ABSTRACT
Nafithromycin (WCK 4873), a novel antimicrobial agent of the lactone ketolide class, is currently in phase 2 development for treatment of community-acquired bacterial pneumonia (CABP). A total of 4,739 nonduplicate isolates were selected from a 2014 global surveillance program at medical institutions located in 43 countries within the United States, Europe, Latin America, and the Asia-Pacific region. Nafithromycin and comparator agents were used for susceptibility testing by reference broth microdilution methods. Nafithromycin was active against Staphylococcus aureus (MIC50/90, 0.06/>2 μg/ml), including erythromycin-resistant strains exhibiting an inducible clindamycin resistance phenotype (MIC50/90, 0.06/0.06 μg/ml) and telithromycin-susceptible strains (MIC50/90, 0.06/0.06 μg/ml), but it exhibited limited activity against most telithromycin-resistant and clindamycin-resistant isolates that were constitutively resistant to macrolides (MIC50/90, >2/>2 μg/ml). Nafithromycin was very active (MIC50/90, 0.015/0.06 μg/ml) against 1,911 Streptococcus pneumoniae strains, inhibiting all strains, with MIC values of ≤0.25 μg/ml. Telithromycin susceptibility was 99.9% for Streptococcus pneumoniae strains, and nafithromycin was up to 8-fold more potent than telithromycin. Overall, 37.9% of S. pneumoniae strains were resistant to erythromycin, and 19.7% were resistant to clindamycin. Nafithromycin was highly active against 606 Streptococcus pyogenes strains (MIC50/90, 0.015/0.015 μg/ml), inhibiting 100.0% of isolates at ≤0.5 μg/ml, and MIC50/90 values (0.015/0.015 to 0.03 μg/ml) were similar for the 4 geographic regions. Nafithromycin and telithromycin demonstrated comparable in vitro activities against 1,002 Haemophilus influenzae isolates and 504 Moraxella catarrhalis isolates. Overall, nafithromycin showed potent in vitro activity against a broad range of contemporary (2014) global pathogens. These results support the continued clinical development of nafithromycin for treatment of CABP.
KEYWORDS: Streptococcus pneumoniae, Streptococcus pyogenes, ketolides
INTRODUCTION
Nafithromycin (WCK 4873) is a novel antimicrobial agent of the lactone ketolide class that was awarded qualified infectious disease product (QIDP) status by the U.S. Food and Drug Administration (U.S. FDA) in 2015. Nafithromycin has been shown to exhibit potent in vitro activity against respiratory tract pathogens, including multidrug-resistant Streptococcus pneumoniae (1, 2). It is currently undergoing clinical development in the United States that includes a pharmacokinetic study (ClinicalTrials.gov identifier NCT02770404) and a phase 2 study for the treatment of community-acquired bacterial pneumonia (CABP) (ClinicalTrials.gov identifier NCT02903836). In Europe, it has completed single ascending dose (SAD) and multiple ascending dose (MAD) phase 1 pharmacokinetic studies (3, 4).
Ketolides are derivatives of the erythromycin A class that lack the l-cladinose sugar at position 3 of the erythronolide ring and have a ketone in its place (5). Ketolides interact at multiple positions on the ribosome, thus allowing for activity against macrolide-resistant organisms even though the presence of ribosome methylation prevents macrolides from being active (5–8). Due to a spectrum of activity that includes macrolide-resistant organisms, the ketolides have been viewed as an attractive choice for treating infections where multidrug-resistant Gram-positive bacteria may occur, such as CABP (5, 9, 10).
In this study, we evaluated the activities of nafithromycin and comparator antimicrobial agents, measured by reference Clinical and Laboratory Standards Institute (CLSI) methods, and tested them against a large collection of contemporary clinical isolates collected in medical centers worldwide as part of the 2014 SENTRY Antimicrobial Surveillance Program.
RESULTS
Nafithromycin demonstrated bimodal activity (MIC50/90, 0.06/>2 μg/ml) against 716 Staphylococcus aureus isolates (Tables 1 and 2). Regardless of the methicillin-resistant S. aureus (MRSA) profile, nafithromycin showed limited activity (MICs of >2 μg/ml) against most (80/83 strains) telithromycin-resistant (n = 80) and telithromycin-intermediate (n = 3) strains that were also clindamycin resistant, i.e., constitutively resistant to macrolides (Tables 1 and 2). Conversely, nafithromycin activity was high (MIC50/90, 0.06/0.06 μg/ml) against telithromycin-susceptible strains as well as against erythromycin-resistant strains that were susceptible to clindamycin (n = 85) and strains with inducible clindamycin resistance (Table 1). The activity of nafithromycin varied by geographic region, with activity being greater in Europe (EU) (MIC50/90, 0.06/0.06 μg/ml) (Table 2) and the Asia-Pacific region (APAC) (MIC50/90, 0.06/0.12 μg/ml) (Table 2) than in the United States (US) (MIC50/90, 0.06/>2 μg/ml) (Table 2) and Latin America (LATAM) (MIC50/90, 0.06/>2 μg/ml) (Table 2). However, the overall MIC distributions were similar (bimodal) for these regions, and the lower MIC90 values observed for the EU and APAC were reflective of the lower rates of telithromycin resistance in these regions (6.9% and 8.4%, respectively) than in the US (12.2%) and LATAM (18.2%) (Table 2).
TABLE 1.
