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Activity of omadacycline tested against Streptococcus pneumoniae from a global surveillance program (2014)
Activity of Omadacycline Tested against Streptococcus pneumoniae from a Global Surveillance Program (2014) M.A. Pfaller, P.R. Rhomberg, M.D. Huband, R.K. Flamm PII: DOI: Reference:
S0732-8893(17)30321-8 doi: 10.1016/j.diagmicrobio.2017.10.010 DMB 14444
To appear in:
Diagnostic Microbiology and Infectious Disease
Received date: Revised date: Accepted date:
9 February 2017 15 September 2017 16 October 2017
Please cite this article as: Pfaller MA, Rhomberg PR, Huband MD, Flamm RK, Activity of Omadacycline Tested against Streptococcus pneumoniae from a Global Surveillance Program (2014), Diagnostic Microbiology and Infectious Disease (2017), doi: 10.1016/j.diagmicrobio.2017.10.010
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ACCEPTED MANUSCRIPT DMID-17-104R2 Activity of Omadacycline Tested against Streptococcus pneumoniae from a Global Surveillance Program (2014)
P.R. Rhomberg M.D. Huband
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R.K. Flamm
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a,b
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M.A. Pfaller
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JMI Laboratories, North Liberty, Iowa, USA b
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University of Iowa, Iowa City, Iowa, USA
Abstract word count:158
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Manuscript word count: 1,256
Michael A. Pfaller, MD
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Contact Information:
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Running title: Omadacycline and Streptococcus pneumoniae
JMI Laboratories
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345 Beaver Kreek Ctr, Ste A North Liberty, IA, 52317, USA Phone: 319-665-3370 Fax: 319-665-3371 [email protected]
Key words: multidrug-resistant pneumococci, aminomethylcycline, in vitro activity
ACCEPTED MANUSCRIPT Abstract The activity of omadacycline and comparators when tested against a subset of Streptococcus pneumoniae from US and European regions of a 2014 global surveillance program (304 isolates) are
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reported. These MIC results were compared to those obtained when testing S. pneumoniae from 2010 surveillance (1,834 isolates). The omadacycline MIC50/90 for S. pneumoniae (2014) was 0.06/0.06 µg/mL, similar to 2010 (MIC50/90, 0.06/0.12 µg/mL). The omadacycline MIC90 (0.06-0.12 µg/mL) was similar for the
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penicillin-susceptible, -intermediate, –resistant, multidrug-resistance (MDR; ≥3 classes), and ceftriaxone
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nonsusceptible subgroups. Omadacycline MIC90 values were 0.06-0.12 µg/mL for S. pneumoniae from the US and Europe. There was a high degree of resistance with doxycycline, erythromycin and
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trimethoprim-sulfamethoxazole in both US and EU. For penicillin-resistant S. pneumoniae, resistance to doxycycline and tetracycline in US/Europe was 64.2/61.0% and 63.8/60.5%, respectively, erythromycin 91.2/75.1, and ceftriaxone 7.3/4.0%. The potent activity of omadacycline against S. pneumoniae indicates
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that omadacycline merits further study in bacterial pneumonia, especially where MDR may be a concern.
ACCEPTED MANUSCRIPT 1 Introduction Community-acquired bacterial pneumonia (CABP) is a common and deadly infectious disease
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despite available potent antibiotics and effective vaccines (File & Marrie, 2010; Mendes, Biek, et al.,
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2014). Streptococcus pneumoniae is the most common pathogen implicated in CABP, and penicillinresistant (PR-SP), multidrug-resistant (MDR-SP) and ceftriaxone–nonsusceptible (CRO-NS SP; MIC, >2
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µg/mL) S. pneumoniae represents a challenge for existing antibacterial agents (Jones, Sader, Mendes, & Flamm, 2013; Mendes, Biek, et al., 2014; Pfaller, Farrell, Sader, & Jones, 2012; Richter, et al., 2014).
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Pneumococcal conjugate vaccines (PCV7 and PCV13) in the United States (US) notably altered the epidemiology of pneumococcal disease with increased rates of colonization and infection caused by non-
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vaccine serotypes (Richter, et al., 2014; Rosen, et al., 2011). Seroprevalence studies in the US conducted in 2011-2012 found that serotypes 19A and 35B were the most prevalent serotypes recovered
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from infected patients (Mendes, Costello, et al., 2014). These serotypes comprised the majority of S. pneumoniae isolates with decreased susceptibility to penicillin, ceftriaxone and other agents employed in
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the treatment of CABP (Mendes, Biek, et al., 2014; Richter, et al., 2014). After PCV13 vaccines were implemented, PR-SP declined due to serotype 19A; however, proportional increases in replacement
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serotypes that have PR-SP or MDR-SP phenotypes (e.g., 35B, 23A, 23B and 15B) have mitigated a more substantial decline in pneumococcal resistance rates (Mendes, Biek, et al., 2014; Richter, et al., 2014).
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Given these concerns, a need exists to continue assessing new and established antibacterial agents for activity against drug-resistant subsets of S. pneumoniae from clinically infected patients (Flamm, Sader, Farrell, & Jones, 2014).
Omadacycline is a semisynthetic derivative of minocycline and the first member of the novel class of 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 subunit of target gram-positive and gram-negative bacteria with resultant inhibition of protein synthesis (Draper, et al., 2014; Honeyman, et al., 2015; Roberts, 2003). Omadacycline exhibits excellent potency against staphylococci, PR-SP, and MDR-SP; maintains activity against ribosomal protection and efflux tetracycline resistance genes; and is not affected by mechanisms of resistance to other classes of
ACCEPTED MANUSCRIPT antibacterial agents (Draper, et al., 2014; Honeyman, et al., 2015; Macone, et al., 2014). Omadacycline has been shown to be safe and non-inferior to linezolid in a phase 2 study of the treatment of acute
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entering phase 3 development for treatment of ABSSI and CABP.
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bacterial skin and skin structure infections (ABSSI) (Noel, Draper, Hait, Tanaka, & Arbeit, 2012) and is
In the present study, we evaluated the in vitro activity of omadacycline (dry-form panels, 2010;
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frozen-form panels, 2014) and comparator agents (dry-form, 2010 and 2014) tested by Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution methods against S. pneumoniae
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causing infections in US and Europe (EU) in 2010 and 2014.
ACCEPTED MANUSCRIPT 2 Materials and methods 2.1 Organism collection A total of 51 penicillin-susceptible (Pen-S), 51 penicillin-intermediate (Pen-I) and 51 penicillin-
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resistant (Pen-R) S. pneumoniae (S, ≤0.06; I, 0.12-1; R, ≥2 g/mL) isolates from the 2014 SENTRY global surveillance program from Europe and 50 Pen-S, 50 Pen-I, and 51 Pen-R S. pneumoniae isolates from US (2014 Global Surveillance; n = 304) were selected for susceptibility testing. The 2014 data were
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compared to the test results of 1,834 S. pneumoniae from US and EU in the 2010 Global surveillance
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program. MDR S. pneumoniae (MDR-SP) were defined as R ≥3 antimicrobial classes and CRO-NS SP were defined as those strains for which the ceftriaxone MIC value was > 2 µg/mL.
