Activity of Solithromycin Tested Against Pathogens Associated with Community-acquired ICAAC 2015 JMI Laboratories Bacterial Pneumonia: Global Surveillance Results for 2014 North Liberty, IA, USA C-622 www.jmilabs.com DJ FARRELL, RK FLAMM, HS SADER, RN JONES ph. 319.665.3370, fax 319.665.3371 JMI Laboratories, North Liberty, Iowa, USA [email protected] • Solithromycin inhibited 85.3% (873/1,024) of the S. aureus isolates at ≤1 Table 2. Activity of solithromycin and comparators when tested AMENDED ABSTRACT INTRODUCTION RESULTS µg/mL (Table 1). Macrolide resistance was high in S. aureus; using CLSI against bacterial pathogens recovered as part of the global CONCLUSIONS breakpoints, 40.9% of S. aureus were resistant to azithromycin (Table 2). surveillance program for 2014. Solithromycin (formerly CEM-101), is a 4th generation oral and As observed in previous surveillance years, the activity of solithromycin Background: Solithromycin (SOL) is a fluoroketolide with • Solithromycin was very active (MIC50/90, 0.008/0.12 µg/mL) against 1,713 S. MIC (µg/mL) CLSIa EUCASTa • Solithromycin demonstrated potent activity intravenous macrolide in Phase III clinical development for the was lower against methicillin-resistant S. aureus (MRSA; MIC50/90, wide spectrum of activity against pathogens associated pneumoniae isolates, demonstrating two-fold greater activity than MIC50 MIC90 Range %S %I %R %S %I %R treatment of moderate to moderately-severe community-acquired telithromycin (MIC , 0.015/0.25 µg/mL) and 16- to >256-fold greater 0.06/>32 µg/mL) when compared to methicillin-susceptible (MSSA; S. pneumoniae (1,713 isolates) against global and contemporary (2014) with community-acquired bacterial pneumonia (CABP). 50/90 Solithromycin 0.008 0.12 0.002 — 1 -b - - - - - bacterial pneumonia (CABP). activity than azithromycin (MIC , 0.12/>32 µg/mL, (Table 2). All MIC50/90, 0.06/0.06 µg/mL; Tables 1 and 2) strains. Additionally, the pathogens that are the major causative agents SOL has a potency generally equal to or two-fold greater 50/90 Telithromycin 0.015 0.25 0.004 — >32 99.7 0.1 0.2 90.4 7.6 2.0 pneumococci were inhibited at solithromycin MIC values of ≤1 µg/mL activity of solithromycin against European S. aureus isolates was greater Azithromycin 0.12 >32 0.015 — >32 62.2 0.2 37.6 61.8 0.4 37.8 than telithromycin (TEL), and azithromycin (AZI), as well Clindamycin ≤0.25 >2 ≤0.25 — >2 79.8 1.1 19.2 80.8 - 19.2 of CABP, including against most macrolide- Streptococcus pneumoniae is the predominant causative agent of (current CLSI susceptibility breakpoint for telithromycin, Tables 1 and 2). (MIC50/90, 0.06/2 µg/mL) than the activity of this compound when tested Amox/Clav ≤1 4 ≤1 — >8 89.4 3.4 7.2c 76.7 9.7 13.6 Ampicillin ≤0.25 4 ≤0.25 — >8 - - - 76.7 9.7 13.6 resistant strains. as demonstrated activity against Gram-positive isolates CABP and solithromycin has demonstrated potent activity against Applying EUCAST breakpoint criteria (susceptible at ≤0.25 µg/mL), against strains recovered in the USA (MIC50/90, 0.06/>32 µg/mL), which is 61.5 24.2 14.4d 61.5 - 38.5e having documented resistances to macrolides or this pathogen, including multidrug-resistant (MDR) and macrolide- telithromycin was active against 90.4% of the isolates tested and, using the most likely associated with the higher MRSA rates among the USA Penicillin ≤0.06 2 ≤0.06 — >8 61.5 - 38.5e 61.5 31.9 6.6g resistant strains and genotypes. same breakpoint, 98.9% of the S. pneumoniae isolates would be isolates (44.1% versus 28.1% in Europe). 93.4 5.9 0.7f - - - • Similar to surveillance studies from previous lincosamides, and measurable potencies versus 80.7 11.4 7.9e 80.7 18.2 1.1 Ceftriaxone ≤0.06 1 ≤0.06 — >8 categorized as susceptible to solithromycin varying from 98.7% in the USA f fastidious Gram-negative species causing CABP. We 92.1 6.8 1.1 - - - years, solithromycin was the most potent Solithromycin has also demonstrated activity comparable to and Europe to 100.0% in Latin America and Asia Pacific. Linezolid 1 1 ≤0.12 — 2 100.0 - - 100.0 0.0 0.0 report results from a global study of SOL potency and Figure 1. Penicillin and azithromycin activity against 1,713 S. pneumoniae Moxifloxacin ≤0.12 0.25 ≤0.12 — >4 98.7 0.9 0.4 98.3 - 1.7 antimicrobial agent tested against S. azithromycin against Haemophilus influenzae, very potent activity isolates by geographical region. Tetracycline ≤0.5 >8 ≤0.5 — >8 