Cumulative frequency distributions of nafithromycin MIC results against 4,739 bacterial isolates (all regions combined)
| Organism or phenotype (MIC)c | No. of isolates | No. of isolates (cumulative %) with nafithromycin MIC (μg/ml) |
MIC50 (μg/ml) | MIC90 (μg/ml) | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.002 | 0.004 | 0.008 | 0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | >a | ||||
| S. aureus | 716 | 1 (0.1) | 39 (5.6) | 562 (84.1) | 27 (87.8) | 3 (88.3) | 2 (88.5) | 0 (88.5) | 2 (88.8) | 80 (100.0) | 0.06 | >2 | ||||||
| MSSA | 468 | 28 (6.0) | 409 (93.4) | 20 (97.6) | 1 (97.9) | 2 (98.3) | 0 (98.3) | 2 (98.7) | 6 (100.0) | 0.06 | 0.06 | |||||||
| MRSA | 248 | 1 (0.4) | 11 (4.8) | 153 (66.5) | 7 (69.4) | 2 (70.2) | 0 (70.2) | 0 (70.2) | 0 (70.2) | 74 (100.0) | 0.06 | >2 | ||||||
| TelithromycinS (≤1 μg/ml) | 633 | 1 (0.2) | 39 (6.3) | 562 (95.1) | 27 (99.4) | 3 (99.8) | 1 (100.0) | 0.06 | 0.06 | |||||||||
| TelithromycinI (2 μg/ml) | 3 | 1 (33.3) | 0 (33.3) | 0 (33.3) | 2 (100.0) | >2 | ||||||||||||
| TelithromycinR (≥4 μg/ml) | 80 | 2 (2.5) | 78 (100.0) | >2 | >2 | |||||||||||||
| ERYr (≥1 μg/ml), CLIs (≤0.5 μg/ml), D test−b | 85 | 3 (3.5) | 74 (90.6) | 8 (100.0) | 0.06 | 0.06 | ||||||||||||
| ERYr (≥1 μg/ml), CLIs (≤0.5 μg/ml), D test+b | 110 | 11 (10.0) | 93 (94.5) | 4 (98.2) | 0 (98.2) | 1 (99.1) | 0 (99.1) | 0 (99.1) | 1 (100.0) | 0.06 | 0.06 | |||||||
| CLINS (≥1 μg/ml) | 85 | 1 (1.2) | 2 (3.5) | 1 (4.7) | 0 (4.7) | 2 (7.1) | 79 (100.0) | >2 | >2 | |||||||||
| ERYs (≤0.5 μg/ml), CLIs (≤0.5 μg/ml) | 436 | 1 (0.2) | 25 (6.0) | 395 (96.6) | 14 (99.8) | 1 (100.0) | 0.06 | 0.06 | ||||||||||
| S. pneumoniae | 1,911 | 1 (0.1) | 20 (1.1) | 396 (21.8) | 1014 (74.9) | 224 (86.6) | 162 (95.1) | 88 (99.7) | 6 (100.0) | 0.015 | 0.06 | |||||||
| PENs (≤2 μg/ml) | 1,762 | 1 (0.1) | 20 (1.2) | 392 (23.4) | 994 (79.9) | 200 (91.2) | 127 (98.4) | 25 (99.8) | 3 (100.0) | 0.015 | 0.03 | |||||||
| PENi (4 μg/ml) | 133 | 4 (3.0) | 18 (16.5) | 21 (32.3) | 29 (54.1) | 59 (98.5) | 2 (100.0) | 0.06 | 0.12 | |||||||||
| PENr (≥8 μg/ml) | 16 | 2 (12.5) | 3 (31.2) | 6 (68.8) | 4 (93.8) | 1 (100.0) | 0.06 | 0.12 | ||||||||||
| ERYs (≤0.25 μg/ml), CLIs (≤0.25 μg/ml) | 1,173 | 19 (1.6) | 371 (33.2) | 765 (98.5) | 14 (99.7) | 3 (99.9) | 1 (100.0) | 0.015 | 0.015 | |||||||||
| ERYr (≥0.5 μg/ml), CLIs (≤0.25 μg/ml) | 344 | 1 (0.3) | 1 (0.6) | 11 (3.8) | 121 (39.0) | 114 (72.1) | 88 (97.7) | 8 (100.0) | 0.03 | 0.06 | ||||||||
| ERYr (≥0.5 μg/ml), CLIr (≥0.5 μg/ml) | 394 | 14 (3.6) | 128 (36.0) | 96 (60.4) | 71 (78.4) | 79 (98.5) | 6 (100.0) | 0.03 | 0.12 | |||||||||
| TelithromycinS (≤0.25 μg/ml) | 1,707 | 1 (0.1) | 20 (1.2) | 396 (24.4) | 1014 (83.8) | 209 (96.1) | 64 (99.8) | 3 (100.0) | 0.015 | 0.03 | ||||||||
| TelithromycinNS (≥0.5 μg/ml) | 204 | 15 (7.4) | 98 (55.4) | 85 (97.1) | 6 (100.0) | 0.06 | 0.12 | |||||||||||
| S. pyogenes | 606 | 46 (7.6) | 513 (92.2) | 22 (95.9) | 10 (97.5) | 6 (98.5) | 2 (98.8) | 7 (100.0) | 0.015 | 0.015 | ||||||||
| ERYs (≤0.25 μg/ml), CLIs (≤0.25 μg/ml) | 542 | 42 (7.7) | 483 (96.9) | 16 (99.8) | 1 (100.0) | 0.015 | 0.015 | |||||||||||
| ERYr (≥0.5 μg/ml), CLIs (≤0.25 μg/ml) | 33 | 3 (9.1) | 18 (63.6) | 4 (75.8) | 7 (97.0) | 1 (100.0) | 0.015 | 0.06 | ||||||||||
| ERYr (≥0.5 μg/ml), CLIr (≥0.5 μg/ml) | 31 | 1 (3.2) | 12 (41.9) | 2 (48.4) | 2 (54.8) | 5 (71.0) | 2 (77.4) | 7 (100.0) | 0.06 | 0.5 | ||||||||
| H. influenzae | 1002 | 2 (0.2) | 2 (0.4) | 6 (1.0) | 42 (5.2) | 428 (47.9) | 455 (93.3) | 56 (98.9) | 5 (99.4) | 6 (100.0) | 4 | 4 | ||||||
| β-Lactamase positive | 210 | 5 (2.4) | 90 (45.2) | 99 (92.4) | 14 (99.0) | 1 (99.5) | 1 (100.0) | 4 | 4 | |||||||||
| β-Lactamase negative | 792 | 2 (0.3) | 2 (0.5) | 6 (1.3) | 37 (5.9) | 338 (48.6) | 356 (93.6) | 42 (98.9) | 4 (99.4) | 5 (100.0) | 4 | 4 | ||||||
| M. catarrhalis | 504 | 1 (0.2) | 6 (1.4) | 1 (1.6) | 6 (2.8) | 58 (14.3) | 265 (66.9) | 159 (98.4) | 8 (100.0) | 0.12 | 0.25 | |||||||
The MIC was greater than the highest concentration tested, which was 16 μg/ml for H. influenzae and 2 μg/ml for all other organisms.
