)
1 (100.0)
--
1
--
NA
2010
19
--
--
3 (15.8)
6 (47.4)
8 (89.5)
2 (100.0)
--
EU
2014
16
--
--
4 (25.0)
4 (50.0)
5 (81.2)
2 (93.8)
1 (100.0)
EU
2010
29
--
--
12 (41.4)
4 (55.2)
10 (89.7)
3 (100.0)
Klebsiella spp. NA+EU
2014
60
--
--
1 (1.7)
22 (38.3)
NA+EU
2010
155
--
--
5 (3.2)
53 (37.4)
NA
2014
31
--
--
1 (3.2)
NA
2010
103
--
--
EU
2014
29
--
EU
2010
52
--
NA+EU
2014
16
--
NA+EU
2010
23
NA
2014
2
Klebsiella spp. ESBL SP phenotype
R C --
S U
N A M
T IP 2
4
1
4
1
4
23 (76.7)
9 (91.7)
5 (100.0)
2
4
67 (80.6)
14 (89.7)
16 (100.0)
2
≥8
13 (90.3)
1 (93.5)
2 (100.0)
2
2
44 (43.7)
38 (80.6)
12 (92.2)
8 (100.0)
2
4
--
8 (27.6)
10 (62.1)
8 (89.7)
3 (100.0)
2
≥8
4 (7.7)
9 (25.0)
29 (80.8)
2 (84.6)
8 (100.0)
2
≥8
--
--
2 (12.5)
5 (43.8)
5 (75.0)
4 (100.0)
4
≥8
--
--
1 (4.3)
1 (8.7)
10 (52.2)
5 (73.9)
6 (100.0)
2
≥8
--
--
--
--
1 (50.0)
0 (50.0)
1 (100.0)
2
--
AC
E C
T P
---
D E
1 (1.0)
14 (48.4)
ACCEPTED MANUSCRIPT NA
2010
7
--
--
--
--
2 (28.6)
4 (85.7)
1 (100.0)
4
--
EU
2014
14
--
--
--
2 (14.3)
4 (42.9)
5 (78.6)
3 (100.0)
4
≥8
EU
2010
16
--
--
1 (6.2)
1 (12.5)
8 (62.5)
1 (68.8)
5 (100.0)
2
≥8
a 51/60 b
isolates were either Proteus, Morganella, or Providencia spp.
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56/82 isolates were either Proteus, Morganella, or Providencia spp.
R C
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D E
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AC
E C
N A M
ACCEPTED MANUSCRIPT Table 2 Activity of Omadacycline and comparator antimicrobial agents when tested against North America and Europe isolates Organism group (no. tested) antimicrobial agent Enterobacteriaceaeb (467 NA/539 EU) Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole Escherichia coli (283 NA/398 EU) Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole Escherichia coli ESBL SP phenotype (27 NA/45 EU) Omadacycline
NAa %S
100.0 79.0 77.1 90.6 78.2 83.5 92.9 91.9 93.1 99.8 74.9
%R
100.0 77.4 75.6 90.8 82.3 77.0 91.5 91.9 92.9 100.0 68.9
0.0c 15.8 21.0 9.2 d
15.7 6.9 7.5 6.0 0.2 25.1
0.0c
MIC50/90
MIC Range
1/2 0.12 / 0.25 1 / >8 1 / >8 <=0.06 / 1 4 / >8 <=0.5 / >4 <=1 / 2 <=0.12 / 1 0.12 / 1 <=0.12 / 0.25 <=0.5 / >4
0.25 — >4 ≤0.015 — 2 0.25 — >8 0.5 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — 4 ≤0.5 — >4
T P
AC
d
23.0 8.1 7.1 5.7 0.0 31.1
99.8 68.3 65.1 82.4 69.4 77.1 87.9 84.8 88.1 98.9 70.1
%R
0.0c 21.3 33.8 16.9 d
0.25 — 4 0.06 — 0.5 0.25 — >8 0.5 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — 32 ≤0.12 — 0.5 ≤0.5 — >4
1/4
0.5 — 4
100.0 68.3 64.3 89.2 79.6 75.6 91.5 91.5 93.5 100.0 69.5
MIC50/90
MIC range
1/4 0.12 / 0.5 2 / >8 2 / >8 <=0.06 / >8 8 / >8 <=0.5 / >4 <=1 / >8 <=0.12 / 16 0.12 / 8 <=0.12 / 0.5 <=0.5 / >4
0.25 — >4 ≤0.03 — 4 ≤0.06 — >8 ≤0.25 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — >8 ≤0.5 — >4
20.4 11.3 12.2 9.1 0.6 29.9
0.0c 21.1 35.2 10.3 d
22.7 7.5 6.8 4.8 0.0 30.5
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R C
S U
N A M
0.5 / 2 0.12 / 0.25 1 / >8 1 / >8 <=0.06 / 0.25 8 / >8 <=0.5 / >4 <=1 / 2 <=0.12 / 0.5 0.12 / 0.5 <=0.12 / <=0.12 <=0.5 / >4
E C 17.7 24.0 9.2
D E
EUa %S
0.5 / 2 0.12 / 0.25 1 / >8 2 / >8 <=0.06 / 4 4 / >8 <=0.5 / >4 <=1 / 2 <=0.12 / 4 0.12 / 2 <=0.12 / <=0.12 <=0.5 / >4
0.25 — >4 ≤0.03 — 1 ≤0.06 — >8 ≤0.25 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — 1 ≤0.5 — >4
1/4
0.5 — >4
ACCEPTED MANUSCRIPT Organism group (no. tested) antimicrobial agent Tigecycline Doxycycline Tetracycline Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole Klebsiella spp. (134 NA/81 EU) Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole Klebsiella spp. ESBL SP phenotype (9 NA/30 EU) Omadacycline Tigecycline Doxycycline Tetracycline
NAa %S 100.0 40.7 33.3 3.7 44.4 25.9 81.5 14.8 25.9 100.0 37.0
100.0 82.1 82.1 94.0 93.3 94.0 95.5 94.8 96.3 99.3 85.8
100.0 33.3 33.3
MIC Range
0.12 / 0.25 8 / >8 >8 / >8 >8 / >8 >8 / >8 >4 / >4 <=1 / >8 >16 / >16 16 / 32 <=0.12 / <=0.12 >4 / >4
