Omadacycline is a derivative of minocycline and the first agent of the aminomethylcycline class. A total of 3,282 organisms (1 per patient) were consecutively collected from patients hospitalized in China (including Hong Kong) and Taiwan.
KEYWORDS: Staphylococcus aureus, Streptococcus pneumoniae, aminomethylcycline, community-acquired pneumonia, skin and soft tissue infections, tetracyclines
ABSTRACT
Omadacycline is a derivative of minocycline and the first agent of the aminomethylcycline class. A total of 3,282 organisms (1 per patient) were consecutively collected from patients hospitalized in China (including Hong Kong) and Taiwan. Susceptibility testing was performed by broth microdilution methods in a central laboratory (JMI Laboratories). The collection included Gram-positive and Gram-negative organisms from patients with pneumonia, bloodstream, skin, community-acquired respiratory, and other infections. Omadacycline was very potent against Staphylococcus aureus (n = 689; MIC50/90, 0.12/0.25 mg/liter), including methicillin-resistant Staphylococcus aureus (MRSA; n = 299; MIC50/90, 0.12/0.5 mg/liter), and had similar activity across geographic regions. Omadacycline was very active against Streptococcus pneumoniae (highest MIC, 0.25 mg/liter), β-hemolytic streptococci (highest MIC, 1 mg/liter), viridans group streptococci (highest MIC, 0.25 mg/liter), and Enterococcus spp. (highest MIC, 0.5 mg/liter) from all geographic regions. Overall, 53.8% of S. pneumoniae isolates were penicillin resistant (penicillin MIC, ≥2 mg/liter) and 10.7% of enterococci (21.2% among E. faecium isolates) were vancomycin resistant. Omadacycline was active against Haemophilus influenzae (MIC50/90, 0.5/1 mg/liter) regardless of β-lactamase production and was active against Moraxella catarrhalis (MIC50/90, ≤0.12/0.25 mg/liter). Against Enterobacteriaceae, omadacycline was most active against Escherichia coli (MIC50/90, 1/2 mg/liter), Klebsiella oxytoca (MIC50/90, 1/4 mg/liter), and Enterobacter cloacae (MIC50/90, 2/4 mg/liter). Omadacycline had potent in vitro activity against Gram-positive and Gram-negative pathogens isolated from China and Taiwan and retained activity against problem pathogens, such as MRSA, vancomycin-resistant enterococci (VRE), penicillin-resistant S. pneumoniae (PRSPN), and extended-spectrum β-lactamase-producing E. coli. The observed MIC profile in Chinese isolates was very similar to that seen in the U.S. and European surveillance studies.
INTRODUCTION
China, including Hong Kong, is the most populous country in the world and comprises approximately one-fifth of the world’s population (1). The high per capita consumption of antibiotics in humans and widespread use in veterinary medicine in China create an environment that fosters the selection of resistant pathogens and their spread (2, 3). Indeed, the prevalence of antimicrobial resistance among Chinese hospitals is a concern, and rising methicillin-resistant Staphylococcus aureus (MRSA) infection and extended-spectrum β-lactamase (ESBL) rates have been reported from inpatients and outpatients in the last decade (4, 5).
Developing antimicrobial agents with novel mechanisms of action and greater potency against resistant strains of bacteria, in addition to assessing their activity among bacterial isolates from specific geographic regions, is of paramount importance to drive further clinical development and combat antimicrobial resistance (6).
Omadacycline (formerly PTK 0796) is a semisynthetic derivative of minocycline and the first agent of the aminomethylcycline class. Similar to other tetracyclines, it acts to inhibit bacterial protein synthesis by binding to the 16S rRNA of the 30S bacterial ribosome subunit. Omadacycline has a broad spectrum of antimicrobial activity, including against Gram-positive, Gram-negative, and atypical bacteria as well as anaerobes (7). However, the omadacycline molecular structure differs from that of tetracycline because of a modification at the C7 position and the presence of an aminomethyl group at the C9 position, which confer the class name and several advantages over older tetracyclines, such as doxycycline and minocycline (7). Among the advantages, omadacycline showed activity against isolates harboring the 2 most common tetracycline resistance mechanisms, namely ribosomal protection and active efflux (7–9).
Omadacycline displayed activity against MRSA, methicillin-resistant coagulase-negative staphylococci (MRCoNS), vancomycin-resistant enterococci (VRE), viridans group streptococci (VGS), beta-hemolytic streptococci (BHS), and penicillin-resistant S. pneumoniae (10), as well as ESBL-producing Escherichia coli, Acinetobacter spp., and Stenotrophomonas maltophilia (7). Its availability as an intravenous or oral formulation, a long serum half-life, and once-daily administration are also benefits of this next-generation tetracycline (7). Of note, it is the only tetracycline with low fractional binding to serum proteins (20%); in contrast, other tetracyclines are characterized by high protein binding and a low percentage of free drug in serum (11). This is important when comparing MIC values, as in vitro tests are done in the absence of serum.