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2.2 Susceptibility testing
Comparator agents were tested in validated dry-form panels (2010 and 2014) manufactured by Thermo Fisher Scientific Inc. (Cleveland, Ohio, USA) by broth microdilution in cation-adjusted Mueller-
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Hinton broth with 2.5-5% lysed horse blood following Clinical and Laboratory Standards Institute (CLSI) methods. Omadacycline was tested in dry-form panels in 2010 (range, 0.015-32 µg/mL). and panels with
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fresh frozen medium made at JMI Laboratories (North Liberty, Iowa, USA) for testing 2014 isolates
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(range, 0.008-4 µg/mL). 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
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all MIC values were within the established testing range (CLSI, 2015, 2016). In the validation process for the dry-form panels we have performed studies that show that the essential agreement (+/- 1 dil) with reference panels (frozen/fresh) was 99.7% (data not shown). Concurrent QC testing was also performed to assure proper test conditions and procedures and all values were within published ranges (CLSI, 2015; 2016). The QC strain tested was S. pneumoniae ATCC 49619 (CLSI, 2016). Interpretive criteria used were those of CLSI (CLSI, 2015, 2016).
ACCEPTED MANUSCRIPT 3 Results 3.1 Activity of omadacycline against S. pneumoniae
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The MIC distributions for the combined data for all S. pneumoniae from EU and US medical centers is shown in Table 1. The MIC50/90 values for all S. pneumoniae in 2010 and for PR-SP, MDR-SP and CRO-NS SP were 0.06/0.12 µg/mL. The 2014 omadacycline MIC50/90 values were 0.06/0.06 µg/mL
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overall as well as for PR-SP, MDR-SP and CRO-NS SP. Identical omadacycline MIC90 values were exhibited by US and EU S. pneumoniae isolates from 2010 (0.12 µg/mL) and 2014 (0.06 µg/mL) (Table
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1). The MIC90 values for PR-SP from EU and US were identical in 2010 (0.12 µg/mL) and in 2014 (0.06
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µg/mL). Likewise, the MIC90 values for MDR-SP and CRO-NS from both the US and EU were 0.12 µg/mL in 2010 and 0.06 µg/mL in 2014. The highest MIC value for all isolates from either EU or US was 0.5 µg/mL in 2010 and 0.12 µg/mL in 2014. Isolates for which omadacycline MIC values were either 0.25
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or 0.5 µg/mL were detected in 2010 but not in 2014 from both US and EU (Table 1). These isolates were distributed among all resistant phenotypes and do not appear to be unique. They were not further
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studied for clonality or resistance mechanisms. The lack of isolates with MIC values > 0.12 µg/ml in 2014
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may also be a function of a smaller sample size in 2014 compared to 2010. 3.2 Susceptibility of EU and US S. pneumoniae isolates to comparator agents
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S. pneumoniae isolates from both EU and US (2010 and 2014 data combined) exhibited high levels of susceptibility to tigecycline (99.9/99.8%, respectively) and levofloxacin (99.0/99.1%, respectively) (Table 2). These agents remained highly active against PR-SP, MDR-SP and CRO-NS SP from EU and US (Table 2). Ceftriaxone, amoxicillin-clavulanate, erythromycin and penicillin were slightly more active against S. pneumoniae isolates from EU versus those from US regardless of the resistant subset, although the activity of these agents was suboptimal in EU and US (Table 2). PR-SP, MDR-SP and CRO-NS SP isolates from US and EU showed reduced susceptibility to doxycycline, tetracycline and erythromycin, but the EU isolates of PR-SP and CRO-NS SP were more susceptible than those from US to doxycycline (37.9/34.6% [EU/US] and 35.6.3/15.7% [EU/US], respectively), tetracycline (38.4/36.2% [EU/US] and 37.3/17.4% [EU/US], respectively) and erythromycin (24.3/8.5% [EU/US] and 16.9/0.0% [EU/US], respectively) (Table 2). Notably, there was no cross-
ACCEPTED MANUSCRIPT resistance detected between omadacycline and either tetracycline or doxycycline (Table 2): the MIC 50/90 values for omadacycline were 0.03/0.06 µg/mL for tetracycline and doxycycline-susceptible isolates and
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0.06/0.12 µg/mL for tetracycline and doxycycline-resistant isolates (data not shown).
4 Discussion
The data from this survey demonstrate that omadacycline was highly active against clinical
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isolates of S. pneumoniae from 2010 and 2014 and across EU and US study sites. The activity of
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omadacycline was comparable for all resistant subsets from EU and US as well. Tigecycline and levofloxacin were highly active against US and EU isolates of S. pneumoniae in both 2010 and 2014
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(data combined). A high degree of resistance was noted with tetracycline, doxycycline and erythromycin in both EU and US, although these agents were less active against US versus EU strains (Table 2). Resistance to erythromycin was elevated (75.1 to 100.0%) among PR-SP, MDR-SP and CRO-SP
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isolates from EU and US. These data build on data reported by Marcone et al, (Macone, et al., 2014) and indicate that omadacycline merits further study in infections due to S. pneumoniae, including CABP
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where MDR may be a problem.
ACCEPTED MANUSCRIPT ACKNOWLEDGMENTS The authors wish to thank the following staff members at JMI Laboratories (North Liberty, Iowa, USA): L.
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Duncan, M. Janechek, J. Oberholser, J. Schuchert, and J. Streit for technical support.
Funding
This study was performed by JMI Laboratories and supported by Paratek Pharmaceuticals Inc., which
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included funding for services related to preparing this manuscript.
Transparency declaration
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JMI Laboratories, Inc. also contracted to perform services in 2016 for Achaogen, Actelion, Allecra, Allergan, Ampliphi, API, Astellas, AstraZeneca, Basilea, Bayer, BD, Biomodels, Cardeas, CEM-102 Pharma, Cempra, Cidara, Cormedix, CSA Biotech, Cubist, Debiopharm, Dipexium, Duke, Durata,
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Entasis, Fortress, Fox Chase Chemical, GSK, Medpace, Melinta, Merck, Micurx, Motif, N8 Medical, Nabriva, Nexcida, Novartis, Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal
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Therapeutics, Synolgoic, TGV Therapeutics, The Medicines Company, Theravance, ThermoFisher,
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Venatorx, Wockhardt, Zavante. Some JMI employees are advisors/consultants for Allergan, Astellas,
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Cubist, Pfizer, Cempra and Theravance. There are no speakers’ bureaus or stock options to declare.
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REFERENCES CLSI (2015) M07-A10. Methods for dilution antimicrobial susceptibility tests for bacteria that grow
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aerobically; approved standard- tenth edition. In. Wayne, PA: Clinical and Laboratory Standards
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Postgrad Med, 122: 130-141.
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File, TM, Jr., & Marrie, TJ (2010) Burden of community-acquired pneumonia in North American adults.
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Antimicrob Agents Chemother, 58: 2468-2471. Honeyman, L, Ismail, M, Nelson, ML, Bhatia, B, Bowser, TE, Chen, J, Mechiche, R, Ohemeng, K, Verma,
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and antimicrobial susceptibility of USA Streptococcus pneumoniae isolates collected prior to and post introduction of 13-valent pneumococcal conjugate vaccine. Diagn Microbiol Infect Dis, 80: 19-25.
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Noel, GJ, Draper, MP, Hait, H, Tanaka, SK, & Arbeit, RD (2012) A randomized, evaluator-blind, phase 2
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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.
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Pfaller, MA, Farrell, DJ, Sader, HS, & Jones, RN (2012) AWARE ceftaroline surveillance program (20082010); Trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis, 55: S187-S193.
