Abstract
Solithromycin, a fourth-generation macrolide (a fluoroketolide with enhanced activity against macrolide-resistant bacteria due to interaction with three ribosomal sites) and the first fluoroketolide, was tested against a 2014 collection of 6,115 isolates, including Streptococcus pneumoniae (1,713 isolates), Haemophilus influenzae (1,308), Moraxella catarrhalis (577), Staphylococcus aureus (1,024), and beta-hemolytic streptococci (1,493), by reference broth microdilution methods. The geographic samples included 2,748 isolates from the United States, 2,536 from Europe, 386 from Latin America, and 445 from the Asia-Pacific region. Solithromycin was observed to be very active against S. pneumoniae (MIC50/90, 0.008/0.12 μg/ml), demonstrating 2-fold greater activity than telithromycin (MIC50/90, 0.015/0.25 μg/ml) and 16- to >256-fold greater activity than azithromycin (MIC50/90, 0.12/>32 μg/ml), with all strains being inhibited at a solithromycin MIC of ≤1 μg/ml. Against H. influenzae, solithromycin showed potency identical to that of telithromycin (MIC50/90, 1/2 μg/ml), and both of these compounds were 2-fold less active than azithromycin (MIC50/90, 0.5/1 μg/ml). All but one of the M. catarrhalis isolates were inhibited by solithromycin at ≤0.25 μg/ml. Solithromycin inhibited 85.3% of S. aureus isolates at ≤1 μg/ml, and its activity was lower against methicillin-resistant (MIC50/90, 0.06/>32 μg/ml) than against methicillin-susceptible (MIC50/90, 0.06/0.06 μg/ml) isolates. Little variation in solithromycin activity was observed by geographic region for the species tested. Solithromycin was very active against beta-hemolytic streptococci (MIC50/90, 0.015/0.03 μg/ml), and all isolates were inhibited at MIC values of ≤0.5 μg/ml. In conclusion, solithromycin demonstrated potent activity against global and contemporary (2014) pathogens that represent the major causes of community-acquired bacterial pneumonia. These data support the continued clinical development of solithromycin for the treatment of this important indication.
INTRODUCTION
Solithromycin is a fluoroketolide that is a semisynthetic macrolide antibiotic derived from erythromycin A and was designed primarily to overcome macrolide-resistant streptococci, including multidrug-resistant (MDR) Streptococcus pneumoniae. Macrolides exert their effect by inhibiting protein synthesis, specifically through the inhibition of the formation of the 50S ribosomal subunit (1). Solithromycin (formerly CEM-101) is a fourth-generation macrolide (a fluoroketolide with enhanced activity against macrolide-resistant bacteria due to interaction with three ribosomal sites) and the first fluoroketolide in phase III clinical development for the treatment of moderate to moderately severe community-acquired bacterial pneumonia (CABP) and gonorrhea. It is being developed to be available in oral, intravenous, and pediatric suspension formulations. Solithromycin has demonstrated potent activity against S. pneumoniae, including MDR and macrolide-resistant strains and genotypes (2–5). Interestingly, unlike older macrolides, solithromycin exhibits bactericidal activity against macrolide-susceptible streptococci and coagulase-negative staphylococci (CoNS) (2). Furthermore, solithromycin had low minimum bactericidal concentration (MBC)/MIC ratios (≤4) for beta-hemolytic streptococci, Staphylococcus aureus, and CoNS, along with 2-fold greater potency than telithromycin (2). The mechanism for the bactericidal activity of solithromycin has been investigated and is believed to be related to incorrect peptide synthesis (6). Solithromycin interacts with three distinct sites on the bacterial ribosome, thereby limiting the emergence of resistant strains (6). This is in contrast to the older macrolides, such as erythromycin and azithromycin, which bind to the bacterial ribosome at a single site and are bacteriostatic. In addition to inhibition of protein synthesis and ribosome formation, solithromycin has also been shown to stimulate 23S rRNA turnover in S. pneumoniae, S. aureus, and Haemophilus influenzae (7).
S. pneumoniae is the predominant causative agent of CABP. The introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) into the United States childhood vaccine schedule in 2000, followed by PCV13 in 2010, and the selective pressure of antimicrobial use have been associated with the emergence of MDR strains outside vaccine coverage (such as serotype 19A post-PCV7/pre-PCV13 introduction) (3–5). These observations serve to highlight the dynamic nature of circulating clones of S. pneumoniae and the prevalence of antimicrobial resistance in this species, which emphasize the need for continued antimicrobial resistance surveillance.