Clinical trials evaluating the safety and efficacy of omadacycline for treating acute bacterial skin and skin structure infections (ABSSSIs; ClinicalTrial.gov identifiers NCT02877927 and NCT02378480) (12, 13) and community-acquired bacterial pneumonia (CABP; ClinicalTrial.gov identifier NCT02531438) (14) were the basis of the drug’s approval by the U.S Food and Drug Administration (FDA) for both indications in October 2018. Therefore, surveillance studies reporting in vitro activity and the potential use of this new compound against clinical isolates from diverse geographic regions are warranted. The aim of this study was to evaluate the in vitro activity of omadacycline against recent clinical bacterial isolates collected in China and Taiwan, with emphasis on pathogens typically encountered in skin infections and community-acquired pneumonia.
RESULTS
A total of 3,282 isolates from patients in Hong Kong, Taiwan, and mainland China between 2013 and 2016 were selected from the SENTRY surveillance collection. Omadacycline was very potent against 689 S. aureus isolates (MIC50/90, 0.12/0.25 mg/liter), including 299 (43.4%) MRSA (MIC50/90, 0.12/0.5 mg/liter [Table 1]) and showed similar activity against isolates recovered from Taiwan and Hong Kong (Tables 1 and 2). When we applied the recently released U.S. FDA omadacycline susceptibility breakpoints for methicillin-susceptible S. aureus (MSSA) in skin and soft tissue infections (SSTIs; ≤0.5 mg/liter) and community-acquired bacterial pneumonia (CABP; ≤0.25 mg/liter) against the entire collection of S. aureus isolates, 98.5% and 93.5% of the isolates were susceptible, respectively (Table 1). Tetracycline-resistant S. aureus (tetracycline MIC, ≥16 mg/liter) represented 46.0% of all S. aureus isolates; however, doxycycline resistance (doxycycline MIC ≥16 mg/liter) was less prevalent, with a resistance rate of 4.8%. Omadacycline remained very active against tetracycline-resistant (MIC50/90, 0.12/0.5 mg/liter) and doxycycline-resistant S. aureus subsets (MIC50/90, 0.25/1 mg/liter). Of note, the omadacycline epidemiological cutoff values (ECVs) 95.0%, 97.5%, and 99.0% were established at 0.25 mg/liter, and at this value, 93.5% of all S. aureus isolates were inhibited and, therefore, classified as wild type.
TABLE 1.
Antimicrobial activity of omadacycline tested against the main organisms and organism groups of isolates from all countries combined
| Organism or organism group (no. of isolates) | No. (cumulative %) of isolates at an MIC (mg/liter) of: |
MIC50 (mg/liter) | MIC90 (mg/liter) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >32 | |||
| Staphylococcus aureus (689) | 1 (0.1) | 39 (5.8) | 487 (76.5) | 117 (93.5) | 35 (98.5) | 10 (100.0) | 0.12 | 0.25 | ||||||
| Methicillin susceptible (390) | 0 (0.0) | 23 (5.9) | 333 (91.3) | 32 (99.5) | 2 (100.0) | 0.12 | 0.12 | |||||||
| Methicillin resistant (299) | 1 (0.3) | 16 (5.7) | 154 (57.2) | 85 (85.6) | 33 (96.7) | 10 (100.0) | 0.12 | 0.5 | ||||||
| Tetracycline resistant (317) | 17 (5.45) | 182 (62.8) | 77 (87.1) | 32 (97.2) | 9 (100.0) | 0.12 | 0.5 | |||||||