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Richter, SS, Diekema, DJ, Heilmann, KP, Dohrn, CL, Riahi, F, & Doern, GV (2014) Changes in pneumococcal serotypes and antimicrobial resistance after introduction of the 13-valent
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Table 1 Cumulative frequency distribution of omadacycline MIC results for S. pneumoniae isolates
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MIC in µg/mL
Year
Isolates
≤0.015
0.03
US + EU
2014
304
6 (2.0)
123 (42.4)
US + EU
2010
1834
77 (4.2)
US
2014
151
US
2010
EU EU
0.12
0.25
0.5
MIC50
MIC90
171 (98.7)
4 (100.0)
--
--
0.06
0.06
795 (47.5)
715 (86.5)
182 (96.5)
51 (99.2)
14 (100.0)
0.06
0.12
4 (2.6)
60 (42.4)
85 (98.7)
2 (100.0)
--
--
0.06
0.06
1028
34 (3.3)
400 (42.2)
482 (89.1)
84 (97.3)
25 (99.7)
3 (100.0)
0.06
0.12
2014
153
2 (1.3)
63 (42.5)
86 (98.7)
2 (100.0)
--
--
0.06
0.06
2010
806
43 (5.3)
233 (83.3)
98 (95.4)
26 (98.6)
11 (100.0)
0.03
0.12
US + EU
2014
101
3 (3.0)
59 (61.4)
38 (99.0)
1 (100.0)
--
--
0.03
0.06
US + EU
2010
1207
61 (5.1)
588 (53.8)
422 (88.7)
96 (96.7)
31 (99.3)
9 (100.0)
0.03
0.12
US
2014
50
2 (4.0)
27 (58.0)
20 (98.0)
1 (100.0)
--
--
0.03
0.06
US
2010
611
25 (4.1)
268 (48.0)
263 (91.0)
38 (97.2)
14 (99.5)
3 (100.0)
0.06
0.06
EU
2014
51
1 (2.0)
32 (64.7)
18 (100.0)
--
--
--
0.03
0.06
EU
2010
596
36 (6.0)
320 (59.7)
159 (86.4)
58 (96.1)
17 (99.0)
6 (100.0)
0.03
0.12
Penicillin-I
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395 (54.3)
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Penicillin-S
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S. pneumoniae
0.06
MA NU S
Organism
CR
No. of
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2014
101
3 (3.0)
38 (40.6)
58 (98.0)
2 (100.0)
--
--
0.06
0.06
US + EU
2010
292
7 (2.4)
114 (41.4)
126 (84.6)
36 (96.9)
8 (99.7)
1 (100.0)
0.06
0.12
US
2014
50
2 (4.0)
20 (44.0)
28 (100.0)
--
--
--
0.06
0.06
US
2010
208
5 (2.4)
76 (38.9)
99 (86.5)
24 (98.1)
4 (100.0)
--
0.06
0.12
EU
2014
51
1 (2.0)
18 (37.3)
30 (96.1)
2 (100.0)
--
--
0.06
0.06
EU
2010
84
2 (2.4)
38 (47.6)
27 (79.8)
12 (94.0)
4 (98.8)
1 (100.0)
0.06
0.12
US + EU
2014
102
--
26 (25.5)
75 (99.0)
1 (100.0)
--
--
0.06
0.06
US + EU
2010
335
9 (2.7)
93 (30.4)
167 (80.3)
50 (95.2)
12 (98.8)
4 (100.0)
0.06
0.12
US
2014
51
--
13 (25.5)
37 (98.0)
1 (100.0)
--
--
0.06
0.06
US
2010
209
4 (1.9)
56 (28.7)
120 (86.1)
22 (96.7)
7 (100.0)
--
0.06
0.12
EU
2014
51
--
13 (25.5)
38 (100.0)
--
--
--
0.06
0.06
EU
2010
126
5 (4.0)
37 (33.3)
47 (70.6)
28 (92.9)
5 (96.8)
4 (100.0)
0.06
0.12
US + EU
2014
137
2 (1.5)
31 (24.1)
101 (97.8)
3 (100.0)
--
--
0.06
0.06
US + EU
2010
434
13 (3.0)
130 (32.9)
206 (80.4)
66 (95.6)
16 (99.3)
3 (100.0)
0.06
0.12
US
2014
66
2 (3.0)
13 (22.7)
50 (98.5)
1 (100.0)
--
--
0.06
0.06
US
2010
277
6 (2.2)
83 (32.1)
146 (84.8)
33 (96.8)
9 (100.0)
--
0.06
0.12
EU
2014
71
--
18 (25.4)
51 (97.2)
2 (100.0)
--
--
0.06
0.06
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MDR
IP
CR
MA NU S
CE
PT
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Penicillin-R
T
US + EU
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EU
2010
157
7 (4.5)
47 (34.4)
60 (72.6)
33 (93.6)
7 (98.1)
3 (100.0)
0.06
0.12
--
--
--
0.06
0.06
14 (96.1)
5 (100.0)
--
0.06
0.12
--
--
--
0.06
0.06
51 (89.1)
7 (96.7)
3 (100.0)
--
0.06
0.12
17 (100.0)
--
--
--
0.06
0.06
19 (75.7)
7 (94.6)
2 (100.0)
--
0.06
0.12
45
--
11 (24.4)
34 (100.0)
US + EU
2010
129
2 (1.6)
38 (31.0)
70 (85.3)
US
2014
23
--
6 (26.1)
17 (100.0)
US
2010
92
2 (2.2)
29 (33.7)
EU
2014
22
--
5 (22.7)
EU
2010
37
--
9 (24.3)
IP
2014
MA NU S
CR
US + EU
T
Ceftriaxone-NS (MIC, ≥2 µg/mL)
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Abbreviations: US, United States of America; EU, Europe; S, susceptible; I, intermediate; R, resistant; NS, nonsusceptible.