The D test was performed by broth microdilution as described in CLSI document M100-S26 (20).
Abbreviations: MSSA, methicillin-susceptible S. aureus; MRSA, methicillin-resistant S. aureus; s, susceptible; i, intermediate; r, resistant; ERY, erythromycin; CLI, clindamycin; PEN, penicillin; ns, nonsusceptible.
TABLE 2.
Activities by geographic region for nafithromycin and comparator antimicrobial agents tested against selected clinical isolates
| Organism or antimicrobial agent | US |
EU |
LATAM |
APAC |
||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | MIC50f | MIC90f | % susceptible/% resistant |
n | MIC50f | MIC90f | % susceptible/% resistant |
n | MIC50f | MIC90f | % susceptible/% resistant |
n | MIC50f | MIC90f | % susceptible/% resistant |
|||||
| CLSIa | EUCASTa | CLSIa | EUCASTa | CLSIa | EUCASTa | CLSIa | EUCASTa | |||||||||||||
| S. aureus | 205 | 203 | 154 | 154 | ||||||||||||||||
| Nafithromycin | 0.06 | >2 | 0.06 | 0.06 | 0.06 | >2 | 0.06 | 0.12 | ||||||||||||
| Telithromycin | 0.12 | >2 | 86.8/12.2 | 0.06 | 0.12 | 93.1/6.9 | 0.06 | >2 | 81.2/18.2 | 0.06 | 0.25 | 91.6/8.4 | ||||||||
| Clindamycin | ≤0.25 | >2 | 86.3/13.7 | 86.3/13.7 | ≤0.25 | ≤0.25 | 92.6/7.4 | 91.6/7.4 | ≤0.25 | >2 | 81.2/18.8 | 80.5/18.8 | ≤0.25 | ≤0.25 | 91.6/8.4 | 90.9/8.4 | ||||
| Erythromycin | 4 | >16 | 40.5/49.3 | 42.0/56.1 | 0.25 | >16 | 73.9/23.2 | 73.9/25.6 | 0.25 | >16 | 57.8/36.4 | 57.8/39.6 | 0.25 | >16 | 74.0/21.4 | 74.0/24.7 | ||||
| Linezolid | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | ||||
| Oxacillin | 1 | >2 | 53.7/46.3 | 53.7/46.3 | 0.5 | >2 | 75.4/24.6 | 75.4/24.6 | 0.5 | >2 | 63.6/36.4 | 63.6/36.4 | 0.5 | >2 | 69.5/30.5 | 69.5/30.5 | ||||
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | 98.5/1.5 | 98.5/1.5 | ≤0.5 | ≤0.5 | 99.5/0.5 | 99.5/0.5 | ≤0.5 | ≤0.5 | 99.4/0.6 | 99.4/0.0 | ≤0.5 | ≤0.5 | 97.4/2.6 | 97.4/1.9 | ||||
| Vancomycin | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | ||||
| MRSA | 95 | 50 | 56 | 47 | ||||||||||||||||
| Nafithromycin | 0.06 | >2 | 0.06 | >2 | 0.06 | >2 | 0.06 | >2 | ||||||||||||
| Telithromycin | 0.12 | >2 | 76.8/23.2 | 0.12 | >2 | 76.0/24.0 | 0.12 | >2 | 51.8/46.4 | 0.06 | >2 | 72.3/27.7 | ||||||||
| Clindamycin | ≤0.25 | >2 | 76.8/23.2 | 76.8/23.2 | ≤0.25 | >2 | 74.0/26.0 | 72.0/26.0 | ≤0.25 | >2 | 51.8/48.2 | 50.0/48.2 | ≤0.25 | >2 | 72.3/27.7 | 70.2/27.7 | ||||
| Erythromycin | >16 | >16 | 18.9/70.5 | 20.0/78.9 | >16 | >16 | 34.0/60.0 | 34.0/66.0 | >16 | >16 | 37.5/62.5 | 37.5/62.5 | >16 | >16 | 34.0/57.4 | 34.0/61.7 | ||||
| Linezolid | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | ||||
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | 96.8/3.2 | 96.8/3.2 | ≤0.5 | ≤0.5 | 98.0/2.0 | 98.0/2.0 | ≤0.5 | ≤0.5 | 100.0/0.0 | 100.0/0.0 | ≤0.5 | 1 | 91.5/8.5 | 91.5/6.4 | ||||
| Vancomycin | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 0.5 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/0.0 | 100.0/0.0 | 1 | 1 | 100.0/00 | 100.0/0.0 | ||||
| S. pneumoniae | 712 | 698 | 250 | 251 | ||||||||||||||||