0.06 — 0.25 1 — >8 1 — >8 0.25 — >8 4 — >8 ≤0.5 — >4 ≤1 — >8 0.5 — >16 0.12 — 32 ≤0.12 — 0.25 ≤0.5 — >4 0.5 — >4 ≤0.015 — 2 0.25 — >8 0.5 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — 4 ≤0.5 — >4
98.8 65.4 69.1 64.2 60.5 75.3 74.1 65.4 70.4 96.3 63.0
0.0c
4.5 4.5 5.2 3.7 0.7 14.2
2/4 0.25 / 0.5 2 / >8 1 / >8 <=0.06 / 0.12 2/8 <=0.5 / <=0.5 <=1 / <=1 <=0.12 / 0.25 0.12 / 0.5 <=0.12 / 0.25 <=0.5 / >4
0.0c 44.4 55.6
4 0.25 8 >8
2 — >4 0.25 — 2 2 — >8 1 — >8
100.0 46.7 50.0
%R 0.0c 33.3 63.0 96.3 d
74.1 18.5 74.1 59.3 0.0 63.0
0.0c 12.7 14.2 6.0 d
D E
T P
E C
AC
EUa %S 100.0 44.4 33.3 4.4 33.3 33.3 75.6 24.4 42.2 100.0 51.1
MIC50/90
%R 0.0c 33.3 64.4 91.1 d
62.2 20.0 60.0 42.2 0.0 48.9
MIC50/90
MIC range
0.12 / 0.25 8 / >8 >8 / >8 >8 / >8 >8 / >8 >4 / >4 <=1 / >8 16 / >16 8 / 32 <=0.12 / 0.25 <=0.5 / >4
0.06 — 0.5 1 — >8 1 — >8 0.5 — >8 4 — >8 ≤0.5 — >4 ≤1 — >8 1 — >16 0.25 — >32 ≤0.12 — 0.5 ≤0.5 — >4
R C
S U
N A M
T IP
19.8 25.9 30.9 22.2 3.7 37.0
2 / >4 0.25 / 0.5 2 / >8 2 / >8 0.12 / >8 4 / >8 <=0.5 / >4 <=1 / >8 <=0.12 / >16 0.25 / >32 <=0.12 / 0.5 <=0.5 / >4
0.5 — >4 0.06 — 4 0.5 — >8 0.5 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — >8 ≤0.5 — >4
0.0c 46.7 46.7
2 / >4 0.25 / 1 8 / >8 4 / >8
0.5 — >4 0.12 — 2 0.5 — >8 0.5 — >8
28.4 29.6 35.8 d
ACCEPTED MANUSCRIPT Organism group (no. tested) antimicrobial agent Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole
NAa %S 11.1 33.3 44.4 44.4 22.2 44.4 88.9 22.2
%R 88.9 d
44.4 55.6 77.8 55.6 11.1 77.8
MIC50/90
MIC Range
>8 >8 4 >8 >16 32 <=0.12 >4
1 — >8 4 — >8 ≤0.5 — >4 ≤1 — >8 2 — >16 1 — >32 ≤0.12 — 4 ≤0.5 — >4
Criteria as published by CLSI [2016] minus Proteus, Providencia and Morganella spp. c Breakpoints from FDA Package Insert revised 12/2014 d Dilution range did not extend high enough to determine between I and R so only susceptible percentage is displayed
EUa %S 3.3 6.7 40.0 30.0 6.7 20.0 90.0 16.7
%R 96.7 d
50.0 70.0 83.3 60.0 10.0 83.3
D E
T P
AC
E C
MIC range
>8 / >8 >8 / >8 4 / >4 >8 / >8 >16 / >16 16 / >32 <=0.12 / 1 >4 / >4
0.5 — >8 8 — >8 ≤0.5 — >4 ≤1 — >8 0.5 — >16 0.25 — >32 ≤0.12 — >8 ≤0.5 — >4
N A M
T IP
R C
S U
a
b Enterobacteriaceae
MIC50/90
ACCEPTED MANUSCRIPT Highlights •
Omadacycline is a novel aminomethylcycline agent with activity against gram-negative pathogens
•
Omadacycline was highly active (MIC ≤4 µg/ml) against ESBL screen-positive isolates of E. coli
•
Omadacycline was active against UTI-causing Enterobacteriaceae isolates from both Europe and North America
•
Activity was unchanged between 2010 to 2014.
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D E
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N A M
M.A. Pfaller, P.R. Rhomberg, M.D. Huband, R.K. Flamm PII: DOI: Reference:
S0732-8893(18)30036-1 doi:10.1016/j.diagmicrobio.2018.01.019 DMB 14523
To appear in: Received date: Revised date: Accepted date:
15 August 2017 22 January 2018 24 January 2018
Please cite this article as: M.A. Pfaller, P.R. Rhomberg, M.D. Huband, R.K. Flamm , Activity of Omadacycline Tested against Enterobacteriaceae Causing Urinary Tract Infections from a Global Surveillance Program (2014). The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Dmb(2018), doi:10.1016/j.diagmicrobio.2018.01.019
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ACCEPTED MANUSCRIPT Activity of Omadacycline Tested against Enterobacteriaceae Causing Urinary Tract Infections from a Global Surveillance Program (2014)
a,b*
M.D. Huband
a
a
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R.K. Flamm
a
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P.R. Rhomberg
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M.A. Pfaller
a
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JMI Laboratories, North Liberty, Iowa, USA b
ED
M
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University of Iowa, Iowa City, Iowa, USA
Michael A. Pfaller, M.D.