| Doxycycline resistant (33) | 9 (27.3) | 10 (57.6) | 10 (87.9) | 4 (100.0) | 0.25 | 1 | ||||||||
| Enterococcus spp. (103) | 15 (14.6) | 54 (67.0) | 28 (94.2) | 5 (99.0) | 1 (100.0) | 0.06 | 0.12 | |||||||
| Vancomycin nonsusceptible (>4 mg/liter; 13) | 2 (15.45) | 9 (84.6) | 2 (100.0) | 0.06 | 0.12 | |||||||||
| Enterococcus faecalis (48) | 5 (10.4) | 19 (50.0) | 18 (87.5) | 5 (97.9) | 1 (100.0) | 0.06 | 0.25 | |||||||
| Enterococcus faecium (52) | 10 (19.2) | 32 (80.8) | 10 (100.0) | 0.06 | 0.12 | |||||||||
| Streptococcus pneumoniae (392) | 20 (5.1) | 233 (64.5) | 134 (98.7) | 5 (100.0) | 0.06 | 0.12 | ||||||||
| Penicillin resistant, oral (≥2 mg/liter; 211) | 6 (2.8) | 125 (62.1) | 77 (98.6) | 3 (100.0) | 0.06 | 0.12 | ||||||||
| Tetracycline resistant (359) | 14 (3.9) | 209 (62.1) | 131 (98.6) | 5 (100.0) | 0.12 | 0.5 | ||||||||
| Tigecycline nonsusceptible (36) | 2 (5.6) | 31 (91.7) | 36 (100.0) | 0.25 | 1 | |||||||||
| Viridans group streptococci (94) | 20 (21.3) | 53 (77.7) | 15 (93.6) | 6 (100.0) | 0.06 | 0.12 | ||||||||
| β-Hemolytic streptococci (166) | 0 (0.0) | 36 (21.7) | 76 (67.5) | 38 (90.4) | 14 (98.8) | 2 (100.0) | 0.12 | 0.25 | ||||||
| Enterobacteriaceae (1,041) | 0 (0.0) | 8 (0.8) | 137 (13.9) | 357 (48.2) | 277 (74.8) | 146 (88.9) | 47 (93.4) | 44 (97.6) | 21 (99.6) | 4 (100.00) | 2 | 8 | ||
| Escherichia coli (425) | 0 (0.0) | 7 (1.6) | 124 (30.8) | 180 (73.2) | 86 (93.4) | 23 (98.8) | 3 (99.5) | 2 (100.0) | 1 | 2 | ||||
| ESBL phenotype (249) | 0 (0.0) | 5 (2.0) | 70 (30.1) | 104 (71.9) | 50 (92.0) | 15 (98.0) | 3 (99.2) | 2 (100.0) | 1 | 2 | ||||
| Klebsiella pneumoniae (307) | 0 (0.0) | 1 (0.3) | 11 (3.9) | 114 (41.0) | 91 (70.7) | 54 (88.3) | 20 (94.8) | 12 (98.7) | 3 (99.7) | 1 (100.0) | 2 | 8 | ||
| ESBL phenotype (134) | 0 (0.0) | 2 (1.5) | 33 (26.1) | 37 (53.7) | 37 (81.3) | 14 (91.8) | 9 (98.5) | 1 (99.3) | 1 (100.0) | 2 | 8 | |||
| Klebsiella oxytoca (16) | 0 (0.0) | 10 (62.5) | 2 (75.0) | 3 (93.8) | 1 (100.0) | 1 | 4 | |||||||
| Enterobacter cloacae species complex (110) | 0 (0.0) | 23 (20.9) | 59 (74.5) | 18 (90.9) | 5 (95.5) | 3 (98.2) | 2 (100.0) | 2 | 4 | |||||
| Ceftazidime nonsusceptible (>4 mg/liter; 52) | 0 (0.0) | 6 (11.5) | 26 (61.5) | 12 (84.6) | 5 (94.2) | 2 (98.1) | 1 (100.0) | 2 | 8 | |||||
| Serratia marcescens (46) | 0 (0.0) | 12 (26.1) | 33 (97.8) | 1 (100.0) | 4 | 4 | ||||||||
| Acinetobacter baumannii (225) | 0 (0.0) | 2 (0.9) | 24 (11.6) | 6 (14.2) | 1 (14.7) | 9 (18.7) | 90 (58.7) | 81 (94.7) | 7 (97.8) | 4 (99.6) | 1 (100.0) | 4 | 8 | |
| Pseudomonas aeruginosa (300) | 0 (0.0) | 4 (1.3) | 2 (2.0) | 20 (8.7) | 121 (49.0) | 153 (100.0) | >32 | >32 | ||||||
| Haemophilus influenzae (181) | 0 (0.0) | 12 (6.6) | 88 (55.2) | 69 (93.4) | 12 (100.0) | 0.5 | 1 | |||||||
| β-Lactamase positive (69) | 0 (0.0) | 35 (50.7) | 29 (92.8) | 5 (100.0) | 0.5 | 1 | ||||||||
| Haemophilus parainfluenzae (7) | 0 (0.0) | 1 (14.3) | 6 (100.0) | 1 | ||||||||||
| Moraxella catarrhalis (75) | 57 (76.0) | 18 (100.0) | ≤0.12 | 0.25 | ||||||||||
TABLE 2.