Solithromycin has also demonstrated activity comparable to that of azithromycin against H. influenzae; very potent activity against Moraxella catarrhalis, beta-hemolytic streptococci, Legionella pneumophila, Mycoplasma pneumoniae (including macrolide-resistant strains), and Chlamydophila pneumoniae; and variable activity against S. aureus (activity dependent upon the type of macrolide resistance mechanisms present) (2, 8–12). This documented wide spectrum of in vitro activity against the major CABP pathogens has provided the impetus for solithromycin to move forward into clinical investigations.
In this study, we report the activities of solithromycin and comparator antimicrobial agents, measured by reference Clinical and Laboratory Standards Institute (CLSI) methods, tested against 6,115 clinical isolates collected in medical centers globally during 2014.
MATERIALS AND METHODS
A total of 6,115 nonduplicated isolates were collected prospectively during 2014 from 94 medical centers located in the United States (38 centers; 2,748 isolates), Europe (36 centers; 2,536 isolates), Latin America (10 centers; 386 isolates), and the Asia-Pacific region (10 centers; 445 isolates). These isolates were recovered consecutively from patients with respiratory tract infections (RTIs), bloodstream infections (BSIs), skin and skin structure infections (SSSIs), and other infection types, with only one strain per patient infection episode defined as being clinically significant being included.
Countries participating (number of centers; number of isolates) were as follows: Argentina (2; 87), Australia (6; 290), Belgium (1; 97), Brazil (4; 154), Chile (2; 78), the Czech Republic (2; 52), France (3; 294), Germany (4; 258), Greece (1; 40), Hong Kong (1; 33), Hungary (1; 59), Ireland (2; 177), Israel (1; 28), Italy (4; 200), Mexico (2; 67), New Zealand (2; 81), Poland (1; 126), Portugal (1; 62), Romania (1; 25), Russia (3; 170), Spain (3; 240), Sweden (2; 211), Taiwan (1; 41), Turkey (2; 180), the United Kingdom (3; 270), Ukraine (1; 47), and the United States (38; 2,748).
Isolates were identified by the submitting laboratories and confirmed by JMI Laboratories (North Liberty, IA, USA) using standard bacteriologic algorithms and methodologies, including the use of Vitek identification systems (bioMérieux, Hazelwood, MO, USA), matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS; Bruker Daltonics, Bremen, Germany), and DNA sequencing-based methods, when required.
Isolates were tested for susceptibility by broth microdilution methods, according to the recommendations of the CLSI (13). For solithromycin, telithromycin, and azithromycin, MIC results were obtained by using validated broth microdilution trays produced by JMI Laboratories (North Liberty, IA), and for other antimicrobial agents, MIC results were obtained by using panels (Sensititre) manufactured by Thermo Scientific (formerly Trek Diagnostics Systems, Cleveland, OH, USA). Validation of the MIC values was performed by concurrent testing of quality control (QC) strains, including S. pneumoniae ATCC 49619, Enterococcus faecalis ATCC 29212, S. aureus ATCC 29213, and H. influenzae ATCC 49247. In addition, the inoculum density was monitored by colony counts to ensure an adequate number of cells for each testing event. MIC interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint criteria (14, 15).
RESULTS
Over 6,000 isolates were evaluated, and MIC distributions and susceptibility profiles of the organisms and organism groups analyzed are listed in Tables 1 and 2. Solithromycin was very active (MIC50/90, 0.008/0.12 μg/ml) against 1,713 S. pneumoniae isolates, demonstrating 2-fold greater activity than telithromycin (MIC50/90, 0.015/0.25 μg/ml) and 16- to >256-fold greater activity than azithromycin (MIC50/90, 0.12/>32 μg/ml) (Table 2). All pneumococci were inhibited at solithromycin MIC values of ≤1 μg/ml (current CLSI susceptibility breakpoint for telithromycin) (Tables 1 and 2). Applying EUCAST breakpoint criteria (susceptible at ≤0.25 μg/ml), telithromycin was active against 90.4% of the isolates tested, and using the same breakpoint, 98.9% of the S. pneumoniae isolates would be categorized as susceptible to solithromycin, with rates varying from 98.7% in the United States and Europe to 100.0% in Latin America and the Asia-Pacific region (data not shown).
TABLE 1.