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Contact Information:
JMI Laboratories
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345 Beaver Kreek Ctr, Ste A North Liberty, Iowa, 52317, USA
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Phone: 319-665-3370 Fax: 319-665-3371 [email protected]
ACCEPTED MANUSCRIPT Abstract Omadacycline is an aminomethylcycline with in vitro activity against many gram-negative pathogens. Omadacycline and comparators were tested against Enterobacteriaceae from urinary tract infections (UTI) selected from a 2014 global surveillance program and compared to results of isolates from 2010 surveillance. The omadacycline MIC50/90 for Enterobacteriaceae collected during 2014 was 2/≥8 µg/mL
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(1/4 µg/mL minus Proteus, Providencia, and Morganella spp.). The MIC50/90 for E. coli was 1/2 µg/mL,
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similar to that in 2010 (MIC50/90, 0.5/2 µg/mL). The MICs for 91.7% of Klebsiella spp. isolates in 2014
CR
(89.7%, 2010) were ≤4 µg/mL. In 2010 and 2014, a total of 100.0% and 95.8% of ESBL screen-positive (SP) phenotype E. coli and 73.9% and 75.0% of ESBL SP Klebsiella spp., respectively, exhibited MIC
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values at ≤4 µg/mL. Omadacycline was active against UTI-causing Enterobacteriaceae isolates from NA
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and EU. Further study of omadacycline to treat UTI caused by Enterobacteriaceae may be indicated.
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CE
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ED
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Key words: urinary tract infections; omadacycline; Enterobacteriaceae
ACCEPTED MANUSCRIPT 1
Introduction
Urinary tract infections (UTI) commonly occur in the community and health care settings (Gupta, et al., 2011; Hooton, et al., 2010; Kobayashi, et al., 2016; Magill, et al., 2014). UTI is a leading diagnosis that results in antibiotics prescribed for women seeking ambulatory care and is the fourth most common health care-associated infection (HAI) (Gupta, et al., 2011; Hooton, et al., 2010; Magill, et al., 2014). The
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vast majority of these infections are treated empirically with antibiotics, resulting in intense selection
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pressure for developing antibacterial resistance (Kobayashi, et al., 2016). In the hospital and long term
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care settings, catheter-associated bacteriuria comprises a large reservoir of antibiotic-resistant organisms that contributes to the problem of cross-infection and frequently triggers inappropriate antibiotic use
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(Hooton, et al., 2010). Studies have demonstrated considerable geographic variation in resistance rates among gram-negative bacteria (GNB) causing UTIs (Kahlmeter & Eco.Sens, 2003; Sanchez, et al., 2012;
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Zhanel, et al., 2006).
Although trimethoprim-sulfamethoxazole and nitrofurantoin are recommended for empiric treatment of
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uncomplicated cystitis (Gupta, et al., 2011), the fluoroquinolones are the most frequently prescribed
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agents for treating UTIs in the United States (U.S.) (Kobayashi, et al., 2016). This extensive use of fluoroquinolones is associated with an increase in fluoroquinolone-resistant uropathogens, including
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fluoroquinolone-resistant Escherichia coli (Sanchez, et al., 2012). In addition, resistance rates of >20% in the U.S. and Europe (EU) to ampicillin and trimethoprim-sulfamethoxazole have been reported for GNB
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uropathogens (Kahlmeter & Eco.Sens, 2003; Sanchez, et al., 2012; Zhanel, et al., 2006). The microbial spectrum of uncomplicated cystitis and pyelonephritis consists mainly (75-95%) of E. coli
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with occasional species of other Enterobacteriaceae such as Klebsiella pneumoniae and Proteus mirabilis (Gupta, et al., 2011; Kobayashi, et al., 2016). Other GNB (eg, Pseudomonas aeruginosa) and grampositive cocci (GPC; methicillin-resistant Staphylococcus aureus [MRSA] and enterococci) are common in more complicated catheter-associated infections, but are rarely isolated in uncomplicated UTIs (Gupta, et al., 2011; Hooton, et al., 2010). Due to varying resistance profiles of E. coli strains causing UTIs, a specific recommendation for empiric therapy may not always be suitable for all regions. Thus, an understanding of local antimicrobial resistance patterns of E. coli and other uropathogens must be considered in empirical antibiotic selection (Gupta, et al., 2011; Kobayashi, et al., 2016).
ACCEPTED MANUSCRIPT Given a trend among uropathogens toward increasing resistance for most antibiotics (Kahlmeter & Eco.Sens, 2003; Sanchez, et al., 2012), prospective resistance surveillance at the regional, local, or health care system level is critical for optimal empiric antibacterial selection. Most agents used for UTI empirical treatment lack established resistance thresholds, above which an antimicrobial agent should not be considered for empiric therapy. Two exceptions, however, are the fluoroquinolones and trimethoprim-
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sulfamethoxazole, for which 10% and 20% resistance have been considered as thresholds for treatment
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of pyelonephritis and cystitis, respectively (Gupta, et al., 2011). These findings underscore the continued
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importance of antibiotic resistance surveillance and the need to assess the potential impact of newly introduced and novel antibacterial agents targeting specific resistance phenotypes (Perez & Villegas,
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2015; van Duin & Bonomo, 2016).
Omadacycline is a semisynthetic derivative of minocycline and the first member of the novel class of
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aminomethylcyclines (Draper, et al., 2014; Honeyman, et al., 2015; Macone, et al., 2014). Similar to the older tetracyclines (doxycycline, minocycline, and tetracycline), omadacycline binds to the 30S ribosomal
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subunit of target GPC and GNB that results in protein synthesis inhibition (Draper, et al., 2014;
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Honeyman, et al., 2015; Roberts, 2003). Notably, omadacycline remains active in bacterial strains expressing ribosomal protection or efflux tetracycline-resistance genes (Honeyman, et al., 2015; Macone,
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et al., 2014; Villano, et al., 2016). Omadacycline also maintains its activity against difficult-to-treat pathogens such as MRSA, vancomycin-resistant enterococci (VRE), and Enterobacteriaceae strains that
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produce a wide array of extended-spectrum β-lactamases (ESBLs) and carbapenemases (CRE) in addition to multidrug-resistant (MDR; resistant to ≥3 classes of agents) strains of Acinetobacter spp. and
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Stenotrophomonas maltophilia (Villano, et al., 2016). Omadacycline has been shown to be non-inferior to linezolid in a Phase 2 study of the treatment of acute bacterial skin and skin structure infections (ABSSI) (Noel, et al., 2012). Phase 3 studies for treatment of ABSSI and community-acquired bacterial pneumonia (CABP) are ongoing (Villano, et al., 2016). A Phase 1B study in uncomplicated urinary tract infections (UTIs) reported positive top-line pharmacokinetic proof-of-principle data in November 2016 (Paratek Pharmaceuticals, data on file). In the present study, we evaluated the in vitro activity of omadacycline and comparator agents tested by Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution methods against
ACCEPTED MANUSCRIPT Enterobacteriaceae isolates causing UTIs in North America (NA) and EU in the 2014 SENTRY Surveillance Program compared to data collected in the 2010 SENTRY Surveillance Program. Evaluations of E. coli and K. pneumoniae resistant subsets are included in the analysis.