Summary of omadacycline activity stratified by geographic regiona
| Organism | Omadacycline MIC50/MIC90 (mg/liter) of strains from: |
||
|---|---|---|---|
| China | Hong Kong | Taiwan | |
| S. aureus | 0.12/0.25 | 0.12/0.25 | 0.12/0.25 |
| MSSA | 0.12/0.12 | 0.12/0.12 | 0.12/0.12 |
| MRSA | 0.25/0.5 | 0.12/0.25 | 0.12/0.25 |
| S. pneumoniae | 0.06/0.12 | 0.06/0.12 | 0.06/0.12 |
| Penicillin S (MIC, ≤0.06 mg/liter)b | 0.06/0.12 | 0.06/0.12 | 0.06/ND |
| Penicillin I (MIC, 0.12–1 mg/liter)b | 0.06/0.12 | 0.06/ND | 0.06/0.12 |
| Penicillin R (MIC, ≥2 mg/liter)b | 0.06/0.12 | 0.06/0.12 | 0.12/0.12 |
| β-Hemolytic streptococci | 0.12/0.25 | 0.12/0.5 | 0.12/0.5 |
| Viridans group streptococci | 0.06/0.12 | 0.06/0.25 | 0.06/0.12 |
| Enterococcus faecalis | 0.06/0.25 | 0.12/ND | 0.12/ND |
| Enterococcus faecium | 0.06/0.12 | 0.06/ND | 0.06/0.12 |
| Vancomycin NS (MIC, ≥8 mg/liter) | 0.06/ND | 0.06/ND | 006/ND |
| H. influenzae | 0.5/1 | 1/1 | 0.5/1 |
| M. catarrhalis | ≤0.12/0.25 | ≤0.12/0.25 | ≤0.12/0.25 |
| Enterobacteriaceae | 1/4 | 2/16 | 2/8 |
| E. coli | 1/2 | 1/2 | 1/2 |
| ESBL phenotype | 1/2 | 1/2 | 1/4 |
| K. pneumoniae | 2/4 | 2/8 | 2/8 |
| ESBL phenotype | 2/8 | 2/ND | 2/16 |
| E. cloacae | 2/8 | 2/ND | 2/4 |
| Citrobacter spp. | 2/8 | 1/ND | 1/ND |
| P. mirabilis | 16/32 | 16/32 | 16/ND |
| Indole-positive Proteus spp. | 4/16 | 8/ND | |
| S. marcescens | 4/4 | 4/4 | 4/ND |
| A. baumannii | 4/8 | 4/32 | 4/8 |
| P. aeruginosa | >32/>32 | >32/>32 | >32/>32 |
MSSA, methicillin-susceptible S. aureus; MRSA, methicillin-resistant S. aureus; S, susceptible; I, intermediate; R, resistant; NS, nonsusceptible; ESBL, extended-spectrum β-lactamase; ND, not determinate due to less than 10 isolates within the group.
Using oral breakpoints (26).
Omadacycline was highly active against Streptococcus pneumoniae (MIC50/90, 0.06/0.12 mg/liter; 98.7% susceptible [Tables 1 and 2]) regardless of penicillin-resistant (omadacycline MIC50/90, 0.06/0.12 mg/liter) or tetracycline-resistant phenotypes (omadacycline MIC50/90, 0.06/0.12 mg/liter). The activity of omadacycline against S. pneumoniae isolates (n = 392) was comparable to the activity of tigecycline (MIC50/90, 0.06/0.06 mg/liter) and at least 64-fold higher than the activity of tetracycline (MIC50/90, >4/>4 mg/liter [Table 3]). Similar omadacycline activity was observed among streptococci isolates recovered from Taiwan, Hong Kong, and China (Table 2). Omadacycline was slightly more active against VGS (MIC50/90, 0.06/0.12 mg/liter) than against BHS (MIC50/90, 0.12/0.25 mg/liter [Table 1]). All S. pneumoniae and VGS isolates were inhibited at the ECVs 95.0%, 97.5%, and 99.0% (0.25 mg/liter) and 98.8% of BHS isolates at ECVs 97.5% and 99.0% (0.5 mg/liter). Low susceptibility rates for azithromycin (5.9%) and penicillin (35.2%, using oral breakpoint) were observed against S. pneumoniae (Table 3). However, linezolid (100% susceptible) and levofloxacin (99.0% susceptible) displayed high susceptibility rates against those isolates. Aside from S. pneumoniae, omadacycline was active against other pathogens frequently recovered from CABP, such as Haemophilus influenzae (MIC50/90, 0.5/1 mg/liter; 100% susceptible) and Moraxella catarrhalis (MIC50/90, ≤0.12/0.25 mg/liter) regardless of β-lactamase production or geographic region (Tables 1 and 2).
TABLE 3.