| Nafithromycin | 0.015 | 0.06 | 0.015 | 0.03 | 0.015 | 0.06 | 0.015 | 0.06 | ||||||||||||
| Telithromycin | 0.015 | 0.5 | 99.9/0.0 | 82.7/2.7 | 0.015 | 0.12 | 99.9/0.0 | 94.8/1.0 | 0.015 | 0.25 | 100.0/0.0 | 90.8/3.2 | 0.015 | 0.25 | 100.0/0.0 | 91.2/0.0 | ||||
| Amoxicillin-clavulanate | ≤1 | 4 | 88.5/7.2b | ≤1 | 2 | 92.6/5.2b | ≤1 | 8 | 79.2/12.8b | ≤1 | 8 | 79.7/16.3b | ||||||||
| Ceftriaxone | ≤0.06 | 1 | 81.6/6.3c | 81.6/0.8 | ≤0.06 | 1 | 84.2/7.2c | 84.2/1.0 | 0.12 | 2 | 69.2/13.6c | 69.2/0.8 | 0.12 | 2 | 64.1/19.5c | 64.1/4.8 | ||||
| 93.7/0.8b | 92.8/1.0b | 86.4/0.8b | 80.5/4.8b | |||||||||||||||||
| Clindamycin | ≤0.25 | >2 | 82.2/16.6 | 83.4/16.6 | ≤0.25 | >2 | 80.8 18.2 | 81.8 18.2 | ≤0.25 | >2 | 78.4/21.6 | 78.4/21.6 | ≤0.25 | >2 | 68.5 30.7 | 69.3 30.7 | ||||
| Erythromycin | 0.25 | >16 | 50.0/49.0 | 50.0/49.0 | ≤0.12 | >16 | 74.1/25.4 | 74.1/25.4 | ≤0.12 | >16 | 62.8/37.2 | 62.8/37.2 | ≤0.12 | >16 | 57.0/42.2 | 57.0/42.2 | ||||
| Penicillin | ≤0.06 | 2 | 58.1/13.6d | 58.1/41.9c | ≤0.06 | 2 | 68.5/11.9d | 68.5/31.5c | 0.12 | 4 | 49.2/26.8d | 49.2/50.8c | ≤0.06 | 4 | 51.8/29.1d | 51.8/48.2c | ||||
| 93.5/0.6e | 95.0/0.7e | 88.4/0.4e | 84.5/2.4e | |||||||||||||||||
| Trimethoprim-sulfamethoxazole | ≤0.5 | >4 | 67.8/20.1 | 75.4/20.1 | ≤0.5 | >4 | 70.6/20.1 | 76.1/20.1 | 1 | >4 | 48.8/39.6 | 53.6/39.6 | ≤0.5 | >4 | 56.6/34.7 | 64.5/34.7 | ||||
| Penicillin-resistant S. pneumoniae | 4 | 5 | 1 | 6 | ||||||||||||||||
| Nafithromycin | 0.03 | 0.06 | 0.06 | |||||||||||||||||
| Telithromycin | 0.25 | 100.0/0.0 | 50.0/25.0 | 0.25 | 100.0/0.0 | 60.0/40.0 | 100.0/0.0 | 0.0/0.0 | 0.25 | 100.0/0.0 | 66.7/0.0 | |||||||||
| Amoxicillin-clavulanate | >8 | 0.0/100.0b | >8 | 0.0/80.0b | 0.0/100.0b | >8 | 0.0/83.3b | |||||||||||||
| Ceftriaxone | 8 | 0.0/100.0c | 0.0/75.0 | 8 | 0.0/80.0c | 0.0/60.0 | 0.0/100.0c | 0.0/0.0 | 4 | 0.0/83.3c | 0.0/66.7 | |||||||||
| 0.0/75.0b | 20.0/60.0b | 0.0/0.0b | 16.7/66.7b | |||||||||||||||||
| Clindamycin | ≤0.25 | 50.0/50.0 | 50.0/50.0 | >2 | 20.0/80.0 | 20.0/80.0 | 0.0/100.0 | 0.0/100.0 | >2 | 0.0/100.0 | 0.0/100.0 | |||||||||
| Erythromycin | 8 | 0.0/100.0 | 0.0/100.0 | >16 | 0.0/100.0 | 0.0/100.0 | 0.0/100.0 | 0.0/100.0 | >16 | 0.0/100.0 | 0.0/100.0 | |||||||||
| Penicillin | 8 | 0.0/100.0d | 0.0/100.0c | 8 | 0.0/100.0d | 0.0/100.0c | 0.0/100.0d | 0.0/100.0c | 8 | 0.0/100.0d | 0.0/100.0c | |||||||||
| 0.0/100.0e | 0.0/100.0e | 0.0/100.0e | 0.0/100.0e | |||||||||||||||||
| Trimethoprim-sulfamethoxazole | 4 | 0.0/100.0 | 0.0/100.0 | >4 | 0.0/60.0 | 40.0/60.0 | 0.0/100.0 | 0.0/100.0 | >4 | 0.0/100.0 | 0.0/100.0 | |||||||||
| Erythromycin-resistant and clindamycin-resistant S. pneumoniae | 127 | 134 | 54 | 79 | ||||||||||||||||
| Nafithromycin | 0.03 | 0.12 | 0.03 | 0.12 | 0.03 | 0.12 | 0.03 | 0.12 | ||||||||||||
| Telithromycin | 0.06 | 0.5 | 100.0/0.0 | 66.9/6.3 | 0.03 | 0.5 | 99.3/0.0 | 79.9/5.2 | 0.12 | 0.5 | 100.0/0.0 | 64.8/9.3 | 0.06 | 0.5 | 100.0/0.0 | 77.2/0.0 | ||||
| Amoxicillin-clavulanate | ≤1 | 8 | 57.5/33.9b | ≤1 | 8 | 79.1/16.4b | 4 | 8 | 46.3/40.7b | 4 | 8 | 45.6/46.8b | ||||||||