Materials and Methods
2.1
Organism collection
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2
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A total of 151 Enterobacteriaceae that were identified as urinary tract isolates from patients in medical
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centers in EU and 150 from NA (2014 global surveillance; n=301) were selected for susceptibility testing. These organisms were chosen to represent approximate percentages of Enterobacteriaceae species in
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the complete collection of UTI (2014). Organisms (number) included Citrobacter amalonaticus (1), C. freundii (11), C. koseri (8), Enterobacter aerogenes (7), E. cloacae (16), Escherichia coli (138), Klebsiella
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oxytoca (8), K. pneumoniae (52), Morganella morganii (14), Proteus mirabilis (22), P. vulgaris (7), Providencia rettgeri (6), P. stuartii (5), and Serratia marcescens (6).
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Susceptibility results for 2014 isolates were compared to the results of 826 UTI isolates of
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Enterobacteriaceae from EU and NA medical centers in 2010. The 2010 organism collection contained Citrobacter freundii (5), C. koseri (3), Enterobacter aerogenes (12), E. asburiae (1), E. cloacae (23),
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unspeciated Enterobacter (1), Escherichia coli (543), Klebsiella oxytoca (32), K. pneumoniae (123), Morganella morganii (8), Proteus mirabilis (50), P. vulgaris (3), Providencia rettgeri (1), P. stuartii (1),
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unspeciated Providencia (4), unspeciated Salmonella (1), and Serratia marcescens (15). Among the 1,127 isolates tested from 2010 and 2014, 253 (22.4%) were from inpatients, 789 (70.0%) were from
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outpatients, and 85 (7.6%) were not designated as inpatient or outpatient in origin. All isolates were identified to the species level at each participating medical center and confirmed by the monitoring laboratory (JMI Laboratories, North Liberty, Iowa, USA) using the VITEK 2 System (bioMérieux, Hazelwood, Missouri, USA) or matrix-assisted laser desorption ionization-time of flight mass spectrometry (Bruker, Billerica, Massachusetts, USA), when necessary. 2.2
Susceptibility testing
Omadacycline and comparators was tested in dry-form panels in 2010 (omadacycline range, 0.015-32 µg/mL). and panels with fresh frozen medium made at JMI Laboratories (North Liberty, Iowa, USA) for
ACCEPTED MANUSCRIPT testing 2014 isolates (omadacycline range, 0.008-8 µg/mL). Comparator agents were selected to represent agents that may be used to treat both uncomplicated and complicated UTI (Gupta et al, 2011; Hooton et al, 2010). Upon receipt of the panels at the monitoring laboratory (JMI Laboratories) each batch of panels was tested against the appropriate CLSI quality control (QC) organisms in triplicate, and all MIC values were within the established testing range (CLSI, 2015, 2016). In the validation process for
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the dry-form panels, we have performed studies that show that the essential agreement (+/- 1 dil) with
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reference panels (frozen/fresh) was 99.7% (data not shown). E. coli and K. pneumoniae were grouped as
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“ESBL SP phenotype” based on the CLSI screening criteria for potential ESBL production—ie, ceftazidime, ceftriaxone, and/or aztreonam MIC values of ≥2 µg/mL (CLSI, 2016). Concurrent QC testing
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was also performed to assure proper test conditions and procedures and all values were within published ranges (CLSI, 2015, 2016). The QC strains tested were Escherichia coli ATCC 25922 and Pseudomonas
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aeruginosa ATCC 27853 (CLSI, 2016). CLSI (CLSI, 2015, 2016) interpretive criteria were used.
Results
3.1
Activity of omadacycline against Enterobacteriaceae
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MIC distributions for all Enterobacteriaceae combined data from EU and NA medical centers are shown in
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Table 1. ESBL SP phenotype strains of E. coli and Klebsiella spp. accounted for 17.4% and 26.7% of isolates, respectively, in the 2014 collection compared to 8.8% and 14.8%, respectively, in the 2010
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collection (Table 1). The MIC50/90 values for all Enterobacteriaceae and for ESBL SP phenotype E. coli in 2010 were 1/4 µg/mL (Table 1). Overall, the omadacycline MIC values for the 2010 isolates were ≤4
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µg/mL for 99.6% of E. coli and 89.7% of Klebsiella spp. ESBL SP phenotype strains of Klebsiella spp. from 2010 were less susceptible to omadacycline (MIC50/90, 2/≥8 µg/mL) than ESBL SP phenotype E. coli (MIC50/90, 1/4 µg/mL). For the 2014 isolates, the omadacycline MIC50/90 values were 2/≥8 µg/mL overall for Enterobacteriaceae and were 1/4 µg/mL for ESBL SP phenotype E. coli and 4/≥8 µg/mL for Klebsiella spp. (Table 1). The majority of Enterobacteriaceae isolates for which MIC values were ≥8 µg/mL in 2010 (56/82, 68.3%) and 2014 (51/60, 85.0% were either Proteus, Providencia or Morganella spp., all of which are intrinsically resistant to tetracyclines and tend to have higher MIC values for omadacycline than either
ACCEPTED MANUSCRIPT E. coli or Klebsiella spp. (Villano, et al., 2016). The MIC50/90 values for Enterobacteriaceae minus Proteus, Providencia, and Morganella spp. were 1/2 µg/mL in 2010 and 1/4 µg/mL in 2014 (data not shown). In 2014, the frequency of ESBL SP phenotype strains of E. coli and Klebsiella spp. was higher among EU isolates (20.3% and 48.3%, respectively) than NA isolates (13.6% and 6.5%, respectively) (Table 1). Omadacycline MIC90 values tended to be higher for EU isolates of E. coli and Klebsiella spp. than for NA
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isolates (eg, in 2014, 1/2 µg/mL [NA/EU], and 4/≥8 µg/mL, respectively) (Table 1). Among the 5 isolates
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of Klebsiella spp. in 2014 (all K. pneumoniae; 2 from NA and 3 from EU [all from different medical
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centers]) for which MIC values were > 4 µg/mL, 4 exhibited an ESBL SP phenotype and an ESBL (3 CTX-M group 1) or MBL (1 VIM)) genotype; all 5 were resistant to tetracycline and doxycycline (data not