Activity of omadacycline and comparator antimicrobial agents for the main organisms from all geographic regions combined
| Antimicrobial agent by organism or organism group (no. of isolates) | MIC50 (mg/liter) | MIC90 (mg/liter) | Susceptibility or resistance (%) according to: |
|||
|---|---|---|---|---|---|---|
| CLSIa
|
EUCASTa
|
|||||
| S | R | S | R | |||
| Staphylococcus aureus (689) | ||||||
| Omadacycline | 0.12 | 0.25 | 98.5b | 0.0b | ||
| 93.5c | 1.5c | |||||
| Tigecycline | 0.12 | 0.25 | 100.0d | 100.0 | 0.0 | |
| Doxycycline | 0.25 | 8 | 78.5 | 4.8 | 62.0 | 26.6 |
| Tetracycline | ≤0.5 | >8 | 53.0 | 46.0 | 52.5 | 47.2 |
| Clindamycin | 0.06 | >2 | 68.2 | 31.5 | 68.1 | 31.8 |
| Daptomycin | 0.25 | 0.25 | 99.9 | 99.9 | 0.1 | |
| Levofloxacin | 0.25 | >4 | 63.0 | 36.9 | 63.0 | 37.0 |
| Linezolid | 1 | 2 | 100.0 | 0.0 | 100.0 | 0.0 |
| Oxacillin | 1 | >2 | 56.6 | 43.4 | 56.6 | 43.4 |
| Trimethoprim-sulfamethoxazole | ≤0.5 | 1 | 93.5 | 6.5 | 93.5 | 5.1 |
| Vancomycin | 1 | 1 | 100.0 | 0.0 | 100.0 | 0.0 |
| Enterococcus spp. (103)e | ||||||
| Omadacycline | 0.06 | 0.12 | 99.0f | 0.0f | ||
| Tigecycline | 0.06 | 0.12 | 100.0 | 0.0 | ||
| Minocycline | 8 | >8 | 46.6 | 40.8 | ||
| Tetracycline | >16 | >16 | 40.8 | 58.3 | ||
| Ampicillin | 2 | >16 | 53.4 | 46.6 | 52.4 | 46.6 |
| Daptomycin | 1 | 2 | 100.0 | |||
| Linezolid | 1 | 2 | 99.0 | 0.0 | 100.0 | 0.0 |
| Vancomycin | 1 | >16 | 87.4 | 10.7 | 87.4 | 12.6 |
| Streptococcus pneumoniae (392) | ||||||
| Omadacycline | 0.06 | 0.12 | 98.7g | 0.0g | ||
| Tigecycline | 0.06 | 0.06 | 90.8d | |||
| Tetracycline | >4 | >4 | 7.7 | 90.6 | 7.7 | 91.6 |
| Amoxicillin-clavulanic acid | 2 | >4 | 70.9 | 24.0 | ||
| Azithromycin | >4 | >4 | 5.9 | 94.1 | 5.9 | 94.1 |
| Ceftriaxone | 1 | >2 | 68.9g | 14.0g | 46.9 | 14.0 |
| Levofloxacin | 1 | 2 | 99.0 | 1.0 | 99.0 | 1.0 |
| Linezolid | 1 | 1 | 100.0 | 100.0 | 0.0 | |
| Penicillin | 2 | 4 | 35.2h | 53.8h | 35.2i | 32.1i |
| 67.9j | 1.8j | |||||
| Enterobacteriaceae (1,041) | ||||||
| Omadacycline | 2 | 8 | 88.9k | 6.6k | ||
| Tigecycline | 0.25 | 1 | 95.8 | 0.2b | 91.3 | 4.2 |
| Doxycycline | 4 | >8 | 52.7 | 34.8 | ||
| Tetracycline | 16 | >16 | 42.8 | 52.1 | ||
| Amikacin | 2 | 4 | 95.3 | 4.3 | 94.0 | 4.7 |
| Ceftazidime | 0.5 | >32 | 66.8 | 29.4 | 58.8 | 33.2 |
| Ceftriaxone | 0.5 | >8 | 53.1 | 46.4 | 53.1 | 46.4 |
| Gentamicin | 0.5 | >16 | 68.3 | 30.9 | 68.0 | 31.7 |
| Imipenem | ≤0.12 | 2 | 89.7 | 6.4 | 93.6 | 4.1 |
| Levofloxacin | 0.5 | >16 | 65.7 | 30.7 | 56.6 | 36.7 |
| Piperacillin-tazobactam | 2 | 128 | 82.9 | 11.6 | 79.0 | 17.1 |
| Acinetobacter baumannii (225) | ||||||
| Omadacycline | 4 | 8 | ||||
| Tigecycline | 4 | 8 | ||||
| Doxycycline | >8 | >8 | 18.2 | 77.8 | ||
| Tetracycline | >16 | >16 | 11.2 | 87.9 | ||
| Amikacin | >32 | >32 | 23.1 | 74.7 | 20.9 | 76.9 |
| Cefepime | >16 | >16 | 14.2 | 81.3 | ||
| Gentamicin | >16 | >16 | 14.7 | 84.4 | 14.7 | 85.3 |
| Imipenem | >8 | >8 | 16.4 | 83.1 | 16.4 | 82.2 |
| Piperacillin-tazobactam | >128 | >128 | 13.4 | 85.3 | ||
| Pseudomonas aeruginosa (300) | ||||||
| Omadacycline | >32 | >32 | ||||
| Tigecycline | 8 | >8 | ||||
| Doxycycline | >8 | >8 | ||||
| Amikacin | 4 | 16 | 93.3 | 5.7 | 88.6 | 6.7 |
| Cefepime | 2 | >16 | 79.3 | 10.3 | 79.3 | 20.7 |
| Colistin | 1 | 1 | 100.0 | 0.0 | 100.0 | 0.0 |
| Gentamicin | 2 | >16 | 81.7 | 13.3 | 81.7 | 18.3 |
| Imipenem | 1 | >8 | 68.3 | 29.0 | 71.0 | 23.3 |
| Piperacillin-tazobactam | 8 | >128 | 71.9 | 18.7 | 71.9 | 28.1 |
| Haemophilus influenzae (181) | ||||||
| Omadacycline | 0.5 | 1 | 100.0g | 0.0g | ||
| Tigecycline | 0.25 | 0.5 | 84.5d | |||
| Tetracycline | 0.5 | 8 | 85.6 | 14.4 | 85.6 | 14.4 |
| Amoxicillin-clavulanic acid | 1 | 4 | 97.2 | 2.8 | 89.0 | 11.0 |
| Ampicillin | 1 | >8 | 56.4 | 40.3 | 56.4 | 43.6 |
| Azithromycin | 1 | 2 | 91.2 | 0.6 | 8.8 | |
| Ceftriaxone | 0.008 | 0.03 | 100.0 | 96.7 | 3.3 | |
| Levofloxacin | 0.015 | 0.25 | 97.8 | 78.9 | 21.1 | |
Using ABSSSI breakpoints, including MRSA, from FDA package insert (28).