| Ceftriaxone | 1 | 2 | 48.8/28.3c | 48.8/1.6 | 0.5 | 2 | 51.5/24.6c | 51.5/3.7 | 1 | 2 | 29.6/31.5c | 29.6/1.9 | 2 | 4 | 19.0/50.6c | 19.0/12.7 | ||||
| 71.7/1.6b | 75.4/3.7b | 68.5/1.9b | 49.4/12.7b | |||||||||||||||||
| Clindamycin | >2 | >2 | 0.0/92.9 | 7.1/92.9 | >2 | >2 | 0.0/94.8 | 5.2/94.8 | >2 | >2 | 0.0/100.0 | 0.0/100.0 | >2 | >2 | 0.0/97.5 | 2.5/97.5 | ||||
| Erythromycin | >16 | >16 | 0.0/100.0 | 0.0/100.0 | >16 | >16 | 0.0/100.0 | 0.0/100.0 | >16 | >16 | 00.0/100.0 | 0.0/100.0 | >16 | >16 | 0.0/98.7 | 0.0/98.7 | ||||
| Penicillin | 1 | 4 | 15.0/44.9d | 15.0/85.0c | 0.5 | 4 | 20.9/38.1d | 20.9/79.1c | 2 | 4 | 9.3/64.8d | 9.3/90.7c | 2 | 4 | 6.3/68.4d | 6.3/93.7c | ||||
| 66.9/1.6e | 82.8/3.0e | 63.0/1.9e | 55.7/7.6e | |||||||||||||||||
| Trimethoprim-sulfamethoxazole | 2 | >4 | 37.8/49.6 | 47.2/49.6 | 1 | >4 | 43.3/41.8 | 53.7/41.8 | 4 | >4 | 29.6/59.3 | 35.2/59.3 | >4 | >4 | 25.3/64.6 | 32.9/64.6 | ||||
| Telithromycin- nonsusceptible S. pneumoniae | 123 | 36 | 23 | 22 | ||||||||||||||||
| Nafithromycin | 0.06 | 0.12 | 0.12 | 0.12 | 0.12 | 0.12 | 0.12 | 0.12 | ||||||||||||
| Telithromycin | 0.5 | 1 | 99.2/0.0 | 0.0/15.4 | 0.5 | 1 | 97.2/0.0 | 0.0/19.4 | 0.5 | 1 | 100.0/0.0 | 0.0/34.8 | 0.5 | 0.5 | 100.0/0.0 | 0.0/0.0 | ||||
| Amoxicillin-clavulanate | ≤1 | 8 | 61.8/26.8b | 4 | 8 | 47.2/41.7b | 8 | 8 | 8.7/65.2b | 8 | 8 | 27.3/59.1b | ||||||||
| Ceftriaxone | 0.5 | 2 | 54.5/23.6c | 54.5/2.4 | 1 | 2 | 22.2/44.4c | 22.2/8.3 | 2 | 2 | 8.7/60.9c | 8.7/0.0 | 2 | 2 | 18.2/54.5c | 18.2/9.1 | ||||
| 76.4/2.4b | 55.6/8.3b | 39.1/0.0b | 45.5/9.1b | |||||||||||||||||
| Clindamycin | ≤0.25 | >2 | 65.9/31.7 | 68.3/31.7 | >2 | >2 | 25.0/75.0 | 25.0/75.0 | >2 | >2 | 17.4/82.6 | 17.4/82.6 | >2 | >2 | 18.2/81.8 | 18.2/81.8 | ||||
| Erythromycin | 16 | >16 | 0.0/100.0 | 0.0/100.0 | >16 | >16 | 0.0/100.0 | 0.0/100.0 | >16 | >16 | 0.0/100.0 | 0.0/100.0 | >16 | >16 | 0.0/100.0 | 0.0/100.0 | ||||
| Penicillin | 1 | 4 | 41.5/40.7d | 41.5/58.5c | 2 | 4 | 19.4/69.4d | 19.4/80.6c | 4 | 4 | 0.0/87.0d | 0.0/100.0c | 4 | 4 | 18.2/81.8d | 18.2/81.8c | ||||
| 72.4/1.6e | 55.6/5.6e | 39.1/4.3e | 40.9/9.1e | |||||||||||||||||
| Trimethoprim-sulfamethoxazole | 1 | >4 | 48.8/41.5 | 56.9/41.5 | >4 | >4 | 16.7/66.7 | 27.8/66.7 | >4 | >4 | 13.0/87.0 | 13.0/87.0 | >4 | >4 | 13.6/81.8 | 13.6/81.8 | ||||
| S. pyogenes | n = 202 | n = 203 | n = 102 | n = 99 | ||||||||||||||||
| Nafithromycin | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.03 | ||||||||||||
| Telithromycin | 0.015 | 0.03 | 97.0/2.5 | 0.015 | 0.03 | 96.6/3.0 | 0.015 | 0.015 | 99.0/0.0 | 0.015 | 0.03 | 98.0/2.0 | ||||||||
| Clindamycin | ≤0.25 | ≤0.25 | 92.6/5.9 | 94.1/5.9 | ≤0.25 | ≤0.25 | 95.1/4.9 | 95.1/4.9 | ≤0.25 | ≤0.25 | 97.1/2.9 | 97.1/2.9 | ≤0.25 | ≤0.25 | 97.0/3.0 | 97.0/3.0 | ||||
| Erythromycin | ≤0.12 | 8 | 83.2/16.8 | 83.2/16.8 | ≤0.12 | 0.25 | 91.1/8.9 | 91.1/8.9 | ≤0.12 | ≤0.12 | 93.1/5.9 | 93.1/5.9 | ≤0.12 | ≤0.12 | 94.9/5.1 | 94.9/5.1 | ||||
| Penicillin | ≤0.06 | ≤0.06 | 100.0/0.0 | 100.0/0.0 | ≤0.06 | ≤0.06 | 100.0/0.0 | 100.0/0.0 | ≤0.06 | ≤0.06 | 100.0/0.0 | 100.0/0.0 | ≤0.06 | ≤0.06 | 100.0/0.0 | 100.0/0.0 | ||||