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Penicillin Penicillin-S SPN Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Levofloxacin Erythromycin Clindamycin Penicillin Penicillin-I SPN Omadacycline
≤0.06 / 1 1/1 ≤0.12 / >8 ≤0.25 / >1 ≤0.06 / 4
(661) 100.0 93.6 97.4 99.5 100.0 99.2 86.5 97.7 100.0 100.0 100.0
b
2.9 2.6 0.0c 0.0d 0.8 12.4 2.1 0.0e 0.0f 0.0g
IP
≤0.015 — 0.5 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
CR
0.06 / 0.06 ≤0.03 / ≤0.03 0.25 / 8 0.5 / >8
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23.6 23.1 9.8c 1.7d 0.8 40.5 20.3 22.1e 43.9f 0.6g
MIC Range
≤0.06 — 8
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Levofloxacin Erythromycin Clindamycin
b
MIC50/90
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1 ≤0.06 — >4
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Ceftriaxone
99.8 74.0 76.9 76.8 90.2 99.1 58.6 79.3 56.1 56.1 86.1
%R
EU CLSIa %S (959) 99.9 73.1 74.5 78.9 93.8 99.0 72.1 79.4 67.5 67.5 94.1
%R
b
24.9 25.2 6.2c 0.7d 1.0 27.3 19.7 18.5e 32.5f 0.3g
MIC50/90
MIC Range
0.03 / 0.12 ≤0.03 / ≤0.03 0.12 / 8 0.5 / >8
≤0.015 — 0.5 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
<=0.06 / 1
≤0.06 — 8
1/1 ≤0.12 / >8 ≤0.25 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
<=0.06 / 2
≤0.06 — >4
0.03 / 0.12 ≤0.03 / ≤0.03 0.12 / 0.5 ≤0.25 / 1
≤0.015 — 0.5 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
≤0.06 / ≤0.06
≤0.06 — 1
1/1 ≤0.12 / ≤0.12 ≤0.25 / ≤0.25
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
≤0.06 / ≤0.06
≤0.06 — ≤0.06
0.06 / 0.12
≤0.015 — 0.5
(647)
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SPN Omadacycline Tigecycline Doxycycline Tetracycline
US CLSIa %S (1,179)
0.06 / 0.06 ≤0.03 / ≤0.03 0.12 / 0.25 0.5 / 0.5
≤0.015 — 0.5 ≤0.03 — 0.06 ≤0.06 — >8 ≤0.25 — >8
≤0.06 / ≤0.06
≤0.06 — 1
1/1 ≤0.12 / 4 ≤0.25 / ≤0.25
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
≤0.06 / ≤0.06
≤0.06 — ≤0.06
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Organism group (no. tested) antimicrobial agent
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Table 2 Activity of Omadacycline and comparator antimicrobial agents when tested against US and EU isolates
(258)
99.8 88.9 90.1 99.8 100.0 99.5 91.2 95.1 100.0 100.0 100.0
b
9.1 9.9 0.0c 0.0d 0.5 8.3 4.6 0.0e 0.0f 0.0g
(135) 0.06 / 0.12
≤0.015 — 0.25
Penicillin-R SPN Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Levofloxacin Erythromycin Clindamycin Penicillin MDR (NS ≥ 3 drugs) SPN Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone
0.12 / 1
≤0.06 — 4
1/1 4 / >8 ≤0.25 / >1
(260) 99.6 34.6 36.2 5.8 56.5 99.2 8.5 36.9 0.0 0.0 36.9
b
64.2 63.8 43.5c 7.3d 0.0 91.2 62.3 100.0e 100.0f 2.7g
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
0.25 / 1
0.12 — 1
EU CLSIa %S 100.0 43.7 46.7 80.0 98.5 97.8 43.0 59.3 0.0 0.0 100.0
%R b
53.3 52.6 1.5c 0.0d 2.2 55.6 37.8 0.0e 100.0f 0.0g
MIC50/90
MIC Range
≤0.03 / 0.06 2 / >8 >8 / >8
≤0.03 — 0.06 ≤0.06 — >8 ≤0.25 — >8
0.25 / 1
≤0.06 — 2
1/1 4 / >8 ≤0.25 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
0.5 / 1
0.12 — 1
0.06 / 0.12 ≤0.03 / 0.06 4/8 >8 / >8
≤0.015 — 0.5 ≤0.03 — 0.06 ≤0.06 — >8 ≤0.25 — >8
1/2
0.5 — 8
1/1 >8 / >8 >1 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
2/4
2 — >4
0.06 / 0.12 ≤0.03 / 0.06 8 / >8 >8 / >8 1/2
≤0.015 — 0.5 ≤0.03 — 0.06 ≤0.06 — >8 ≤0.25 — >8 ≤0.06 — 8
(177)
0.06 / 0.12 ≤0.03 / ≤0.03 4/8 >8 / >8
≤0.015 — 0.25 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
1/2
0.5 — 8
1/1 >8 / >8 >1 / >1
≤0.5 — 4 ≤0.12 — >8 ≤0.25 — >1
4/4
2 — >4
0.06 / 0.12 ≤0.03 / 0.06 4 / >8 >8 / >8 1/2
≤0.015 — 0.25 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8 ≤0.06 — 8
(343) 99.4 23.9 25.4 37.6
IP
≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
CR
≤0.03 / ≤0.03 0.25 / >8 0.5 / >8
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Penicillin
35.7 34.5 0.8c 0.4d 1.6 61.2 24.4 0.0e 100.0f 0.0g
MIC Range
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Levofloxacin Erythromycin Clindamycin
b
MIC50/90
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Ceftriaxone
%R
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Tigecycline Doxycycline Tetracycline
US CLSIa %S 99.6 63.6 65.5 89.9 99.2 98.4 37.6 74.8 0.0 0.0 100.0
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Organism group (no. tested) antimicrobial agent
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100.0 37.9 38.4 1.7 67.8 97.7 24.3 37.3 0.0 0.0 67.8
b
61.0 60.5 32.2c 4.0d 2.3 75.1 61.0 100.0e 100.0f 1.7g
(228) b
75.2 74.6 33.5c
100.0 15.8 15.8 30.7
b
83.3 82.9 25.4c
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Ceftriaxone Levofloxacin Erythromycin Clindamycin Penicillin
Criteria as published by CLSI [2016] Breakpoints from FDA Package Insert revised 12/2014 c Using meningitis breakpoints d Using non-meningitis breakpoints e Using oral breakpoints f Using parenteral, meningitis breakpoints g Using parenteral, non-meningitis breakpoints a b
1/1 >8 / >8 >1 / >1
≤0.5 — >4 ≤0.06 — >8 ≤0.25 — >1
CR
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2/4
≤0.06 — >4
(115) 98.3 15.7 17.4 0.0 0.0 99.1 0.0 16.5 0.0 0.0 5.2
b
83.5 82.6 100.0c 17.4d 0.0 100.0 82.6 98.3e 100.0f 6.1g
0.06 / 0.06 ≤0.03 / 0.06 4/8 >8 / >8 2/4 1/1 >8 / >8 >1 / >1 4/4
IP
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MIC Range
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Ceftriaxone-NS SPN Omadacycline Tigecycline Doxycycline Tetracycline
MIC50/90
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Penicillin
%R 5.8d 0.9 98.3 65.3 60.9e 99.7f 2.0g
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Levofloxacin Erythromycin Clindamycin
US CLSIa %S 66.5 98.5 0.9 33.8 0.3 0.3 53.1
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Organism group (no. tested) antimicrobial agent
≤0.015 — 0.25 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8 2—8 ≤0.5 — 4 2 — >8 ≤0.25 — >1 0.25 — >4
EU CLSIa %S 74.6 95.6 8.8 26.3 6.1 6.1 76.3
%R 2.6d 4.4 89.9 70.6 61.8e 93.9f 1.3g
MIC50/90
MIC Range
1/1 >8 / >8 >1 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
2/4
≤0.06 — >4
0.06 / 0.12 ≤0.03 / 0.06 4/8 >8 / >8
0.03 — 0.25 ≤0.03 — 0.06 0.12 — >8 ≤0.25 — >8
2/4
2—8
1/1 >8 / >8 >1 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
4/4
1 — >4
(59) 100.0 35.6 37.3 0.0 0.0 98.3 16.9 28.8 0.0 0.0 39.0
b
62.7 62.7 100.0c 11.9d 1.7 83.1 71.2 96.6e 100.0f 5.1g
Highlights
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ACCEPTED MANUSCRIPT
Omadacycline activity against S. pneumoniae comparable over time (2010-2014) Omadacycline MIC90 values were similar for penicillin-S, -I, -R, MDR, and ceftriaxone-NS subgroups A high degree of resistance exists for doxycycline, erythromycin, and trimethoprim/sulfamethoxazole
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S0732-8893(17)30321-8 doi: 10.1016/j.diagmicrobio.2017.10.010 DMB 14444
To appear in:
Diagnostic Microbiology and Infectious Disease
Received date: Revised date: Accepted date:
9 February 2017 15 September 2017 16 October 2017
Please cite this article as: Pfaller MA, Rhomberg PR, Huband MD, Flamm RK, Activity of Omadacycline Tested against Streptococcus pneumoniae from a Global Surveillance Program (2014), Diagnostic Microbiology and Infectious Disease (2017), doi: 10.1016/j.diagmicrobio.2017.10.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT DMID-17-104R2 Activity of Omadacycline Tested against Streptococcus pneumoniae from a Global Surveillance Program (2014)
P.R. Rhomberg M.D. Huband
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R.K. Flamm
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M.A. Pfaller
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JMI Laboratories, North Liberty, Iowa, USA b
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University of Iowa, Iowa City, Iowa, USA
Abstract word count:158
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Manuscript word count: 1,256
Michael A. Pfaller, MD
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Contact Information:
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Running title: Omadacycline and Streptococcus pneumoniae
JMI Laboratories
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345 Beaver Kreek Ctr, Ste A North Liberty, IA, 52317, USA Phone: 319-665-3370 Fax: 319-665-3371 [email protected]
Key words: multidrug-resistant pneumococci, aminomethylcycline, in vitro activity
ACCEPTED MANUSCRIPT Abstract The activity of omadacycline and comparators when tested against a subset of Streptococcus pneumoniae from US and European regions of a 2014 global surveillance program (304 isolates) are
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reported. These MIC results were compared to those obtained when testing S. pneumoniae from 2010 surveillance (1,834 isolates). The omadacycline MIC50/90 for S. pneumoniae (2014) was 0.06/0.06 µg/mL, similar to 2010 (MIC50/90, 0.06/0.12 µg/mL). The omadacycline MIC90 (0.06-0.12 µg/mL) was similar for the
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penicillin-susceptible, -intermediate, –resistant, multidrug-resistance (MDR; ≥3 classes), and ceftriaxone
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nonsusceptible subgroups. Omadacycline MIC90 values were 0.06-0.12 µg/mL for S. pneumoniae from the US and Europe. There was a high degree of resistance with doxycycline, erythromycin and
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trimethoprim-sulfamethoxazole in both US and EU. For penicillin-resistant S. pneumoniae, resistance to doxycycline and tetracycline in US/Europe was 64.2/61.0% and 63.8/60.5%, respectively, erythromycin 91.2/75.1, and ceftriaxone 7.3/4.0%. The potent activity of omadacycline against S. pneumoniae indicates
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that omadacycline merits further study in bacterial pneumonia, especially where MDR may be a concern.