Frequency distributions of solithromycin tested against bacterial pathogens recovered as part of a global surveillance program (2014)
| Organism group (no. of isolates tested) | No. (%) of isolates inhibited at MIC (μg/ml) ofb: |
MIC50/90 (μg/ml) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.002 | 0.004 | 0.008 | 0.015 | 0.03 | 0.06a | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | >8 | ||
| S. pneumoniae (1,713) | 1 (0.1) | 7 (0.5) | 1,035 (60.9) | 227 (74.1) | 111 (80.6) | 92 (86.0) | 128 (93.5) | 93 (98.9) | 16 (99.8) | 3 (100.0) | 0.008/0.12 | ||||
| USA (715) | 1 (0.1) | 1 (0.3) | 371 (52.2) | 73 (62.4) | 62 (71.0) | 49 (77.9) | 86 (89.9) | 63 (98.7) | 8 (99.9) | 1 (100.0) | 0.008/0.25 | ||||
| Europe (797) | 5 (0.6) | 532 (67.4) | 128 (83.4) | 37 (88.1) | 32 (92.1) | 29 (95.7) | 24 (98.7) | 8 (99.7) | 2 (100.0) | 0.008/0.06 | |||||
| Latin America (97) | 57 (58.8) | 12 (71.1) | 9 (80.4) | 10 (90.7) | 5 (95.9) | 4 (100.0) | 0.008/0.06 | ||||||||
| Asia-Pacific (104) | 1 (1.0) | 75 (73.1) | 14 (86.5) | 3 (89.4) | 1 (90.4) | 8 (98.1) | 2 (100.0) | 0.008/0.06 | |||||||
| H. influenzae (1,308) | — | — | — | — | — | 1 (0.1) | 6 (0.5) | 37 (3.4) | 238 (21.6) | 680 (73.5) | 314 (97.6) | 22 (99.2) | 4 (99.5) | 6 (100.0) | 1/2 |
| USA (615) | — | — | — | — | — | 1 (0.2) | 4 (0.8) | 24 (4.7) | 97 (20.5) | 305 (70.1) | 164 (96.7) | 14 (99.0) | 2 (99.4) | 4 (100.0) | 1/2 |
| Europe (572) | — | — | — | — | — | 0 (0.0) | 2 (0.3) | 10 (2.1) | 117 (22.6) | 308 (76.4) | 126 (98.4) | 6 (99.5) | 1 (99.7) | 2 (100.0) | 1/2 |
| Latin America (60) | — | — | — | — | — | 0 (0.0) | 0 (0.0) | 2 (3.3) | 19 (35.0) | 30 (85.0) | 8 (98.3) | 0 (98.3) | 1 (100.0) | 1/2 | |
| Asia-Pacific (61) | — | — | — | — | — | 0 (0.0) | 0 (0.0) | 1 (1.6) | 5 (9.8) | 37 (70.5) | 16 (96.7) | 2 (100.0) | 1/2 | ||
| M. catarrhalis (577) | 1 (0.2) | 2 (0.5) | 10 (2.3) | 10 (4.0) | 29 (9.0) | 340 (67.9) | 179 (99.0) | 5 (99.8) | 0 (99.8) | 0 (99.8) | 1 (100.0) | 0.06/0.12 | |||
| USA (281) | 1 (0.4) | 1 (0.7) | 4 (2.1) | 5 (3.9) | 16 (9.6) | 180 (73.7) | 70 (98.6) | 3 (99.6) | 0 (99.6) | 0 (99.6) | 1 (100.0) | 0.06/0.12 | |||
| Europe (216) | 1 (0.5) | 3 (1.9) | 2 (2.8) | 9 (6.9) | 122 (63.4) | 77 (99.1) | 2 (100.0) | 0.06/0.12 | |||||||
| Latin America (30) | 2 (6.7) | 1 (10.0) | 1 (13.3) | 16 (66.7) | 10 (100.0) | 0.06/0.12 | |||||||||
| Asia-Pacific (50) | 1 (2.0) | 2 (6.0) | 3 (12.0) | 22 (56.0) | 22 (100.0) | 0.06/0.12 | |||||||||
| S. aureus (1,024) | 2 (0.2) | 3 (0.5) | 152 (15.3) | 693 (83.0) | 16 (84.6) | 2 (84.8) | 2 (85.0) | 3 (85.3) | 3 (85.5) | 3 (85.8) | 1 (85.9) | 144 (100.0) | 0.06/>32 | ||
| USA (401) | 2 (0.5) | 1 (0.7) | 33 (9.0) | 284 (79.8) | 8 (81.8) | 1 (82.0) | 2 (82.5) | 1 (82.8) | 0 (82.8) | 2 (83.3) | 1 (83.5) | 66 (100.0) | 0.06/>32 | ||