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shown). ESBL SP phenotype strains of E. coli from EU and NA (2014) showed comparable susceptibility with 93.8% and 100.0%, respectively, inhibited by ≤4 µg/mL of omadacycline (Table 1). Omadacycline
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was considerably less active against EU and NA strains of ESBL SP phenotype Klebsiella spp. (collected in 2014) with 78.6% and 50.0%, respectively, inhibited by ≤4 µg/mL. Susceptibility of EU and NA Enterobacteriaceae isolates to comparator agents
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3.2
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All Enterobacteriaceae isolates (minus Proteus, Providencia and Morganella spp.) from NA and EU demonstrated high susceptibility for tigecycline (100.0/99.8% [NA/EU]), aztreonam (91.9/84.8%
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[NA/EU]), ceftazidime (93.1/88.1% [NA/EU]), ceftriaxone (90.6/82.4% [NA/EU]), gentamicin (92.9/87.9% [NA/EU]), and imipenem (99.8/98.9% [NA/EU]) (Table 2). All comparator agents were slightly more
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active against Enterobacteriaceae isolates from NA versus those from EU, although the activity of most of these agents was suboptimal in both regions (Table 2). Resistance to doxycycline, tetracycline,
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levofloxacin, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole all exceeded 15%, suggesting that these agents may not be reliable for use as empiric therapy (Table 2). All E. coli isolates from both regions were susceptible to tigecycline and imipenem (Table 2). The least active agents from both regions were doxycycline, tetracycline, levofloxacin, and trimethoprimsulfamethoxazole. Among the ESBL SP phenotype isolates of E. coli only tigecycline, imipenem and gentamicin were active against more than 50% of isolates. Although Klebsiella spp. isolates from NA and EU were highly susceptible to tigecycline (100.0/98.8% susceptible [NA/EU]) and imipenem (99.3/96.3% susceptible [NA/EU]), the EU isolates were considerably
ACCEPTED MANUSCRIPT less susceptible to all other comparators than the NA isolates (Table 2). Specifically, less than 70% of EU isolates of Klebsiella spp. were susceptible to doxycycline, tetracycline, amoxicillin-clavulanate, aztreonam, ceftriaxone, and trimethoprim-sulfamethoxazole, whereas all were active against more than 80% of NA isolates. Only tigecycline (100.0/100.0% susceptible [NA/EU]) and imipenem (88.9/90.0% susceptible [NA/EU]) were active against ESBL SP phenotype isolates of Klebsiella spp. None of the
Conclusions
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4
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comparator agents tested were active against more than 50% of isolates from either region (Table 2).
In the present survey, we examined the in vitro susceptibility profiles of 1,127 UTI isolates of
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Enterobacteriaceae from EU and NA medical centers for the years 2010 and 2014. Overall, we found higher rates of ESBL SP phenotype E. coli and Klebsiella spp. among EU isolates versus those from NA
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(Table 1). Enterobacteriaceae isolates from EU were less susceptible to omadacycline and all comparators than the NA isolates.
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Data from the present survey document the in vitro activity of omadacycline against GNB uropathogens
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from a global survey. Overall, the broadest coverage of tested pathogens was observed with imipenem and tigecycline (Table 2). Omadacycline was active against ESBL SP phenotype strains of E. coli but was
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less active against ESBL SP phenotype Klebsiella spp. Tigecycline and imipenem were the most active agents against Enterobacteriaceae, including ESBL SP phenotype strains.
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These data build on those reported by previous investigators (Almer, et al., 2004; Flamm, et al., 2016; Harnett, et al., 2004; Nilius, et al., 2003; Remy, et al., 2012) and indicate that omadacycline merits further
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study in treating cUTI in which mixed GPC and GNB infections may occur and pathogens resistant to older antimicrobials are common.
ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS This study at JMI Laboratories was supported by Paratek Pharmaceuticals (King of Prussia, Pennsylvania), and JMI Laboratories received compensation fees for services in relation to preparing the manuscript, which was funded by Paratek.
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FUNDING
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JMI Laboratories contracted to perform services in 2016 for Achaogen, Actelion, Allecra Therapeutics,
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Allergan, AmpliPhi Biosciences, API, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer AG, BD, Biomodels, Cardeas Pharma Corp., CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc.,
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CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Debiopharm Group, Dipexium Pharmaceuticals, Inc., Duke, Entasis Therapeutics, Inc., Fortress Biotech, Fox Chase Chemical Diversity Center, Inc.,
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Geom Therapeutics, Inc., GSK, Laboratory Specialists, Inc., Medpace, Melinta Therapeutics, Inc., Merck & Co., Micromyx, MicuRx Pharmaceuticals, Inc., Motif Bio, N8 Medical, Inc., Nabriva Therapeutics, Inc.,
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Nexcida Therapeutics, Inc., Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synlogic, TenNor Therapeutics, TGV Therapeutics,
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The Medicines Company, Theravance Biopharma, ThermoFisher Scientific, VenatoRx Pharmaceuticals,
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Inc., Wockhardt, Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.
ACCEPTED MANUSCRIPT References Almer, LS, Hoffrage, JB, Keller, EL, Flamm, RK, & Shortridge, VD (2004) In vitro and bactericidal activities of ABT-492, a novel fluoroquinolone, against Gram-positive and Gram-negative organisms. Antimicrob Agents Chemother, 48: 2771-2777. CLSI. 2015. M07-A10. Methods for dilution antimicrobial susceptibility tests for bacteria that grow
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aerobically; approved standard- tenth edition. Clinical and Laboratory Standards Institute, Wayne, PA.
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CLSI. 2016. M100-S26. Performance standards for antimicrobial susceptibility testing: 26th informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA.