ACCEPTED MANUSCRIPT 1 Introduction Community-acquired bacterial pneumonia (CABP) is a common and deadly infectious disease
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despite available potent antibiotics and effective vaccines (File & Marrie, 2010; Mendes, Biek, et al.,
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2014). Streptococcus pneumoniae is the most common pathogen implicated in CABP, and penicillinresistant (PR-SP), multidrug-resistant (MDR-SP) and ceftriaxone–nonsusceptible (CRO-NS SP; MIC, >2
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µg/mL) S. pneumoniae represents a challenge for existing antibacterial agents (Jones, Sader, Mendes, & Flamm, 2013; Mendes, Biek, et al., 2014; Pfaller, Farrell, Sader, & Jones, 2012; Richter, et al., 2014).
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Pneumococcal conjugate vaccines (PCV7 and PCV13) in the United States (US) notably altered the epidemiology of pneumococcal disease with increased rates of colonization and infection caused by non-
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vaccine serotypes (Richter, et al., 2014; Rosen, et al., 2011). Seroprevalence studies in the US conducted in 2011-2012 found that serotypes 19A and 35B were the most prevalent serotypes recovered
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from infected patients (Mendes, Costello, et al., 2014). These serotypes comprised the majority of S. pneumoniae isolates with decreased susceptibility to penicillin, ceftriaxone and other agents employed in
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the treatment of CABP (Mendes, Biek, et al., 2014; Richter, et al., 2014). After PCV13 vaccines were implemented, PR-SP declined due to serotype 19A; however, proportional increases in replacement
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serotypes that have PR-SP or MDR-SP phenotypes (e.g., 35B, 23A, 23B and 15B) have mitigated a more substantial decline in pneumococcal resistance rates (Mendes, Biek, et al., 2014; Richter, et al., 2014).
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Given these concerns, a need exists to continue assessing new and established antibacterial agents for activity against drug-resistant subsets of S. pneumoniae from clinically infected patients (Flamm, Sader, Farrell, & Jones, 2014).
Omadacycline is a semisynthetic derivative of minocycline and the first member of the novel class of 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 subunit of target gram-positive and gram-negative bacteria with resultant inhibition of protein synthesis (Draper, et al., 2014; Honeyman, et al., 2015; Roberts, 2003). Omadacycline exhibits excellent potency against staphylococci, PR-SP, and MDR-SP; maintains activity against ribosomal protection and efflux tetracycline resistance genes; and is not affected by mechanisms of resistance to other classes of
ACCEPTED MANUSCRIPT antibacterial agents (Draper, et al., 2014; Honeyman, et al., 2015; Macone, et al., 2014). Omadacycline has been shown to be safe and non-inferior to linezolid in a phase 2 study of the treatment of acute
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entering phase 3 development for treatment of ABSSI and CABP.
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bacterial skin and skin structure infections (ABSSI) (Noel, Draper, Hait, Tanaka, & Arbeit, 2012) and is
In the present study, we evaluated the in vitro activity of omadacycline (dry-form panels, 2010;
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frozen-form panels, 2014) and comparator agents (dry-form, 2010 and 2014) tested by Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution methods against S. pneumoniae
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causing infections in US and Europe (EU) in 2010 and 2014.
ACCEPTED MANUSCRIPT 2 Materials and methods 2.1 Organism collection A total of 51 penicillin-susceptible (Pen-S), 51 penicillin-intermediate (Pen-I) and 51 penicillin-
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resistant (Pen-R) S. pneumoniae (S, ≤0.06; I, 0.12-1; R, ≥2 g/mL) isolates from the 2014 SENTRY global surveillance program from Europe and 50 Pen-S, 50 Pen-I, and 51 Pen-R S. pneumoniae isolates from US (2014 Global Surveillance; n = 304) were selected for susceptibility testing. The 2014 data were
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compared to the test results of 1,834 S. pneumoniae from US and EU in the 2010 Global surveillance
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program. MDR S. pneumoniae (MDR-SP) were defined as R ≥3 antimicrobial classes and CRO-NS SP were defined as those strains for which the ceftriaxone MIC value was > 2 µg/mL.
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2.2 Susceptibility testing
Comparator agents were tested in validated dry-form panels (2010 and 2014) manufactured by Thermo Fisher Scientific Inc. (Cleveland, Ohio, USA) by broth microdilution in cation-adjusted Mueller-
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Hinton broth with 2.5-5% lysed horse blood following Clinical and Laboratory Standards Institute (CLSI) methods. Omadacycline was tested in dry-form panels in 2010 (range, 0.015-32 µg/mL). and panels with
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fresh frozen medium made at JMI Laboratories (North Liberty, Iowa, USA) for testing 2014 isolates
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(range, 0.008-4 µg/mL). 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
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all MIC values were within the established testing range (CLSI, 2015, 2016). In the validation process for the dry-form panels we have performed studies that show that the essential agreement (+/- 1 dil) with reference panels (frozen/fresh) was 99.7% (data not shown). Concurrent QC testing was also performed to assure proper test conditions and procedures and all values were within published ranges (CLSI, 2015; 2016). The QC strain tested was S. pneumoniae ATCC 49619 (CLSI, 2016). Interpretive criteria used were those of CLSI (CLSI, 2015, 2016).