| Europe (405) | 1 (0.2) | 58 (14.6) | 295 (87.4) | 7 (89.1) | 1 (89.4) | 0 (89.4) | 1 (89.6) | 3 (90.4) | 0 (90.4) | 0 (90.4) | 39 (100.0) | 0.06/2 | |||
| Latin America (110) | 29 (26.4) | 50 (71.8) | 0 (71.8) | 0 (71.8) | 0 (71.8) | 1 (72.7) | 0 (72.7) | 1 (73.6) | 0 (73.6) | 29 (100.0) | 0.06/>32 | ||||
| Asia-Pacific (108) | 1 (0.9) | 32 (30.6) | 64 (89.8) | 1 (90.7) | 0 (90.7) | 0 (90.7) | 0 (90.7) | 0 (90.7) | 0 (90.7) | 0 (90.7) | 10 (100.0) | 0.06/0.12 | |||
| ΒHSc (1,493) | 1 (0.1) | 739 (49.6) | 549 (86.3) | 74 (91.3) | 89 (97.3) | 19 (98.5) | 20 (99.9) | 2 (100.0) | 1 (0.1) | 0.015/0.03 | |||||
| USA (736) | 1 (0.1) | 338 (46.1) | 275 (83.4) | 49 (90.1) | 57 (97.8) | 9 (99.0) | 6 (99.9) | 1 (100.0) | 1 (0.1) | 0.015/0.03 | |||||
| Europe (546) | 216 (88.1) | 19 (91.6) | 28 (96.7) | 7 (98.0) | 11 (100.0) | — | 0.015/0.03 | ||||||||
| Latin America (89) | 63 (70.8) | 20 (93.3) | 2 (95.5) | 2 (97.8) | 1 (98.9) | 1 (100.0) | — | 0.008/0.015 | |||||||
| Asia-Pacific (122) | 73 (59.8) | 38 (91.0) | 4 (94.3) | 2 (95.9) | 2 (97.5) | 2 (99.2) | 1 (100.0) | — | 0.008/0.015 | ||||||
MIC of ≤0.06 μg/ml for H. influenzae.
—, not tested at this concentration.
BHS, beta-hemolytic streptococci.
TABLE 2.
Activities of solithromycin and comparators against bacterial pathogens recovered as part of a global surveillance program for 2014
| Organism (no. of isolates) and drugg | MIC50 (μg/ml) | MIC90 (μg/ml) | MIC range (μg/ml) | % of isolates with breakpoint according toa: |
|||||
|---|---|---|---|---|---|---|---|---|---|
| CLSI |
EUCAST |
||||||||
| S | I | R | S | I | R | ||||
| S. pneumoniae (1,713) | |||||||||
| Solithromycin | 0.008 | 0.12 | 0.002–1 | — | — | — | — | — | — |
| Telithromycin | 0.015 | 0.25 | 0.004–>32 | 99.7 | 0.1 | 0.2 | 90.4 | 7.6 | 2.0 |
| Azithromycin | 0.12 | >32 | 0.015–>32 | 62.2 | 0.2 | 37.6 | 61.8 | 0.4 | 37.8 |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 79.8 | 1.1 | 19.2 | 80.8 | — | 19.2 |
| Amoxicillin-clavulanate | ≤1 | 4 | ≤1–>8 | 89.4 | 3.4 | 7.2b | 76.7 | 9.7 | 13.6 |
| Ampicillin | ≤0.25 | 4 | ≤0.25–>8 | — | — | — | 76.7 | 9.7 | 13.6 |
| Penicillin | ≤0.06 | 2 | ≤0.06–>8 | 61.5 | 24.2 | 14.4c | 61.5 | — | 38.5d |
| 61.5 | — | 38.5d | 61.5 | 31.9 | 6.6f | ||||
| 93.4 | 5.9 | 0.7e | — | — | — | ||||
| Ceftriaxone | ≤0.06 | 1 | ≤0.06–>8 | 80.7 | 11.4 | 7.9d | 80.7 | 18.2 | 1.1 |
| 92.1 | 6.8 | 1.1e | — | — | — | ||||
| Linezolid | 1 | 1 | ≤0.12–2 | 100.0 | — | — | 100.0 | 0.0 | 0.0 |
| Moxifloxacin | ≤0.12 | 0.25 | ≤0.12–>4 | 98.7 | 0.9 | 0.4 | 98.3 | — | 1.7 |
| Tetracycline | ≤0.5 | >8 | ≤0.5–>8 | 73.0 | 0.6 | 26.4 | 73.0 | 0.6 | 26.4 |
| TMP-SMX | ≤0.5 | >4 | ≤0.5–>4 | 66.0 | 11.2 | 22.9 | 72.9 | 4.2 | 22.9 |