| Erythromycin-resistant and clindamycin-resistant S. pyogenes | 15 | 10 | 3 | 3 | ||||||||||||||||
| Nafithromycin | 0.015 | 0.25 | 0.12 | 0.5 | 0.015 | 0.5 | ||||||||||||||
| Telithromycin | 0.015 | 2 | 66.7/33.3 | 0.5 | >2 | 40.0/50.0 | 0.015 | 66.7/0.0 | 2 | 33.3/66.7 | ||||||||||
| Clindamycin | >2 | >2 | 0.0/80.0 | 20.0/80.0 | >2 | >2 | 0.0/100.0 | 0.0/100.0 | >2 | 0.0/100.0 | 0.0/100.0 | >2 | 0.0/100.0 | 0.0/100.0 | ||||||
| Erythromycin | >16 | >16 | 0.0/100.0 | 0.0/100.0 | >16 | >16 | 0.0/100.0 | 0.0/100.0 | 8 | 0.0/100.0 | 0.0/100.0 | >16 | 0.0/100.0 | 0.0/100.0 | ||||||
| Penicillin | ≤.06 | ≤0.06 | 100.0/0.0 | 100.0/0.0 | ≤0.06 | ≤0.06 | 100.0/0.0 | 100.0/0.0 | ≤0.06 | 100.0/0.0 | 100.0/0.0 | ≤0.06 | 100.0/0.0 | 100.0/0.0 | ||||||
| H. influenzae | 398 | 402 | 100 | 102 | ||||||||||||||||
| Nafithromycin | 4 | 4 | 4 | 4 | 2 | 4 | 2 | 4 | ||||||||||||
| Telithromycin | 2 | 4 | 96.7/1.3 | 0.5/1.3 | 2 | 4 | 98.8/0.5 | 0.0/0.5 | 2 | 4 | 98.0/1.0 | 0.0/1.0 | 2 | 4 | 99.0/1.0 | 99.0/1.0 | ||||
| Amoxicillin-clavulanate | ≤1 | 2 | 99.7/0.3 | 99.0/1.0 | ≤1 | ≤1 | 100.0/0.0 | 99.3/0.7 | ≤1 | ≤1 | 100.0/0.0 | 99.0/1.0 | ≤1 | 4 | 97.1/2.9 | 85.3/14.7 | ||||
| Ampicillin | ≤0.25 | >8 | 72.4/26.9 | 72.4/27.6b | ≤0.25 | >8 | 84.1/13.9 | 84.1/15.9b | ≤0.25 | >8 | 78.0/21.0 | 78.0/22.0b | 1 | >8 | 65.7/26.5 | 65.7/34.3b | ||||
| Azithromycin | 0.5 | 2 | 98.7/ | 2.3/1.3 | 0.5 | 1 | 100.0/0.0 | 3.0/0.0 | 0.5 | 1 | 99.0/ | 4.0/1.0 | 0.5 | 1 | 99.0/ | 2.0/1.0 | ||||
| Ciprofloxacin | ≤0.03 | ≤0.03 | 100.0/0.0 | 99.5/0.5 | ≤0.03 | ≤0.03 | 99.8/ | 99.3/0.7 | ≤0.03 | ≤0.03 | 100.0/0.0 | 100.0/0.0 | ≤0.03 | ≤0.03 | 97.1/ | 96.1/3.9 | ||||
| Clarithromycin | 4 | 8 | 93.2/1.8 | 2.8/0.0 | 4 | 8 | 97.0/0.7 | 2.8/0.0 | 4 | 8 | 99.0/1.0 | 4.0/0.0 | 4 | 8 | 97.1/2.0 | 2.0/0.0 | ||||
| Trimethoprim-sulfamethoxazole | ≤0.5 | >4 | 65.6/27.4 | 65.6/32.7 | ≤0.5 | >4 | 68.4/25.1 | 68.4/29.6 | ≤0.5 | ≥4 | 71.0/24.0 | 71.0/28.0 | ≤0.5 | >4 | 59.8/38.2 | 59.8/39.2 | ||||
| M. catarrhalis | 197 | 202 | 54 | 51 | ||||||||||||||||
| Nafithromycin | 0.12 | 0.25 | 0.12 | 0.25 | 0.12 | 0.25 | 0.25 | 0.25 | ||||||||||||
| Telithromycin | 0.06 | 0.12 | 99.0/0.0 | 0.12 | 0.12 | 100.0/0.0 | 0.06 | 0.12 | 100.0/0.0 | 0.12 | 0.25 | 100.0/0.0 | ||||||||
| Amoxicillin-clavulanate | ≤1 | ≤1 | 100.0/0.0 | 100.0/0.0 | ≤1 | ≤1 | 100.0/0.0 | 100.0/0.0 | ≤1 | ≤1 | 100.0/0.0 | 100.0/0.0 | <1 | <1 | 100.0/0.0 | 100.0/0.0 | ||||
| Azithromycin | 0.03 | 0.06 | 100.0/0.0 | 100.0/0.0 | 0.03 | 0.06 | 100.0/0.0 | 100.0/0.0 | ≤0.03 | 0.06 | 100.0/0.0 | 100.0/0.0 | 0.03 | 0.06 | 100.0/0.0 | 100.0/0.0 | ||||
| Clarithromycin | ≤0.12 | ≤0.12 | 100.0/0.0 | 100.0/0.0 | ≤0.12 | ≤0.12 | 100.0/0.0 | 99.5/0.0 | ≤0.12 | ≤0.12 | 100.0/0.0 | 100.0/0.0 | ≤0.12 | ≤0.12 | 100.0/0.0 | 98.0/0.0 | ||||
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | 94.4/0.0 | 94.4/3.6 | ≤0.5 | ≤0.5 | 94.6/0.0 | 94.6/0.5 | ≤0.5 | ≤0.5 | 100.0/0.0 | 100.0/0.0 | ≤0.5 | ≤0.5 | 98.0/0.0 | 98.0/0.0 | ||||
Breakpoint interpretive criteria following the respective guidelines were used.