ACCEPTED MANUSCRIPT 3 Results 3.1 Activity of omadacycline against S. pneumoniae
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The MIC distributions for the combined data for all S. pneumoniae from EU and US medical centers is shown in Table 1. The MIC50/90 values for all S. pneumoniae in 2010 and for PR-SP, MDR-SP and CRO-NS SP were 0.06/0.12 µg/mL. The 2014 omadacycline MIC50/90 values were 0.06/0.06 µg/mL
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overall as well as for PR-SP, MDR-SP and CRO-NS SP. Identical omadacycline MIC90 values were exhibited by US and EU S. pneumoniae isolates from 2010 (0.12 µg/mL) and 2014 (0.06 µg/mL) (Table
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1). The MIC90 values for PR-SP from EU and US were identical in 2010 (0.12 µg/mL) and in 2014 (0.06
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µg/mL). Likewise, the MIC90 values for MDR-SP and CRO-NS from both the US and EU were 0.12 µg/mL in 2010 and 0.06 µg/mL in 2014. The highest MIC value for all isolates from either EU or US was 0.5 µg/mL in 2010 and 0.12 µg/mL in 2014. Isolates for which omadacycline MIC values were either 0.25
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or 0.5 µg/mL were detected in 2010 but not in 2014 from both US and EU (Table 1). These isolates were distributed among all resistant phenotypes and do not appear to be unique. They were not further
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studied for clonality or resistance mechanisms. The lack of isolates with MIC values > 0.12 µg/ml in 2014
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may also be a function of a smaller sample size in 2014 compared to 2010. 3.2 Susceptibility of EU and US S. pneumoniae isolates to comparator agents
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S. pneumoniae isolates from both EU and US (2010 and 2014 data combined) exhibited high levels of susceptibility to tigecycline (99.9/99.8%, respectively) and levofloxacin (99.0/99.1%, respectively) (Table 2). These agents remained highly active against PR-SP, MDR-SP and CRO-NS SP from EU and US (Table 2). Ceftriaxone, amoxicillin-clavulanate, erythromycin and penicillin were slightly more active against S. pneumoniae isolates from EU versus those from US regardless of the resistant subset, although the activity of these agents was suboptimal in EU and US (Table 2). PR-SP, MDR-SP and CRO-NS SP isolates from US and EU showed reduced susceptibility to doxycycline, tetracycline and erythromycin, but the EU isolates of PR-SP and CRO-NS SP were more susceptible than those from US to doxycycline (37.9/34.6% [EU/US] and 35.6.3/15.7% [EU/US], respectively), tetracycline (38.4/36.2% [EU/US] and 37.3/17.4% [EU/US], respectively) and erythromycin (24.3/8.5% [EU/US] and 16.9/0.0% [EU/US], respectively) (Table 2). Notably, there was no cross-
ACCEPTED MANUSCRIPT resistance detected between omadacycline and either tetracycline or doxycycline (Table 2): the MIC 50/90 values for omadacycline were 0.03/0.06 µg/mL for tetracycline and doxycycline-susceptible isolates and
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0.06/0.12 µg/mL for tetracycline and doxycycline-resistant isolates (data not shown).
4 Discussion
The data from this survey demonstrate that omadacycline was highly active against clinical
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isolates of S. pneumoniae from 2010 and 2014 and across EU and US study sites. The activity of
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omadacycline was comparable for all resistant subsets from EU and US as well. Tigecycline and levofloxacin were highly active against US and EU isolates of S. pneumoniae in both 2010 and 2014
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(data combined). A high degree of resistance was noted with tetracycline, doxycycline and erythromycin in both EU and US, although these agents were less active against US versus EU strains (Table 2). Resistance to erythromycin was elevated (75.1 to 100.0%) among PR-SP, MDR-SP and CRO-SP
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isolates from EU and US. These data build on data reported by Marcone et al, (Macone, et al., 2014) and indicate that omadacycline merits further study in infections due to S. pneumoniae, including CABP
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where MDR may be a problem.
ACCEPTED MANUSCRIPT ACKNOWLEDGMENTS The authors wish to thank the following staff members at JMI Laboratories (North Liberty, Iowa, USA): L.
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Duncan, M. Janechek, J. Oberholser, J. Schuchert, and J. Streit for technical support.
Funding
This study was performed by JMI Laboratories and supported by Paratek Pharmaceuticals Inc., which
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included funding for services related to preparing this manuscript.
Transparency declaration
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JMI Laboratories, Inc. also contracted to perform services in 2016 for Achaogen, Actelion, Allecra, Allergan, Ampliphi, API, Astellas, AstraZeneca, Basilea, Bayer, BD, Biomodels, Cardeas, CEM-102 Pharma, Cempra, Cidara, Cormedix, CSA Biotech, Cubist, Debiopharm, Dipexium, Duke, Durata,
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Entasis, Fortress, Fox Chase Chemical, GSK, Medpace, Melinta, Merck, Micurx, Motif, N8 Medical, Nabriva, Nexcida, Novartis, Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal
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Therapeutics, Synolgoic, TGV Therapeutics, The Medicines Company, Theravance, ThermoFisher,
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Venatorx, Wockhardt, Zavante. Some JMI employees are advisors/consultants for Allergan, Astellas,
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Cubist, Pfizer, Cempra and Theravance. There are no speakers’ bureaus or stock options to declare.
ACCEPTED MANUSCRIPT
REFERENCES CLSI (2015) M07-A10. Methods for dilution antimicrobial susceptibility tests for bacteria that grow
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aerobically; approved standard- tenth edition. In. Wayne, PA: Clinical and Laboratory Standards
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CLSI (2016) M100-S26. Performance standards for antimicrobial susceptibility testing: 26th informational
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supplement. In. Wayne, PA: Clinical and Laboratory Standards Institute. Draper, MP, Weir, S, Macone, A, Donatelli, J, Trieber, CA, Tanaka, SK, & Levy, SB (2014) Mechanism of
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Postgrad Med, 122: 130-141.
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File, TM, Jr., & Marrie, TJ (2010) Burden of community-acquired pneumonia in North American adults.
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Flamm, RK, Sader, HS, Farrell, DJ, & Jones, RN (2014) Antimicrobial activity of ceftaroline tested against drug resistant subsets of Streptococcus pneumoniae from United States medical centers.
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Antimicrob Agents Chemother, 58: 2468-2471. Honeyman, L, Ismail, M, Nelson, ML, Bhatia, B, Bowser, TE, Chen, J, Mechiche, R, Ohemeng, K, Verma,
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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:
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ACCEPTED MANUSCRIPT the USA (2011 - 2012): Ceftaroline remains active in vitro among beta-lactam agents. Antimicrob Agents Chemother, 58: 4923-4927. Mendes, RE, Costello, AJ, Jacobs, MR, Biek, D, Critchley, IA, & Jones, RN (2014) Serotype distribution
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and antimicrobial susceptibility of USA Streptococcus pneumoniae isolates collected prior to and post introduction of 13-valent pneumococcal conjugate vaccine. Diagn Microbiol Infect Dis, 80: 19-25.
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Noel, GJ, Draper, MP, Hait, H, Tanaka, SK, & Arbeit, RD (2012) A randomized, evaluator-blind, phase 2
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Pfaller, MA, Farrell, DJ, Sader, HS, & Jones, RN (2012) AWARE ceftaroline surveillance program (20082010); Trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis, 55: S187-S193.