| Vancomycin | 0.25 | 0.5 | ≤0.12–1 | 100.0 | — | — | 100.0 | — | 0.0 |
| H. influenzae (1,308) | |||||||||
| Solithromycin | 1 | 2 | ≤0.06–>8 | — | — | — | — | — | — |
| Telithromycin | 1 | 2 | ≤0.06–>8 | 98.7 | 0.7 | 0.6 | 0.5 | 98.9 | 0.6 |
| Azithromycin | 0.5 | 1 | ≤0.03–>4 | 99.4 | — | — | 2.5 | 96.9 | 0.6 |
| Clarithromycin | 4 | 8 | ≤0.12–>16 | 94.5 | 4.2 | 1.3 | 2.2 | 97.8 | 0.0 |
| Amoxicillin-clavulanate | ≤1 | 2 | ≤1–8 | 99.9 | — | 0.1 | 98.9 | — | 1.1 |
| Ampicillin | ≤0.25 | >8 | ≤0.25–>8 | 76.9 | 1.3 | 21.8 | 76.9 | — | 23.1 |
| Ceftriaxone | ≤0.06 | ≤0.06 | ≤0.06–0.25 | 100.0 | — | — | 99.9 | — | 0.1 |
| Moxifloxacin | ≤0.12 | ≤0.12 | ≤0.12–4 | 99.8 | — | — | 99.5 | — | 0.5 |
| Tetracycline | 0.5 | 0.5 | ≤0.12–>16 | 98.5 | 0.1 | 1.4 | 98.5 | 0.1 | 1.5 |
| TMP-SMX | ≤0.5 | >4 | ≤0.5–>4 | 65.2 | 7.0 | 27.8 | 65.2 | 2.1 | 32.7 |
| M. catarrhalis (577) | |||||||||
| Solithromycin | 0.06 | 0.12 | 0.002–2 | — | — | — | — | — | — |
| Telithromycin | 0.12 | 0.12 | 0.002–2 | — | — | — | 99.7 | 0.2 | 0.2 |
| Azithromycin | 0.03 | 0.06 | 0.002–0.5 | 99.8 | — | — | 99.8 | 0.2 | 0.0 |
| Clarithromycin | ≤0.12 | ≤0.12 | ≤0.12–16 | 99.8 | — | — | 99.7 | 0.2 | 0.2 |
| Amoxicillin-clavulanate | ≤1 | ≤1 | ≤1–≤1 | 100.0 | — | 0.0 | 100.0 | — | 0.0 |
| Ampicillin | 1 | 2 | ≤0.25–>8 | — | — | — | — | — | — |
| 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 |
| Moxifloxacin | ≤0.12 | ≤0.12 | ≤0.12–0.5 | — | — | — | 100.0 | — | 0.0 |
| Tetracycline | ≤0.12 | 0.25 | ≤0.12–>16 | 99.7 | 0.0 | 0.3 | 99.7 | 0.0 | 0.3 |
| TMP-SMX | ≤0.5 | ≤0.5 | ≤0.5–2 | 94.5 | 5.5 | 0.0 | 94.5 | 3.8 | 1.7 |
| S. aureus (1,024) | |||||||||
| Solithromycin | 0.06 | >32 | 0.008–>32 | — | — | — | — | — | — |
| Telithromycin | 0.06 | >32 | 0.008–>32 | 84.5 | 0.1 | 15.4 | — | — | — |
| Azithromycin | 1 | >32 | 0.008–>32 | 58.7 | 0.4 | 40.9 | 57.8 | 0.9 | 41.3 |
| Oxacillin | 0.5 | >2 | ≤0.25–>2 | 65.1 | — | 34.9 | 65.1 | — | 34.9 |
| Amoxicillin-clavulanate | ≤1 | >8 | ≤1–>8 | 65.1 | — | 34.9 | 65.1 | — | 34.9 |
| Penicillin | 8 | >8 | ≤0.06–>8 | 16.5 | — | 83.5 | 16.6 | — | 83.4 |
| Ceftriaxone | 4 | >8 | 1–>8 | 65.1 | — | 34.9 | — | — | — |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 84.7 | 0.1 | 15.2 | 84.2 | 0.5 | 15.3 |
| Linezolid | 1 | 1 | ≤0.12–2 | 100.0 | — | 0.0 | 100.0 | — | 0.0 |
| Moxifloxacin | ≤0.12 | 4 | ≤0.12–>4 | 68.0 | 7.6 | 24.5 | 68.0 | 7.6 | 24.5 |
| Tetracycline | ≤0.5 | ≤0.5 | ≤0.5–>8 | 93.7 | 0.4 | 5.9 | 92.2 | 0.6 | 7.2 |
| TMP-SMX | ≤0.5 | ≤0.5 | ≤0.5–>4 | 97.8 | — | 2.2 | 97.8 | 0.2 | 2.1 |
| Vancomycin | 1 | 1 | 0.25–2 | 100.0 | 0.0 | 0.0 | 100.0 | — | 0.0 |
| MSSA (667) | |||||||||
| Solithromycin | 0.06 | 0.06 | 0.03–>32 | — | — | — | — | — | — |
| Telithromycin | 0.06 | 0.12 | 0.015–>32 | 96.6 | 0.0 | 3.4 | — | — | — |