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Draper, MP, Weir, S, Macone, A, Donatelli, J, Trieber, CA, Tanaka, SK, & Levy, SB (2014) Mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob Agents Chemother,
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58: 1279-1283.
Flamm, RK, Rhomberg, PR, Huband, MD, & Farrell, DJ (2016) In vitro activity of delafloxacin tested
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against isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella
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catarrhalis. Antimicrob Agents Chemother, 60: 6381-6385. Gupta, K, Hooton, TM, Naber, KG, Wullt, B, Colgan, R, Miller, LG, Moran, GJ, Nicolle, LE, Raz, R,
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Schaeffer, AJ, & Soper, DE (2011) International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious
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Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis, 52: e103-e120.
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Harnett, SJ, Fraise, AP, Andrews, JM, Jevons, G, Brenwald, NP, & Wise, R (2004) Comparative study of the in vitro activity of a new fluoroquinolone, ABT-492. J Antimicrob Chemother, 53: 783-792. Honeyman, L, Ismail, M, Nelson, ML, Bhatia, B, Bowser, TE, Chen, J, Mechiche, R, Ohemeng, K, Verma, AK, Cannon, EP, Macone, A, Tanaka, SK, & Levy, S (2015) Structure-activity relationship of the aminomethylcyclines and the discovery of omadacycline. Antimicrob Agents Chemother, 59: 7044-7053. Hooton, TM, Bradley, SF, Cardenas, DD, Colgan, R, Geerlings, SE, Rice, JC, Saint, S, Schaeffer, AJ, Tambayh, PA, Tenke, P, Nicolle, LE, & Infectious Diseases Society of, A (2010) Diagnosis,
ACCEPTED MANUSCRIPT prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis, 50: 625-663. Kahlmeter, G, & Eco.Sens (2003) An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO.SENS Project. J Antimicrob Chemother, 51:
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69-76.
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Kobayashi, M, Shapiro, DJ, Hersh, AL, Sanchez, GV, & Hicks, LA (2016) Outpatient antibiotic prescribing
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practices for uncomplicated urinary tract infection in women in the United States, 2002-2011. Open Forum Infect Dis: in press
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Macone, AB, Caruso, BK, Leahy, RG, Donatelli, J, Weir, S, Draper, MP, Tanaka, SK, & Levy, SB (2014) In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline.
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Antimicrob Agents Chemother, 58: 1127-1135.
Magill, SS, Edwards, JR, Bamberg, W, Beldavs, ZG, Dumyati, G, Kainer, MA, Lynfield, R, Maloney, M,
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McAllister-Hollod, L, Nadle, J, Ray, SM, Thompson, DL, Wilson, LE, Fridkin, SK, Emerging
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Infections Program Healthcare-Associated, I, & Antimicrobial Use Prevalence Survey, T (2014) Multistate point-prevalence survey of health care-associated infections. N Engl J Med, 370: 1198-
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1208.
Nilius, AM, Shen, LL, Hensey-Rudloff, D, Almer, LS, Beyer, JM, Balli, DJ, Cai, Y, & Flamm, RK (2003) In
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vitro antibacterial potency and spectrum of ABT-492, a new fluoroquinolone. Antimicrob Agents Chemother, 47: 3260-3269.
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Noel, GJ, Draper, MP, Hait, H, Tanaka, SK, & Arbeit, RD (2012) A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of linezolid for treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother, 56: 5650-5654. Perez, F, & Villegas, MV (2015) The role of surveillance systems in confronting the global crisis of antibiotic-resistant bacteria. Curr Opin Infect Dis, 28: 375-383. Remy, JM, Tow-Keogh, CA, McConnell, TS, Dalton, JM, & Devito, JA (2012) Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: resistance selection and characterization. J Antimicrob Chemother, 67: 2814-2820.
ACCEPTED MANUSCRIPT Roberts, MC (2003) Tetracycline therapy: update. Clin Infect Dis, 36: 462-467. Sanchez, GV, Master, RN, Karlowsky, JA, & Bordon, JM (2012) In vitro antimicrobial resistance of urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010. Antimicrob Agents Chemother, 56: 2181-2183. van Duin, D, & Bonomo, RA (2016) Ceftazidime/avibactam and ceftolozane/tazobactam: Second-
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generation beta-lactam/beta-lactamase inhibitor combinations. Clin Infect Dis, 63: 234-241.
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Villano, S, Steenbergen, J, & Loh, E (2016) Omadacycline: development of a novel aminomethylcycline
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antibiotic for treating drug-resistant bacterial infections. Future Microbiol, 11: 1421-1434. Zhanel, GG, Hisanaga, TL, Laing, NM, DeCorby, MR, Nichol, KA, Weshnoweski, B, Johnson, J,
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Noreddin, A, Low, DE, Karlowsky, JA, Group, N, & Hoban, DJ (2006) Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract
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Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents, 27: 468-475.