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Richter, SS, Diekema, DJ, Heilmann, KP, Dohrn, CL, Riahi, F, & Doern, GV (2014) Changes in pneumococcal serotypes and antimicrobial resistance after introduction of the 13-valent
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Table 1 Cumulative frequency distribution of omadacycline MIC results for S. pneumoniae isolates
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MIC in µg/mL
Year
Isolates
≤0.015
0.03
US + EU
2014
304
6 (2.0)
123 (42.4)
US + EU
2010
1834
77 (4.2)
US
2014
151
US
2010
EU EU
0.12
0.25
0.5
MIC50
MIC90
171 (98.7)
4 (100.0)
--
--
0.06
0.06
795 (47.5)
715 (86.5)
182 (96.5)
51 (99.2)
14 (100.0)
0.06
0.12
4 (2.6)
60 (42.4)
85 (98.7)
2 (100.0)
--
--
0.06
0.06
1028
34 (3.3)
400 (42.2)
482 (89.1)
84 (97.3)
25 (99.7)
3 (100.0)
0.06
0.12
2014
153
2 (1.3)
63 (42.5)
86 (98.7)
2 (100.0)
--
--
0.06
0.06
2010
806
43 (5.3)
233 (83.3)
98 (95.4)
26 (98.6)
11 (100.0)
0.03
0.12
US + EU
2014
101
3 (3.0)
59 (61.4)
38 (99.0)
1 (100.0)
--
--
0.03
0.06
US + EU
2010
1207
61 (5.1)
588 (53.8)
422 (88.7)
96 (96.7)
31 (99.3)
9 (100.0)
0.03
0.12
US
2014
50
2 (4.0)
27 (58.0)
20 (98.0)
1 (100.0)
--
--
0.03
0.06
US
2010
611
25 (4.1)
268 (48.0)
263 (91.0)
38 (97.2)
14 (99.5)
3 (100.0)
0.06
0.06
EU
2014
51
1 (2.0)
32 (64.7)
18 (100.0)
--
--
--
0.03
0.06
EU
2010
596
36 (6.0)
320 (59.7)
159 (86.4)
58 (96.1)
17 (99.0)
6 (100.0)
0.03
0.12
Penicillin-I
PT CE
395 (54.3)
AC
Penicillin-S
ED
S. pneumoniae
0.06
MA NU S
Organism
CR
No. of
ACCEPTED MANUSCRIPT
2014
101
3 (3.0)
38 (40.6)
58 (98.0)
2 (100.0)
--
--
0.06
0.06
US + EU
2010
292
7 (2.4)
114 (41.4)
126 (84.6)
36 (96.9)
8 (99.7)
1 (100.0)
0.06
0.12
US
2014
50
2 (4.0)
20 (44.0)
28 (100.0)
--
--
--
0.06
0.06
US
2010
208
5 (2.4)
76 (38.9)
99 (86.5)
24 (98.1)
4 (100.0)
--
0.06
0.12
EU
2014
51
1 (2.0)
18 (37.3)
30 (96.1)
2 (100.0)
--
--
0.06
0.06
EU
2010
84
2 (2.4)
38 (47.6)
27 (79.8)
12 (94.0)
4 (98.8)
1 (100.0)
0.06
0.12
US + EU
2014
102
--
26 (25.5)
75 (99.0)
1 (100.0)
--
--
0.06
0.06
US + EU
2010
335
9 (2.7)
93 (30.4)
167 (80.3)
50 (95.2)
12 (98.8)
4 (100.0)
0.06
0.12
US
2014
51
--
13 (25.5)
37 (98.0)
1 (100.0)
--
--
0.06
0.06
US
2010
209
4 (1.9)
56 (28.7)
120 (86.1)
22 (96.7)
7 (100.0)
--
0.06
0.12
EU
2014
51
--
13 (25.5)
38 (100.0)
--
--
--
0.06
0.06
EU
2010
126
5 (4.0)
37 (33.3)
47 (70.6)
28 (92.9)
5 (96.8)
4 (100.0)
0.06
0.12
US + EU
2014
137
2 (1.5)
31 (24.1)
101 (97.8)
3 (100.0)
--
--
0.06
0.06
US + EU
2010
434
13 (3.0)
130 (32.9)
206 (80.4)
66 (95.6)
16 (99.3)
3 (100.0)
0.06
0.12
US
2014
66
2 (3.0)
13 (22.7)
50 (98.5)
1 (100.0)
--
--
0.06
0.06
US
2010
277
6 (2.2)
83 (32.1)
146 (84.8)
33 (96.8)
9 (100.0)
--
0.06
0.12
EU
2014
71
--
18 (25.4)
51 (97.2)
2 (100.0)
--
--
0.06
0.06
AC
MDR
IP
CR
MA NU S
CE
PT
ED
Penicillin-R
T
US + EU
ACCEPTED MANUSCRIPT
EU
2010
157
7 (4.5)
47 (34.4)
60 (72.6)
33 (93.6)
7 (98.1)
3 (100.0)
0.06
0.12
--
--
--
0.06
0.06
14 (96.1)
5 (100.0)
--
0.06
0.12
--
--
--
0.06
0.06
51 (89.1)
7 (96.7)
3 (100.0)
--
0.06
0.12
17 (100.0)
--
--
--
0.06
0.06
19 (75.7)
7 (94.6)
2 (100.0)
--
0.06
0.12
45
--
11 (24.4)
34 (100.0)
US + EU
2010
129
2 (1.6)
38 (31.0)
70 (85.3)
US
2014
23
--
6 (26.1)
17 (100.0)
US
2010
92
2 (2.2)
29 (33.7)
EU
2014
22
--
5 (22.7)
EU
2010
37
--
9 (24.3)
IP
2014
MA NU S
CR
US + EU
T
Ceftriaxone-NS (MIC, ≥2 µg/mL)
AC
CE
PT
ED
Abbreviations: US, United States of America; EU, Europe; S, susceptible; I, intermediate; R, resistant; NS, nonsusceptible.