| Azithromycin | 1 | >32 | 0.008–>32 | 77.5 | 0.6 | 21.9 | 76.5 | 1.0 | 22.5 |
| Clindamycin | ≤0.25 | ≤0.25 | ≤0.25–>2 | 96.3 | 0.0 | 3.7 | 95.7 | 0.6 | 3.7 |
| Amoxicillin-clavulanate | ≤1 | ≤1 | ≤1–>8 | 100.0 | — | 0.0 | 100.0 | — | 0.0 |
| Penicillin | 2 | >8 | ≤0.06–>8 | 25.3 | — | 74.7 | 25.3 | — | 74.7 |
| Ceftriaxone | 4 | 4 | 1–>8 | 100.0 | — | 0.0 | — | — | — |
| Linezolid | 1 | 1 | 0.25–2 | 100.0 | — | 0.0 | 100.0 | — | 0.0 |
| Moxifloxacin | ≤0.12 | ≤0.12 | ≤0.12–>4 | 93.8 | 1.6 | 4.7 | 93.8 | 1.6 | 4.7 |
| Tetracycline | ≤0.5 | ≤0.5 | ≤0.5–>8 | 96.1 | 0.3 | 3.6 | 94.9 | 0.0 | 5.1 |
| TMP-SMX | ≤0.5 | ≤0.5 | ≤0.5–>4 | 99.1 | — | 0.9 | 99.1 | 0.1 | 0.7 |
| Vancomycin | 1 | 1 | 0.25–2 | 100.0 | 0.0 | 0.0 | 100.0 | — | 0.0 |
| MRSA (357) | |||||||||
| Solithromycin | 0.06 | >32 | 0.008–>32 | — | — | — | — | — | — |
| Telithromycin | 0.12 | >32 | 0.008–>32 | 61.9 | 0.3 | 37.8 | — | — | — |
| Azithromycin | >32 | >32 | 0.25–>32 | 23.5 | 0.0 | 76.5 | 23.0 | 0.6 | 76.5 |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 63.0 | 0.3 | 36.7 | 62.7 | 0.3 | 37.0 |
| Amoxicillin-clavulanate | >8 | >8 | ≤1–>8 | 0.0 | — | 100.0 | 0.0 | — | 100.0 |
| Penicillin | >8 | >8 | 0.12–>8 | 0.0 | — | 100.0 | 0.3 | — | 99.7 |
| Ceftriaxone | >8 | >8 | 8–>8 | 0.0 | — | 100.0 | — | — | — |
| Linezolid | 1 | 1 | ≤0.12–2 | 100.0 | — | 0.0 | 100.0 | — | 0.0 |
| Moxifloxacin | 2 | >4 | ≤0.12–>4 | 22.3 | 18.2 | 59.5 | 22.3 | 18.2 | 59.5 |
| Tetracycline | ≤0.5 | >8 | ≤0.5–>8 | 89.2 | 0.6 | 10.2 | 87.3 | 1.7 | 11.0 |
| TMP-SMX | ≤0.5 | ≤0.5 | ≤0.5–>4 | 95.2 | — | 4.8 | 95.2 | 0.3 | 4.5 |
| Vancomycin | 1 | 1 | 0.25–2 | 100.0 | 0.0 | 0.0 | 100.0 | — | 0.0 |
| Beta-hemolytic streptococci (1,493)h | |||||||||
| Solithromycin | 0.015 | 0.03 | 0.004–0.5 | — | — | — | — | — | — |
| Telithromycin | 0.015 | 0.12 | 0.008–>32 | — | — | — | 96.9 | 0.7 | 2.4 |
| Azithromycin | 0.12 | >32 | 0.03–>32 | 75.2 | 0.4 | 24.4 | 75.0 | 0.2 | 24.8 |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 84.9 | 1.1 | 14.0 | 86.0 | — | 14.0 |
| Penicillin | ≤0.06 | ≤0.06 | ≤0.06–0.12 | 100.0 | — | — | 100.0 | — | 0.0 |
| Amoxicillin-clavulanate | ≤1 | ≤1 | ≤1–2 | — | — | — | 100.0 | — | 0.0 |
| Ceftriaxone | ≤0.06 | 0.12 | ≤0.06–0.5 | 100.0 | — | — | 100.0 | — | 0.0 |
| Linezolid | 1 | 1 | ≤0.12–1 | 100.0 | — | — | 100.0 | 0.0 | 0.0 |
| Moxifloxacin | ≤0.12 | 0.25 | ≤0.12–4 | — | — | — | 99.5 | 0.0 | 0.5 |
| Tetracycline | ≤0.5 | >8 | ≤0.5–>8 | 53.5 | 1.7 | 44.8 | 52.5 | 1.0 | 46.5 |
| TMP-SMX | ≤0.5 | ≤0.5 | ≤0.5–>4 | — | — | — | 98.9 | 0.3 | 0.9 |
| Vancomycin | 0.25 | 0.5 | ≤0.12–1 | 100.0 | — | — | 100.0 | — | 0.0 |
Criteria reported by the CLSI (2015) and EUCAST (2015). S, sensitive; I, intermediate; R, resistant; —, breakpoints not available to interpret.