Using CABP breakpoints for MSSA from FDA package insert (28).
Breakpoints from FDA package insert (31).
Organisms include Enterococcus avium (1), E. faecalis (48), E. faecium (52), and E. gallinarum (2).
Using ABSSSI breakpoints for E. faecalis from FDA package insert (28).
Using CABP breakpoints from FDA package insert (28).
Using oral breakpoints.
Using nonmeningitis breakpoints.
Using parenteral, meningitis breakpoints.
Breakpoints from FDA package insert revised 05/2018, K. pneumoniae and E. cloacae (ABSSSI) and K. pneumoniae only (CABP) (28).
All Enterococcus sp. (n = 103) isolates were inhibited by omadacycline at the MIC of 0.5 mg/liter (Table 1). Of note, omadacycline was slightly more active against E. faecium (n = 52; MIC50/90, 0.06/0.12 mg/liter) than against E. faecalis (n = 48; MIC50/90, 0.06/0.25 mg/liter; 99.0% susceptible) and was not adversely affected by vancomycin nonsusceptibility (12.6% overall, 21.2% among E. faecium isolates) and tetracycline resistance (58.3% overall; omadacycline MIC50/90, 0.06/0.12 mg/liter for both phenotypes). Interestingly, 100% and 97.9% of E. faecium and E. faecalis isolates, respectively, were considered wild type when the ECVs 95.0%, 97.5%, and 99.0% were applied (all values established at 0.25 mg/liter).
When tested against Enterobacteriaceae, omadacycline demonstrated low MIC values against E. coli (MIC50/90, 1/2 mg/liter), Klebsiella oxytoca (MIC50/90, 1/4 mg/liter), and Enterobacter cloacae (MIC50/90, 2/4 mg/liter; 90.9% susceptible) isolates; moderate activity against Klebsiella pneumoniae (MIC50/90, 2/8 mg/liter; 88.3% susceptible), Citrobacter spp. (MIC50/90, 1/8 mg/liter), and Serratia marcescens (MIC50/90, 4/4 mg/liter) isolates; and very limited activity against Proteus mirabilis (MIC50/90, 16/32 mg/liter) and indole-positive Proteus spp. (MIC50/90, 4/16 mg/liter) isolates, with some geographic variation (Tables 1 and 2). Overall, 88.9%, 93.4%, and 93.4% of Enterobacteriaceae isolates were considered wild type at ECVs 95.0% (4 mg/liter), 97.5% (8 mg/liter), and 99.0% (8 mg/liter), respectively. Omadacycline MIC values (MIC50/90, 2/8 mg/liter) were lower than those observed for tetracycline (MIC50/90, 16/>16 mg/liter) and doxycycline (MIC50/90, 4/>8 mg/liter) against Enterobacteriaceae isolates and higher than those displayed by tigecycline (MIC50/90, 0.25/1 mg/liter). Furthermore, omadacycline inhibited 58.7% of 225 Acinetobacter baumannii isolates at ≤4 mg/liter (MIC50/90, 4/8 mg/liter) but had negligible in vitro activity against Pseudomonas aeruginosa (MIC50/90, >32/>32 mg/liter; Tables 1 and 2); these organisms exhibited low susceptibility to most antimicrobial agents tested (Table 3).
DISCUSSION
While antimicrobial resistance is a serious public health problem worldwide, there are often considerable regional geographic differences. Therefore, surveillance studies have become an important tool to document such differences in resistance across regions and over time. Antibiotic resistance has been rising steadily and antimicrobial-resistant bacteria are now highly prevalent in China (15). Previous studies have reported elevated bacterial resistance rates among hospitalized patients in Chinese medical centers, including Hong Kong and Taiwan (4, 5). Treatment options for these bacteria, which are often MDR, are increasingly difficult to find; remaining options are often less effective or less safe. This scenario generates a challenge for new drugs that have often been developed in countries with much lower resistance rates than those encountered in China. Hence, assessing and confirming pathogen susceptibility by region is important to appropriately use antimicrobials in patient care. In this study, omadacycline, a semisynthetic derivative of minocycline (tetracycline family), displayed good activity against diverse bacterial species of isolates from China and Taiwan. In particular, its activity against the pathogens associated with ABSSSI and CABP was excellent.