Using nonmeningitis breakpoints.
Using meningitis breakpoints.
Using oral breakpoints.
Using parenteral, nonmeningitis breakpoints.
MIC, µg/ml.
Against S. aureus isolates from all geographic regions combined, nafithromycin (MIC50/90, 0.06/>2 μg/ml) demonstrated a potency most similar to that of telithromycin (MIC50/90, 0.06/>2 μg/ml) (88.4% susceptible). Overall, resistance rates were higher for oxacillin (MRSA) (34.6%), erythromycin (33.1 to 37.2% [CLSI/EUCAST]), ciprofloxacin (25.1 to 27.1% [CLSI/EUCAST]), and clindamycin (11.9% [data not shown]). MRSA rates ranged from 24.6% in the EU (Table 2) to 46.3% in the US (Table 2). Erythromycin resistance rates ranged from 24.7% in APAC (Table 2) to 56.1% in the US (Table 2). No resistance was observed when S. aureus isolates were tested against linezolid and vancomycin (Table 2).
Nafithromycin was very active (MIC50/90, 0.015/0.06 μg/ml) against S. pneumoniae isolates, with all isolates inhibited at MIC values of 0.25 μg/ml or less (Tables 1 and 2). Similar MIC50/90 values were observed for the 4 geographic regions sampled (Table 2). Overall, telithromycin susceptibility was 99.9%/89.3% (CLSI/EUCAST criteria [data not shown]). Nafithromycin (MIC90, 0.06 μg/ml) was 8-fold more potent than telithromycin (MIC90, 0.5 μg/ml) against S. pneumoniae. Against erythromycin- and clindamycin-resistant pneumococci (constitutively macrolide resistant), the MIC50 and MIC90 of nafithromycin were 0.03 and 0.12 μg/ml, respectively (Tables 1 and 2). Importantly, nafithromycin was very active against telithromycin-nonsusceptible S. pneumoniae isolates, with MIC50 and MIC90 values of 0.06 and 0.12 μg/ml, respectively (Tables 1 and 2).
Using the EUCAST susceptibility breakpoint of ≤0.25 μg/ml for telithromycin, 204 S. pneumoniae isolates were nonsusceptible to telithromycin, and all of these strains demonstrated nafithromycin MIC values of ≤0.25 μg/ml (MIC50/90, 0.06/0.12 μg/ml) (Table 1). Nafithromycin retained good activity against erythromycin-resistant/clindamycin-susceptible (MIC50/90, 0.03/0.06 μg/ml) and erythromycin-resistant/clindamycin-resistant (MIC50/90, 0.03/0.12 μg/ml) (Table 1) isolates. Using CLSI breakpoints, resistance to oral penicillin V among S. pneumoniae isolates was 16.7% overall, with rates of 29.1% in APAC, 11.9% in the EU, 13.6% in the US, and 26.8% in LATAM (Table 2). Nafithromycin was 4-fold less active against penicillin-intermediate and -resistant isolates than against penicillin-susceptible isolates, with nafithromycin MIC50/90 values of 0.06/0.12, 0.06/0.12, and 0.015/0.03 μg/ml, respectively (Table 1).
Nafithromycin showed potent activity (MIC50/90, 0.015/0.015 μg/ml) against Streptococcus pyogenes, inhibiting 100.0% of isolates, with an MIC value of ≤0.5 μg/ml (Table 1). Nafithromycin MIC50/90 values (0.015/0.015 to 0.03 μg/ml) were similar for the 4 geographic regions (Table 2). Erythromycin resistance was only 10.4% overall (data not shown), with rates ranging from 5.1% in APAC to 16.8% in the US (Table 2). Nafithromycin (MIC50/90, 0.015/0.015 μg/ml) demonstrated up to 2-fold greater activity than that of telithromycin (MIC50/90, 0.015/0.03 μg/ml) (data not shown).
Against Haemophilus influenzae, nafithromycin demonstrated moderate activity (MIC50/90, 4/4 μg/ml) (Table 2). MIC50/90 results were similar (4/4 μg/ml) for the 4 geographic regions and regardless of β-lactamase production (Table 2). Nafithromycin activity (MIC50/90, 4/4 μg/ml) showed equal or 2-fold less potency than that of telithromycin (MIC50/90, 2/4 μg/ml) against H. influenzae (Table 2 and data not shown).
Nafithromycin exhibited good activity (MIC50/90, 0.12/0.25 μg/ml) against Moraxella catarrhalis isolates (Table 1). MIC50/90 results for nafithromycin were similar (0.12 to 0.25/0.25 μg/ml) for the 4 geographic regions and were not influenced by β-lactamase production (Table 2). Nafithromycin (MIC50/90, 0.12/0.25 μg/ml) demonstrated a potency comparable to that of telithromycin (MIC50/90, 0.06 to 0.12/0.12 to 0.25 μg/ml) (Table 2).