ACCEPTED MANUSCRIPT Table 1. Cumulative frequency distribution of omadacycline MIC results for urinary tract isolates from Europe (EU) and North America (NA) MIC in µg/mL (cumulative %): Year
No. of Isolates
≤0.12
0.25
0.5
1
2
4
≥8
NA + EU
2014
301
--
2 (0.7)
66 (22.6)
78 (48.5)
67 (70.8)
28 (80.1)
60 (100.0)a
NA + EU
2010
826
--
49 (5.9)
279 (39.7)
199 (63.8)
170 (84.4)
47 (90.1)
82 (100.0)b
NA
2014
150
--
--
39 (26.0)
33 (48.0)
35 (71.3)
8 (76.7)
NA
2010
377
--
27 (7.2)
124 (40.1)
103 (67.4)
69 (85.7)
17 (90.2)
EU
2014
151
--
2 (1.3)
27 (19.2)
45 (49.0)
32 (70.2)
EU
2010
449
--
22 (4.9)
155 (39.4)
96 (60.8)
Organism Enterobacteriaceae
MIC50
T P
Escherichia coli NA+EU
2014
138
NA+EU
2010
543
NA
2014
59
NA
2010
224
EU
2014
EU
2010
--
E C
2 (1.4)
AC
D E
MIC90
T IP 2
≥8
R C
1
4
35 (100.0)
2
≥8
37 (100.0)
1
4
20 (83.4)
25 (100.0)
2
≥8
101 (83.3)
30 (90.0)
45 (100.0)
1
≥8
S U
AN
M
58 (43.5)
49 (79.0)
20 (93.5)
8 (99.3)
1 (100.0)
1
2
--
49 (9.0)
273 (59.3)
134 (84.0)
70 (96.9)
15 (99.6)
2 (100.0)
0.5
2
--
--
33 (55.9)
16 (83.1)
9 (98.3)
1 (100.0)
--
0.5
2
--
27 (12.1)
122 (66.5)
56 (91.5)
16 (98.7)
3 (100.0)
--
0.5
1
79
--
2 (2.5)
25 (34.2)
33 (75.9)
11 (89.9)
7 (98.7)
1 (100.0)
1
4
319
--
22 (6.9)
151 (54.2)
78 (78.7)
54 (95.6)
12 (99.4)
2 (100.0)
0.5
2
ACCEPTED MANUSCRIPT Escherichia coli ESBL SP phenotype NA+EU
2014
24
--
--
6 (25.0)
8 (58.3)
6 (83.3)
3 (95.8)
1 (100.0)
1
4
NA+EU
2010
48
--
--
15 (31.2)
10 (52.1)
18 (89.6)
5 (100.0)
--
1
4
NA
2014
8
--
--
2 (25.0)
4 (75.0)
1 (87.5)
1 (100.0)
--
1
--
NA
2010
19
--
--
3 (15.8)
6 (47.4)
8 (89.5)
2 (100.0)
--
EU
2014
16
--
--
4 (25.0)
4 (50.0)
5 (81.2)
2 (93.8)
1 (100.0)
EU
2010
29
--
--
12 (41.4)
4 (55.2)
10 (89.7)
3 (100.0)
Klebsiella spp. NA+EU
2014
60
--
--
1 (1.7)
22 (38.3)
NA+EU
2010
155
--
--
5 (3.2)
53 (37.4)
NA
2014
31
--
--
1 (3.2)
NA
2010
103
--
--
EU
2014
29
--
EU
2010
52
--
NA+EU
2014
16
--
NA+EU
2010
23
NA
2014
2
Klebsiella spp. ESBL SP phenotype
R C --
S U
N A M
T IP 2
4
1
4
1
4
23 (76.7)
9 (91.7)
5 (100.0)
2
4
67 (80.6)
14 (89.7)
16 (100.0)
2
≥8
13 (90.3)
1 (93.5)
2 (100.0)
2
2
44 (43.7)
38 (80.6)
12 (92.2)
8 (100.0)
2
4
--
8 (27.6)
10 (62.1)
8 (89.7)
3 (100.0)
2
≥8
4 (7.7)
9 (25.0)
29 (80.8)
2 (84.6)
8 (100.0)
2
≥8
--
--
2 (12.5)
5 (43.8)
5 (75.0)
4 (100.0)
4
≥8
--
--
1 (4.3)
1 (8.7)
10 (52.2)
5 (73.9)
6 (100.0)
2
≥8
--
--
--
--
1 (50.0)
0 (50.0)
1 (100.0)
2
--
AC
E C
T P
---
D E
1 (1.0)
14 (48.4)
ACCEPTED MANUSCRIPT NA
2010
7
--
--
--
--
2 (28.6)
4 (85.7)
1 (100.0)
4
--
EU
2014
14
--
--
--
2 (14.3)
4 (42.9)
5 (78.6)
3 (100.0)
4
≥8
EU
2010
16
--
--
1 (6.2)
1 (12.5)
8 (62.5)
1 (68.8)
5 (100.0)
2
≥8
a 51/60 b
isolates were either Proteus, Morganella, or Providencia spp.
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56/82 isolates were either Proteus, Morganella, or Providencia spp.
R C
S U
D E
T P
AC
E C
N A M
ACCEPTED MANUSCRIPT Table 2 Activity of Omadacycline and comparator antimicrobial agents when tested against North America and Europe isolates Organism group (no. tested) antimicrobial agent Enterobacteriaceaeb (467 NA/539 EU) Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole Escherichia coli (283 NA/398 EU) Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole Escherichia coli ESBL SP phenotype (27 NA/45 EU) Omadacycline
NAa %S
100.0 79.0 77.1 90.6 78.2 83.5 92.9 91.9 93.1 99.8 74.9
%R
100.0 77.4 75.6 90.8 82.3 77.0 91.5 91.9 92.9 100.0 68.9
0.0c 15.8 21.0 9.2 d
15.7 6.9 7.5 6.0 0.2 25.1
0.0c
MIC50/90
MIC Range
1/2 0.12 / 0.25 1 / >8 1 / >8 <=0.06 / 1 4 / >8 <=0.5 / >4 <=1 / 2 <=0.12 / 1 0.12 / 1 <=0.12 / 0.25 <=0.5 / >4
0.25 — >4 ≤0.015 — 2 0.25 — >8 0.5 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — 4 ≤0.5 — >4
T P
AC
d
23.0 8.1 7.1 5.7 0.0 31.1
99.8 68.3 65.1 82.4 69.4 77.1 87.9 84.8 88.1 98.9 70.1
%R
0.0c 21.3 33.8 16.9 d
0.25 — 4 0.06 — 0.5 0.25 — >8 0.5 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — 32 ≤0.12 — 0.5 ≤0.5 — >4
1/4
0.5 — 4
100.0 68.3 64.3 89.2 79.6 75.6 91.5 91.5 93.5 100.0 69.5
MIC50/90