MRSA rates among medical centers in China were above 50% in 2004 but showed a slight decrease in more recent years to values similar to that reported in this study (43.4%). (2). Omadacycline displayed good activity against S. aureus recovered from all medical centers, including MRSA and tetracycline-resistant isolates. These results agree with previous reports of omadacycline activity against a bacterial collection from the United States and Europe (16, 17). High omadacycline activity rates were observed against bacterial species frequently responsible for community-acquired pneumonia, such as S. pneumoniae, H. influenzae, and Moraxella spp. These results also agree with those reported in other continents (16, 18) and support further clinical development of omadacycline against CABP pathogens in China. The same rationale can be used for evaluating the role of omadacycline in SSSI therapy, because in addition to its activity against S. aureus isolates, potent activity was also observed against VGS and BHS isolates.
Enterococcus spp. are among the most common species causing nosocomial infections across China (3, 19) and have become a clinical concern due to resistance to various antimicrobial agents, particularly among E. faecium and E. faecalis (20) isolates. In this study, a high vancomycin-resistant rate was observed among E. faecium. Omadacycline showed potent in vitro activity against all enterococci isolates, regardless of resistance to vancomycin, tetracycline, or minocycline. Of interest, the omadacycline ECVs observed against S. aureus strains, streptococci, and enterococci cover >90% of the respective bacterial species from this collection, indicating a high frequency of omadacycline wild-type population in this region.
Enterobacteriaceae were also commonly recovered from hospitalized patients in China and Taiwan; resistance to β-lactam agents was quite prevalent, as indicated by the reduced susceptibility rates observed herein for cephalosporins (66.8% and 53.1% susceptible to ceftazidime and ceftriaxone, respectively). These rates are in accordance to those showed by Jones et al. in a collection of E. coli clinical isolates (ceftazidime susceptible rate of 62.8%) recovered from Chinese medical centers in 2011 (3, 19). Omadacycline activity differed across Enterobacteriaceae species. Good activity was observed against E. coli, including ESBL-producing isolates, K. oxytoca, and E. cloacae isolates; moderate activity against K. pneumoniae and S. marcescens isolates; and more limited activity against Proteus spp. and nonfermentative Gram-negative pathogens (P. aeruginosa and A. baumannii) in this collection. Recently conducted surveillance studies reported very similar MIC ranges and MIC90 values for these pathogens in areas outside China, including the United States and European countries (10, 21).
When comparing antibacterial activity across newer tetracyclines (tigecycline and eravacycline), omadacycline displayed similar MIC values against Gram-positive pathogens and higher MIC values against Gram-negative bacterial isolates (22, 23). Of note, the ratio of the area under the concentration-time curve (AUC) to the MIC (fAUC/MIC) has been the pharmacokinetic/pharmacodynamic parameter that best correlates with antibacterial efficacy for the tetracycline class of antibiotics (24). Gotfried and colleagues showed that omadacycline has significantly higher free AUC than tigecycline; hence, corresponding U.S. FDA susceptibility breakpoints for omadacycline and tigecycline are different against Enterobacteriaceae (4 and 2 mg/liter, respectively) (24). Clinical studies are warranted to evaluate the correlation of omadacycline in vitro MIC results and pharmacokinetic-pharmacodynamic (PK/PD) parameters into clinical response.
In summary, omadacycline showed potent in vitro activity against Gram-positive organisms and useful activity against most Enterobacteriaceae pathogens isolated from China and Taiwan. Omadacycline has potent activity against the organisms most frequently encountered in bacterial skin infection and community-acquired pneumonia. In addition, omadacycline retains activity against problem pathogens, such as MRSA, VRE, penicillin-resistant S. pneumoniae, and ESBL-producing E. coli. There were no discernible differences in susceptibility profiles among China, Hong Kong, and Taiwan isolates compared with other geographic areas recently studied in the SENTRY network (16–18, 21).
MATERIALS AND METHODS
Organism collection.
A total of 3,282 nonduplicate bacterial isolates were consecutively collected from patients hospitalized in China (10 medical centers [excluding Hong Kong]; n = 2,243; 2013), Hong Kong (1 medical center; n = 452; 2013 to 2014), and Taiwan (1 medical center; n = 587; 2014 to 2016). Organisms were isolated from patients hospitalized with pneumonia (n = 974; 29.7%), bloodstream infections (n = 826; 25.2%), skin and skin structure infections (n = 772; 23.5%), community-acquired respiratory tract infections (n = 555; 16.9%), and other types of infections (n = 155; 4.7%). Medical records were not available to make clinical inferences about the infection source for patients hospitalized with pneumonia (e.g., community acquired or hospital acquired); thus, this category includes patients hospitalized for any reason who were diagnosed with pneumonia while hospitalized. Isolates were identified to the species level at each participating medical center and confirmed by the monitoring laboratory (JMI Laboratories, North Liberty, IA, USA) using the Vitek 2 system (bioMérieux, Hazelwood, MO, USA) or matrix-assisted laser desorption ionization–time of flight mass spectrometry (Bruker, Billerica, MA, USA) when necessary.