DISCUSSION
Multidrug-resistant S. pneumoniae isolates are a current concern in community-acquired pneumonia in adults (11–13). These multidrug-resistant organisms are included in the serious threat list in the Centers for Disease Control and Prevention (CDC) 2013 report on current antimicrobial threats (14). The potential for the presence of these resistant organisms affects therapy choices (11, 15).
Ketolides are newer macrolides that are active against macrolide-resistant S. pneumoniae. The ketolide class derived its name from the ketone functional group at the 3 position, where traditional macrolides have an l-cladinose sugar attached (6–9). The lack of the l-cladinose moiety is believed to reduce the potential for the induction of inducible macrolide resistance. Additionally, ketolides have a bridged 11,12-aryl side chain that allows for an additional interaction with the 23S ribosome in domain II, at A752 (6, 8, 9). The fluoroketolide solithromycin exhibits tight binding to the ribosome, presumably due to the fluorine at the C-2 position of the 14-membered ring, and therefore provides low MICs for ermB-expressing S. pneumoniae (7). However, in the past, certain ketolides and fluoroketolides have been reported to be associated with an unacceptable safety profile (9, 16). Nafithromycin has unique structural features, with a lactone ketolide nucleus bearing a 2-pyridine-1,3,4-thiadiazole biaryl side chain that is spaced through a four-atom spacer containing a cis double bond and a chiral methyl group. The nonflexible spacer possibly aligns the biaryl ring system, resulting in a favorable interaction with dual 23S rRNA targets. Thus, these structural features enabled nafithromycin to demonstrate potent activity against ermB-expressing as well as telithromycin-resistant S. pneumoniae, without the need to have a fluorine moiety at the C-2 position (5–10). Moreover, it has been reported that compared to solithromycin, nafithromycin retains a higher degree of activity under hyper-ermB-induction conditions in S. pneumoniae, indicating a better target interaction even for methylated 23S rRNA (17).
Nafithromycin is a novel antimicrobial agent of the lactone ketolide class that is in clinical development for treatment of CABP. In this report, nafithromycin was shown to be as active in vitro as the comparator ketolide, telithromycin (88.4% of isolates were susceptible), against a global collection of S. aureus isolates cultured during 2014. The activities of nafithromycin and telithromycin were considerably lowered against S. aureus strains demonstrating a constitutively expressed macrolide resistance phenotype. Nafithromycin was also very active against S. pneumoniae, with 100.0% of isolates inhibited, with MIC values of ≤0.25 μg/ml. Nafithromycin also showed excellent activity against S. pyogenes (all MIC values were ≤0.5 μg/ml), moderate activity (MIC50/90, 4/4 μg/ml) against H. influenzae, and potent activity (MIC50/90, 0.12/0.25 μg/ml) against M. catarrhalis.
In a phase 1 intrapulmonary pharmacokinetic study involving an 800-mg once-daily dose administered over 3 days, nafithromycin showed high lung epithelial lining fluid and alveolar macrophage concentrations that lasted at clinically relevant levels (1.62 ± 0.86 and 22.4 ± 10.4 μg/ml for epithelial lining fluid and alveolar macrophages, respectively) for at least 48 h after the last dose (18). The spectrum of activity of nafithromycin and its chemical characteristics, which allow for the development of oral and intravenous formulations, indicate that further clinical development to treat infections caused by multidrug-resistant Gram-positive organisms is warranted.
MATERIALS AND METHODS
Organisms.
A total of 4,739 nonduplicate isolates were selected from a 2014 global surveillance program at medical institutions located in 43 countries within the US, EU, LATAM, and APAC (Table 1). Only clinically significant isolates were included in the study (1 per infection episode). Species identification was performed at the site and confirmed at the central monitoring laboratory, when necessary, by standard biochemical tests and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), using a Bruker Daltonics MALDI Biotyper machine (Billerica, MA, USA) per the manufacturer's instructions. Organisms chosen for this study were a selected group of species generally recognized as respiratory pathogens and were primarily Gram positive.
Antimicrobial susceptibility testing.
MIC values were determined using CLSI broth microdilution methods as described in CLSI document M07-A10 (2015) (19). Cation-adjusted Mueller-Hinton broth (CA-MHB) was used for inoculation of MIC panels for all nonfastidious organisms. Haemophilus influenzae isolates were tested in Haemophilus test medium (HTM). In addition, lysed horse blood (3.75%) was used to supplement the CA-MHB for testing of S. pneumoniae and S. pyogenes. For nafithromycin and telithromycin, MIC results were obtained using validated broth microdilution panels produced by JMI Laboratories (North Liberty, IA). For other antimicrobial agents, dry-form MIC panels were manufactured by Thermo Fisher Scientific (formerly TREK Diagnostics Systems/Sensititre; Cleveland, OH, USA). MIC value validation was performed by concurrent testing of the following quality control (QC) reference strains: S. pneumoniae ATCC 49619, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, and H. influenzae ATCC 49247. All nafithromycin and telithromycin MIC values were within the QC ranges recommended by the CLSI. MIC interpretations were based on CLSI and EUCAST breakpoint criteria (20, 21).
ACKNOWLEDGMENTS
We thank the following staff members at JMI Laboratories (North Liberty, IA, USA) for technical support: L. Duncan, M. Huband, M. Janechek, J. Oberholser, J. Schuchert, and J. Streit.
This study was performed by JMI Laboratories and supported by Wockhardt Bio AG, which included funding for services related to preparing the manuscript.
JMI Laboratories was 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, Entasis, Fortress, Fox Chase Chemical, GSK, Medpace, Melinta, Merck, Micurx, Motif, N8 Medical, Nabriva, Nexcida, Novartis, Paratek, Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synolgoic, TGV Therapeutics, The Medicines Company, Theravance, Thermo Fisher, Venatorx, and Zavante. There are no speakers' bureaus or stock options to declare.
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