MIC range
1/4 0.12 / 0.5 2 / >8 2 / >8 <=0.06 / >8 8 / >8 <=0.5 / >4 <=1 / >8 <=0.12 / 16 0.12 / 8 <=0.12 / 0.5 <=0.5 / >4
0.25 — >4 ≤0.03 — 4 ≤0.06 — >8 ≤0.25 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — >8 ≤0.5 — >4
20.4 11.3 12.2 9.1 0.6 29.9
0.0c 21.1 35.2 10.3 d
22.7 7.5 6.8 4.8 0.0 30.5
T IP
R C
S U
N A M
0.5 / 2 0.12 / 0.25 1 / >8 1 / >8 <=0.06 / 0.25 8 / >8 <=0.5 / >4 <=1 / 2 <=0.12 / 0.5 0.12 / 0.5 <=0.12 / <=0.12 <=0.5 / >4
E C 17.7 24.0 9.2
D E
EUa %S
0.5 / 2 0.12 / 0.25 1 / >8 2 / >8 <=0.06 / 4 4 / >8 <=0.5 / >4 <=1 / 2 <=0.12 / 4 0.12 / 2 <=0.12 / <=0.12 <=0.5 / >4
0.25 — >4 ≤0.03 — 1 ≤0.06 — >8 ≤0.25 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — 1 ≤0.5 — >4
1/4
0.5 — >4
ACCEPTED MANUSCRIPT Organism group (no. tested) antimicrobial agent Tigecycline Doxycycline Tetracycline Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole Klebsiella spp. (134 NA/81 EU) Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole Klebsiella spp. ESBL SP phenotype (9 NA/30 EU) Omadacycline Tigecycline Doxycycline Tetracycline
NAa %S 100.0 40.7 33.3 3.7 44.4 25.9 81.5 14.8 25.9 100.0 37.0
100.0 82.1 82.1 94.0 93.3 94.0 95.5 94.8 96.3 99.3 85.8
100.0 33.3 33.3
MIC Range
0.12 / 0.25 8 / >8 >8 / >8 >8 / >8 >8 / >8 >4 / >4 <=1 / >8 >16 / >16 16 / 32 <=0.12 / <=0.12 >4 / >4
0.06 — 0.25 1 — >8 1 — >8 0.25 — >8 4 — >8 ≤0.5 — >4 ≤1 — >8 0.5 — >16 0.12 — 32 ≤0.12 — 0.25 ≤0.5 — >4 0.5 — >4 ≤0.015 — 2 0.25 — >8 0.5 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — 4 ≤0.5 — >4
98.8 65.4 69.1 64.2 60.5 75.3 74.1 65.4 70.4 96.3 63.0
0.0c
4.5 4.5 5.2 3.7 0.7 14.2
2/4 0.25 / 0.5 2 / >8 1 / >8 <=0.06 / 0.12 2/8 <=0.5 / <=0.5 <=1 / <=1 <=0.12 / 0.25 0.12 / 0.5 <=0.12 / 0.25 <=0.5 / >4
0.0c 44.4 55.6
4 0.25 8 >8
2 — >4 0.25 — 2 2 — >8 1 — >8
100.0 46.7 50.0
%R 0.0c 33.3 63.0 96.3 d
74.1 18.5 74.1 59.3 0.0 63.0
0.0c 12.7 14.2 6.0 d
D E
T P
E C
AC
EUa %S 100.0 44.4 33.3 4.4 33.3 33.3 75.6 24.4 42.2 100.0 51.1
MIC50/90
%R 0.0c 33.3 64.4 91.1 d
62.2 20.0 60.0 42.2 0.0 48.9
MIC50/90
MIC range
0.12 / 0.25 8 / >8 >8 / >8 >8 / >8 >8 / >8 >4 / >4 <=1 / >8 16 / >16 8 / 32 <=0.12 / 0.25 <=0.5 / >4
0.06 — 0.5 1 — >8 1 — >8 0.5 — >8 4 — >8 ≤0.5 — >4 ≤1 — >8 1 — >16 0.25 — >32 ≤0.12 — 0.5 ≤0.5 — >4
R C
S U
N A M
T IP
19.8 25.9 30.9 22.2 3.7 37.0
2 / >4 0.25 / 0.5 2 / >8 2 / >8 0.12 / >8 4 / >8 <=0.5 / >4 <=1 / >8 <=0.12 / >16 0.25 / >32 <=0.12 / 0.5 <=0.5 / >4
0.5 — >4 0.06 — 4 0.5 — >8 0.5 — >8 ≤0.06 — >8 ≤1 — >8 ≤0.5 — >4 ≤1 — >8 ≤0.12 — >16 0.03 — >32 ≤0.12 — >8 ≤0.5 — >4
0.0c 46.7 46.7
2 / >4 0.25 / 1 8 / >8 4 / >8
0.5 — >4 0.12 — 2 0.5 — >8 0.5 — >8
28.4 29.6 35.8 d
ACCEPTED MANUSCRIPT Organism group (no. tested) antimicrobial agent Ceftriaxone Amoxicillin-clavulanic acid Levofloxacin Gentamicin Aztreonam Ceftazidime Imipenem Trimethoprim-sulfamethoxazole
NAa %S 11.1 33.3 44.4 44.4 22.2 44.4 88.9 22.2
%R 88.9 d
44.4 55.6 77.8 55.6 11.1 77.8
MIC50/90
MIC Range
>8 >8 4 >8 >16 32 <=0.12 >4
1 — >8 4 — >8 ≤0.5 — >4 ≤1 — >8 2 — >16 1 — >32 ≤0.12 — 4 ≤0.5 — >4
Criteria as published by CLSI [2016] minus Proteus, Providencia and Morganella spp. c Breakpoints from FDA Package Insert revised 12/2014 d Dilution range did not extend high enough to determine between I and R so only susceptible percentage is displayed
EUa %S 3.3 6.7 40.0 30.0 6.7 20.0 90.0 16.7
%R 96.7 d
50.0 70.0 83.3 60.0 10.0 83.3
D E
T P
AC
E C
MIC range
>8 / >8 >8 / >8 4 / >4 >8 / >8 >16 / >16 16 / >32 <=0.12 / 1 >4 / >4
0.5 — >8 8 — >8 ≤0.5 — >4 ≤1 — >8 0.5 — >16 0.25 — >32 ≤0.12 — >8 ≤0.5 — >4
N A M
T IP
R C
S U
a
b Enterobacteriaceae
MIC50/90
ACCEPTED MANUSCRIPT Highlights •
Omadacycline is a novel aminomethylcycline agent with activity against gram-negative pathogens
•
Omadacycline was highly active (MIC ≤4 µg/ml) against ESBL screen-positive isolates of E. coli
•
Omadacycline was active against UTI-causing Enterobacteriaceae isolates from both Europe and North America
•
Activity was unchanged between 2010 to 2014.
T IP
R C
S U
D E
T P
AC
E C
N A M