73.0 0.6 26.4 73.0 0.6 26.4 resistance (R) rates for 2014. • Penicillin (using CLSI oral breakpoints)/azithromycin susceptibility rates TMP/SMX ≤0.5 >4 ≤0.5 — >4 66.0 11.2 22.9 72.9 4.2 22.9 against Moraxella catarrhalis, beta-hemolytic streptococci, Legionella pneumoniae. were 61.5/62.2% overall (Table 2, Figure 1), 57.2/51.3% in the USA, Vancomycin 0.25 0.5 ≤0.12 — 1 100.0 - - 100.0 - 0.0 pneumophila, Mycoplasma pneumoniae (including macrolide- H. influenzae (1,308 isolates) Methods: A total of 4,622 isolates, including 66.0/70.3% in Europe, 53.6/63.9% in Latin America, and 63.5/73.1% in Asia Penicillin Solithromycin 1 2 ≤0.06 — >8 - - - - - - resistant strains), and Chlamydophila pneumoniae, and variable 100 Pacific (note: 8/10 centers were in Australia and New Zealand hence these Telithromycin 1 2 ≤0.06 — >8 98.7 0.7 0.6 0.5 98.9 0.6 • These data support and encourage the Streptococcus pneumoniae (SPN; 1,713), Haemophilus 14.4 13.3 14.4 14.4 activity against S. aureus (activity dependent upon the type of values may not reflect the true prevalence in the region). Overall, 90 21.6 Azithromycin 0.5 1 ≤0.03 — >4 99.4 - - 2.5 96.9 0.6 influenzae (HI; 1,308), Moraxella catarrhalis (MC; 577), 80 Clarithromycin 4 8 ≤0.12 — >16 94.5 4.2 1.3 2.2 97.8 0.0 continued clinical development of macrolide resistance mechanisms present). 24.2 19.6 22.1 Amox/Clav ≤1 2 ≤1 — 8 99.9 - 0.1 98.9 - 1.1 ceftriaxone susceptibility (using CLSI non-meningitis breakpoints) was 70 29.5 and Staphylococcus aureus (SA; 1,024), were 24.7 Ampicillin ≤0.25 >8 ≤0.25 — >8 76.9 1.3 21.8 76.9 - 23.1b solithromycin for the treatment of community- 92.1%, tetracycline 73.0%, trimethoprim-sulfamethoxazole 66.0%, 60 Ceftriaxone ≤0.06 ≤0.06 ≤0.06 — 0.25 100.0 - - 99.9 - 0.1 susceptibility (S) tested by CLSI broth microdilution In this study, we report solithromycin and comparator antimicrobial clindamycin 79.8%, moxifloxacin 98.7%, and vancomycin 100.0% (Table 2). 50 Moxifloxacin ≤0.12 ≤0.12 ≤0.12 — 4 99.8 - - 99.5 - 0.5 acquired bacterial pneumonia. agent activities, measured by reference Clinical and Laboratory 40 Tetracycline 0.5 0.5 ≤0.12 — >16 98.5 0.1 1.4 98.5 0.1 1.5 methods with categorical interpretations (M07-A10, TMP/SMX ≤0.5 >4 ≤0.5 — >4 65.2 7.0 27.8 65.2 2.1 32.7 30 61.5 66.0 63.5 Standards Institute (CLSI) methods, tested against a total of 4,622 • Among 1,308 H. influenzae isolates collected in 2014, nearly all (99.2%) 57.2 53.6 M100-S25) against SOL, TEL, AZI, and other comparator M. catarrhalis (577 isolates) CABP pathogens collected in medical centers globally during 2014. were inhibited by solithromycin at ≤4 µg/mL (Table 1). At the same 20 Solithromycin 0.06 0.12 0.002 — 2 - - - - - - agents. The geographic samples included 2,012 strains breakpoint MIC value, telithromycin inhibited 98.7% of these isolates 10 Telithromycin 0.12 0.12 0.002 — 2 - - - 99.7 0.2 0.2 0 Azithromycin 0.03 0.06 0.002 — 0.5 99.8 - - 99.8 0.2 0.0 from the USA, 1,990 from Europe, 297 from Latin (Tables 1 and 2). Solithromycin showed identical potency to that of All isolates (1713) USA (715) Europe (797) Latin America (97) Asia Pacific (104) Clarithromycin ≤0.12 ≤0.12 ≤0.12 — 16 99.8 - - 99.7 0.2 0.2 ACKNOWLEDGEMENT Amox/Clav ≤1 ≤1 ≤1 — ≤1 100.0 - 0.0 100.0 - 0.0 America, and 323 from Asia Pacific. telithromycin (MIC50/90, 1/2 µg/mL) and both were two-fold less active than Penicillin %S Penicillin %I Penicillin %R Ampicillin 1 2 ≤0.25 — >8 - - - - - - This work was funded through a grant provided by CEMPRA MATERIALS AND METHODS azithromycin (MIC50/90, 0.5/1 µg/mL) against these isolates (Table 2). Penicillin >0.12 >0.12 ≤0.03 — >0.12 - - - - - - Ceftriaxone 0.25 0.5 ≤0.06 — 2 100.0 - - 99.8 0.2 0.0 Pharmaceuticals (Chapel Hill, North Carolina). Results: SOL was very active (Table) against SPN, Telithromycin and azithromycin were active against 98.7 and 99.4%, Azithromycin Moxifloxacin ≤0.12 ≤0.12 ≤0.12 — 0.5 - - - 100.0 - 0.0 demonstrating two-fold greater activity than TEL (MIC , A total of 4,622 non-duplicated isolates were collected prospectively respectively, of H. influenzae isolates at current CLSI breakpoints. 100 Tetracycline ≤0.12 0.25 ≤0.12 — >16 99.7 0.0 0.3 99.7 0.0 0.3 50/90 TMP/SMX ≤0.5 ≤0.5 ≤0.5 — 2 94.5 5.5 0.0 94.5 3.8 1.7 during 2014 from 91 medical centers located in the USA (38 centers, 90 25.0 Susceptibility rates were very low against telithromycin and azithromycin 29.7 S.