Using nonmeningitis breakpoints.
Using oral breakpoints.
Using parenteral meningitis breakpoints.
Using parenteral nonmeningitis breakpoints.
Using EUCAST breakpoints for “infections other than meningitis.”
TMP-SMX, trimethoprim-sulfamethoxazole.
Organisms include Streptococcus pyogenes (689 isolates), Streptococcus agalactiae (579), and Streptococcus dysgalactiae (225).
Penicillin (using CLSI oral breakpoints) and azithromycin susceptibility rates were 61.5% and 62.2% overall (Table 2 and Fig. 1), 57.2 and 51.3% in the United States, 66.0% and 70.3% in Europe, 53.6% and 63.9% in Latin America, and 63.5% and 73.1% in the Asia-Pacific region, respectively. Overall, the ceftriaxone susceptibility rate (using CLSI nonmeningitis breakpoints) was 92.1%, the tetracycline susceptibility rate was 73.0%, the trimethoprim-sulfamethoxazole susceptibility rate was 66.0%, the clindamycin susceptibility rate was 79.8%, the moxifloxacin susceptibility rate was 98.7%, and the vancomycin susceptibility rate was 100.0% (Table 2).
FIG 1.
Penicillin and azithromycin activities against 1,713 S. pneumoniae isolates by geographical region. (a) Penicillin (CLSI oral breakpoints). (b) Azithromycin (CLSI breakpoints).
Among 1,308 H. influenzae isolates collected in 2014, nearly all (99.2%) were inhibited by solithromycin at ≤4 μg/ml. At the same breakpoint MIC value, telithromycin inhibited 98.7% of these isolates (Tables 1 and 2). Solithromycin showed potency identical to that of telithromycin (MIC50/90, 1/2 μg/ml), and both agents were 2-fold less active than azithromycin (MIC50/90, 0.5/1 μg/ml) against these isolates (Table 2). Telithromycin and azithromycin were active against 98.7% and 99.4%, respectively, of H. influenzae isolates at current CLSI breakpoints. Susceptibility rates were very low for telithromycin (0.5%) and azithromycin (2.5%) when applying EUCAST breakpoint criteria. Additional comparators showing >99% susceptibility rates included moxifloxacin, amoxicillin-clavulanate, and ceftriaxone (Table 2).
All but one of the M. catarrhalis isolates were inhibited by solithromycin at ≤0.25 μg/ml. The single isolate displaying solithromycin and telithromycin MIC results of 2 μg/ml was recovered from the tracheal aspirate of a 3-year-old male ambulatory patient in New York. Solithromycin (MIC50/90, 0.06/0.12 μg/ml) was up to 2-fold more potent than telithromycin (MIC50/90, 0.12/0.12 μg/ml) (Table 2). M. catarrhalis isolates were generally very susceptible to the tested antimicrobial agents (Table 2).
Solithromycin inhibited 85.3% (873/1,024) of the S. aureus isolates at ≤1 μg/ml (Tables 1 and 2). At this same MIC value (currently the CLSI telithromycin breakpoint), telithromycin inhibited 84.5% of these isolates, and azithromycin inhibited only 58.7%. As observed in previous surveillance years, the activity of solithromycin is lower against methicillin-resistant S. aureus (MRSA) (MIC50/90, 0.06/>32 μg/ml) than against methicillin-susceptible S. aureus (MSSA) (MIC50/90, 0.06/0.06 μg/ml) (Tables 1 and 2) strains. Additionally, the activity of solithromycin against European S. aureus isolates was greater (MIC50/90, 0.06/2 μg/ml) than the activity of this compound against strains recovered in the United States (MIC50/90, 0.06/>32 μg/ml), which is most likely associated with the higher MRSA rates among the U.S. isolates (44.1%, versus 28.1% in Europe). The activity of solithromycin against Latin American S. aureus isolates (MIC50/90, 0.06/>32 μg/ml) was similar to that seen in the United States, while the activity of this compound against strains recovered in the Asia-Pacific region (MIC50/90, 0.06/0.12 μg/ml) was the highest among all four regions.