ACCEPTED MANUSCRIPT
Penicillin Penicillin-S SPN Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Levofloxacin Erythromycin Clindamycin Penicillin Penicillin-I SPN Omadacycline
≤0.06 / 1 1/1 ≤0.12 / >8 ≤0.25 / >1 ≤0.06 / 4
(661) 100.0 93.6 97.4 99.5 100.0 99.2 86.5 97.7 100.0 100.0 100.0
b
2.9 2.6 0.0c 0.0d 0.8 12.4 2.1 0.0e 0.0f 0.0g
IP
≤0.015 — 0.5 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
CR
0.06 / 0.06 ≤0.03 / ≤0.03 0.25 / 8 0.5 / >8
MA NU S
23.6 23.1 9.8c 1.7d 0.8 40.5 20.3 22.1e 43.9f 0.6g
MIC Range
≤0.06 — 8
ED
Levofloxacin Erythromycin Clindamycin
b
MIC50/90
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1 ≤0.06 — >4
PT
Ceftriaxone
99.8 74.0 76.9 76.8 90.2 99.1 58.6 79.3 56.1 56.1 86.1
%R
EU CLSIa %S (959) 99.9 73.1 74.5 78.9 93.8 99.0 72.1 79.4 67.5 67.5 94.1
%R
b
24.9 25.2 6.2c 0.7d 1.0 27.3 19.7 18.5e 32.5f 0.3g
MIC50/90
MIC Range
0.03 / 0.12 ≤0.03 / ≤0.03 0.12 / 8 0.5 / >8
≤0.015 — 0.5 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
<=0.06 / 1
≤0.06 — 8
1/1 ≤0.12 / >8 ≤0.25 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
<=0.06 / 2
≤0.06 — >4
0.03 / 0.12 ≤0.03 / ≤0.03 0.12 / 0.5 ≤0.25 / 1
≤0.015 — 0.5 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
≤0.06 / ≤0.06
≤0.06 — 1
1/1 ≤0.12 / ≤0.12 ≤0.25 / ≤0.25
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
≤0.06 / ≤0.06
≤0.06 — ≤0.06
0.06 / 0.12
≤0.015 — 0.5
(647)
CE
SPN Omadacycline Tigecycline Doxycycline Tetracycline
US CLSIa %S (1,179)
0.06 / 0.06 ≤0.03 / ≤0.03 0.12 / 0.25 0.5 / 0.5
≤0.015 — 0.5 ≤0.03 — 0.06 ≤0.06 — >8 ≤0.25 — >8
≤0.06 / ≤0.06
≤0.06 — 1
1/1 ≤0.12 / 4 ≤0.25 / ≤0.25
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
≤0.06 / ≤0.06
≤0.06 — ≤0.06
AC
Organism group (no. tested) antimicrobial agent
T
Table 2 Activity of Omadacycline and comparator antimicrobial agents when tested against US and EU isolates
(258)
99.8 88.9 90.1 99.8 100.0 99.5 91.2 95.1 100.0 100.0 100.0
b
9.1 9.9 0.0c 0.0d 0.5 8.3 4.6 0.0e 0.0f 0.0g
(135) 0.06 / 0.12
≤0.015 — 0.25
Penicillin-R SPN Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone Levofloxacin Erythromycin Clindamycin Penicillin MDR (NS ≥ 3 drugs) SPN Omadacycline Tigecycline Doxycycline Tetracycline Ceftriaxone
0.12 / 1
≤0.06 — 4
1/1 4 / >8 ≤0.25 / >1
(260) 99.6 34.6 36.2 5.8 56.5 99.2 8.5 36.9 0.0 0.0 36.9
b
64.2 63.8 43.5c 7.3d 0.0 91.2 62.3 100.0e 100.0f 2.7g
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
0.25 / 1
0.12 — 1
EU CLSIa %S 100.0 43.7 46.7 80.0 98.5 97.8 43.0 59.3 0.0 0.0 100.0
%R b
53.3 52.6 1.5c 0.0d 2.2 55.6 37.8 0.0e 100.0f 0.0g
MIC50/90
MIC Range
≤0.03 / 0.06 2 / >8 >8 / >8
≤0.03 — 0.06 ≤0.06 — >8 ≤0.25 — >8
0.25 / 1
≤0.06 — 2
1/1 4 / >8 ≤0.25 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
0.5 / 1
0.12 — 1
0.06 / 0.12 ≤0.03 / 0.06 4/8 >8 / >8
≤0.015 — 0.5 ≤0.03 — 0.06 ≤0.06 — >8 ≤0.25 — >8
1/2
0.5 — 8
1/1 >8 / >8 >1 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
2/4
2 — >4
0.06 / 0.12 ≤0.03 / 0.06 8 / >8 >8 / >8 1/2
≤0.015 — 0.5 ≤0.03 — 0.06 ≤0.06 — >8 ≤0.25 — >8 ≤0.06 — 8
(177)
0.06 / 0.12 ≤0.03 / ≤0.03 4/8 >8 / >8
≤0.015 — 0.25 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
1/2
0.5 — 8
1/1 >8 / >8 >1 / >1
≤0.5 — 4 ≤0.12 — >8 ≤0.25 — >1
4/4
2 — >4
0.06 / 0.12 ≤0.03 / 0.06 4 / >8 >8 / >8 1/2
≤0.015 — 0.25 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8 ≤0.06 — 8
(343) 99.4 23.9 25.4 37.6
IP
≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8
CR
≤0.03 / ≤0.03 0.25 / >8 0.5 / >8
MA NU S
Penicillin
35.7 34.5 0.8c 0.4d 1.6 61.2 24.4 0.0e 100.0f 0.0g
MIC Range
ED
Levofloxacin Erythromycin Clindamycin
b
MIC50/90
PT
Ceftriaxone
%R
CE
Tigecycline Doxycycline Tetracycline
US CLSIa %S 99.6 63.6 65.5 89.9 99.2 98.4 37.6 74.8 0.0 0.0 100.0
AC
Organism group (no. tested) antimicrobial agent
T
ACCEPTED MANUSCRIPT
100.0 37.9 38.4 1.7 67.8 97.7 24.3 37.3 0.0 0.0 67.8
b
61.0 60.5 32.2c 4.0d 2.3 75.1 61.0 100.0e 100.0f 1.7g
(228) b
75.2 74.6 33.5c
100.0 15.8 15.8 30.7
b
83.3 82.9 25.4c
ACCEPTED MANUSCRIPT
Ceftriaxone Levofloxacin Erythromycin Clindamycin Penicillin
Criteria as published by CLSI [2016] Breakpoints from FDA Package Insert revised 12/2014 c Using meningitis breakpoints d Using non-meningitis breakpoints e Using oral breakpoints f Using parenteral, meningitis breakpoints g Using parenteral, non-meningitis breakpoints a b
1/1 >8 / >8 >1 / >1
≤0.5 — >4 ≤0.06 — >8 ≤0.25 — >1
CR
MA NU S
2/4
≤0.06 — >4
(115) 98.3 15.7 17.4 0.0 0.0 99.1 0.0 16.5 0.0 0.0 5.2
b
83.5 82.6 100.0c 17.4d 0.0 100.0 82.6 98.3e 100.0f 6.1g
0.06 / 0.06 ≤0.03 / 0.06 4/8 >8 / >8 2/4 1/1 >8 / >8 >1 / >1 4/4
IP
T
MIC Range
ED
Ceftriaxone-NS SPN Omadacycline Tigecycline Doxycycline Tetracycline
MIC50/90
PT
Penicillin
%R 5.8d 0.9 98.3 65.3 60.9e 99.7f 2.0g
CE
Levofloxacin Erythromycin Clindamycin
US CLSIa %S 66.5 98.5 0.9 33.8 0.3 0.3 53.1
AC
Organism group (no. tested) antimicrobial agent
≤0.015 — 0.25 ≤0.03 — 0.12 ≤0.06 — >8 ≤0.25 — >8 2—8 ≤0.5 — 4 2 — >8 ≤0.25 — >1 0.25 — >4
EU CLSIa %S 74.6 95.6 8.8 26.3 6.1 6.1 76.3
%R 2.6d 4.4 89.9 70.6 61.8e 93.9f 1.3g
MIC50/90
MIC Range
1/1 >8 / >8 >1 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
2/4
≤0.06 — >4
0.06 / 0.12 ≤0.03 / 0.06 4/8 >8 / >8
0.03 — 0.25 ≤0.03 — 0.06 0.12 — >8 ≤0.25 — >8
2/4
2—8
1/1 >8 / >8 >1 / >1
≤0.5 — >4 ≤0.12 — >8 ≤0.25 — >1
4/4
1 — >4
(59) 100.0 35.6 37.3 0.0 0.0 98.3 16.9 28.8 0.0 0.0 39.0
b
62.7 62.7 100.0c 11.9d 1.7 83.1 71.2 96.6e 100.0f 5.1g
Highlights
PT RI SC NU MA ED PT CE
ACCEPTED MANUSCRIPT
Omadacycline activity against S. pneumoniae comparable over time (2010-2014) Omadacycline MIC90 values were similar for penicillin-S, -I, -R, MDR, and ceftriaxone-NS subgroups A high degree of resistance exists for doxycycline, erythromycin, and trimethoprim/sulfamethoxazole
AC