Solithromycin was very potent against beta-hemolytic streptococcal strains (MIC50/90, 0.015/0.03 μg/ml), and all 1,493 isolates were inhibited at solithromycin MIC values of ≤0.5 μg/ml (Table 1). Solithromycin was up to 4-fold more active than telithromycin (MIC50/90, 0.015/0.12 μg/ml) (Table 2) and at least 8-fold more active than azithromycin (MIC50/90, 0.12/>32 μg/ml) (Table 2). Against all beta-hemolytic streptococci, the azithromycin susceptibility rate was 75.0/75.2% (EUCAST/CLSI criteria) overall, and the clindamycin resistance rate was 14.0% (Table 2). All isolates were susceptible to penicillin, linezolid, and vancomycin.
DISCUSSION
Empirical therapy for patients with CABP remains a significant challenge due to the breadth of causative pathogens and increasing antimicrobial resistance (16). In this study, solithromycin displayed broad coverage (100.0% of isolates at ≤1 μg/ml) and potency against S. pneumoniae (MIC90, 0.12 μg/ml). These results were identical to those of a previous study by our group performed on isolates collected in 2009 (8). The macrolide resistance rate for S. pneumoniae was shown to be 34.0% in 2009 (erythromycin was tested, and only the United States and Europe were surveyed), remains high at 37.6% (azithromycin tested) overall, and is highest in the United States, at 48.4% (Fig. 1b). Similarly, the penicillin nonsusceptibility rate remains high among the pneumococci, at 38.6% overall, ranging from 34.0% in Europe to 42.8 and 46.3% in the United States and Latin America, respectively (Fig. 1a). These data demonstrate that the activity of solithromycin against S. pneumoniae has been refractory to the geographical and temporal changes observed for other antimicrobial agents. Importantly, because of the above-discussed changes occurring in the distribution of circulating serotypes, solithromycin was recently documented to maintain activity against the most prevalent macrolide-resistant serotypes circulating in U.S. medical centers during 2012 (2 years after the introduction of PCV13) (5).
Against H. influenzae (MIC90, 2 μg/ml), solithromycin displayed activity similar to those of azithromycin (MIC90, 1 μg/ml) and telithromycin (MIC90, 2 μg/ml), regardless of β-lactam resistance phenotype patterns. Hence, these 2014 data confirm data from previous surveillance reports of solithromycin's potent activity against a large number of geographically diverse (including Latin American and Asia-Pacific countries in the present report) isolates of the major CABP pathogens (8).
Solithromycin was more potent overall against MSSA (MIC50/90, 0.06/0.06 μg/ml) than against MRSA (MIC50/90, 0.06/>32 μg/ml) isolates and had activity similar to the activity seen for telithromycin against MSSA (96.6% susceptible) and MRSA (61.9% susceptible) isolates (Table 2). Solithromycin was very active against beta-hemolytic streptococci (MIC90, 0.03 μg/ml), showing up to 4-fold more activity than telithromycin and at least 8-fold greater potency than azithromycin (Table 2).
Overall, and in contrast to that observed with comparator antimicrobial agents, little variation in solithromycin activity was documented by geographical region for all of the species tested (Table 1). In summary, solithromycin demonstrated potent activity against global and contemporary (2014) CABP pathogens. These data support and encourage the continued clinical development of solithromycin.
ACKNOWLEDGMENTS
This work was funded through a grant provided by Cempra Pharmaceuticals (Chapel Hill, NC).
JMI Laboratories, Inc., has received research and educational grants in 2012 to 2015 from Achaogen, Actelion, Affinium, the American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas, Cempra, Cerexa, Cubist, Daiichi, Dipexium, Durata, Exela, Fedora, the Forest Research Institute, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Merck, Methylgene, Nabriva, Nanosphere, Novartis, Pfizer, Polyphor, Rempex, Roche, Seachaid, Shionogi, Synthes, The Medicines Co., Theravance, Thermo Fisher, Venatorx, Vertex, Waterloo, Wockhardt, and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, and Theravance. In regard to speakers' bureaus and stock options, we have no conflicts of interest to declare.
Funding Statement
This work was funded through a grant provided by Cempra Pharmaceuticals (Chapel Hill, NC).
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