Susceptibility testing.
Susceptibility testing was performed by broth microdilution in frozen-form panels produced by JMI Laboratories following Clinical and Laboratory Standards Institute (CLSI) recommendations (25). Omadacycline powder was purchased from Carbogen AMCIS (Bubendorf, Switzerland), and comparator agents include tigecycline, doxycycline, tetracycline, minocycline, azithromycin, clindamycin, levofloxacin, linezolid, trimethoprim-sulfamethoxazole, ampicillin, amoxicillin-clavulanic acid, cefepime, ceftazidime, ceftriaxone, imipenem, penicillin, amikacin, gentamicin (powders purchased from US Pharmacopeia, Rockville, MD, USA), colistin, oxacillin, vancomycin (Sigma-Aldrich, St. Louis, MO, USA), piperacillin-tazobactam (Sigma-Aldrich and US Pharmacopeia, respectively), and daptomycin (TOKU-E, Bellingham, WA, USA). The quality of results was ensured by concurrently testing CLSI quality-control organisms (strains S. aureus ATCC 29213, E. faecalis ATCC 29212, S. pneumoniae ATCC 49619, E. coli ATCC 25922, and H. influenzae ATCC 49247) on each day of testing. Quality control and result interpretation were performed in accordance with CLSI M100 and European Committee on Antimicrobial Susceptibility Testing (EUCAST, v.8.1) guidelines (26, 27). Omadacycline clinical breakpoints recently approved by the U.S. FDA were used to interpret omadacycline results for the indicated species (28). E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis isolates were considered screen positive for ESBL production based on the CLSI screening criteria for potential ESBL production, i.e., ceftazidime, ceftriaxone, and/or aztreonam MIC of ≥2 mg/liter (26). S. pneumoniae isolates were classified as penicillin susceptible (MIC, ≤0.06 mg/liter) and penicillin resistant (MIC, ≥2) based on the CLSI breakpoint for oral penicillin V (26). ECVs for omadacycline were evaluated as described by Turnidge et al. for each bacterial species (29, 30), and the ECOFFinder program is available at http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/MIC_distributions/ECOFFinder_XL_2010_v2.0.xlsm.
ACKNOWLEDGMENTS
We thank Jennifer M. Streit for the support on the JMI surveillance studies.
This study was performed by JMI Laboratories and supported by Zai Laboratories (Shanghai, China), which included funding for services related to preparing the manuscript.
JMI Laboratories contracted to perform services in 2017 for Achaogen, Allecra Therapeutics, Allergan, Amplyx Pharmaceuticals, Antabio, API, Astellas Pharma, AstraZeneca, Athelas, Basilea Pharmaceutica, Bayer AG, Becton, Dickinson and Co., Boston Pharmaceuticals, CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Entasis Therapeutics, Inc., Geom Therapeutics, Inc., GSK, Iterum Pharma, Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., MicuRx Pharmaceuticals, Inc., N8 Medical, Inc., Nabriva Therapeutics, Inc., NAEJA-RGM, Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Ra Pharma, Rempex, Riptide Bioscience, Inc., Roche, Scynexis, Shionogi, Sinsa Labs, Inc., Skyline Antiinfectives, Sonoran Biosciences, Spero Therapeutics, Symbiotica, Synlogic, Synthes Biomaterials, TenNor Therapeutics, Tetraphase, The Medicines Company, Theravance Biopharma, VenatoRx Pharmaceuticals, Inc., Wockhardt, Yukon Pharma, Zai Laboratory, and Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.
REFERENCES
- 1.Department of Economic and Social Affairs. 2017. World population prospects: the 2017 revision, key findings and advance tables. United Nations, New York, NY: https://population.un.org/wpp/Publications/Files/WPP2017_KeyFindings.pdf. [Google Scholar]
- 2.Chen CJ, Huang YC. 2014. New epidemiology of Staphylococcus aureus infection in Asia. Clin Microbiol Infect 20:605–623. doi: 10.1111/1469-0691.12705. [DOI] [PubMed] [Google Scholar]
- 3.Yezli S, Li H. 2012. Antibiotic resistance amongst healthcare-associated pathogens in China. Int J Antimicrob Agents 40:389–397. doi: 10.1016/j.ijantimicag.2012.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Xiao YH, Giske CG, Wei ZQ, Shen P, Heddini A, Li LJ. 2011. Epidemiology and characteristics of antimicrobial resistance in China. Drug Resist Updat 14:236–250. doi: 10.1016/j.drup.2011.07.001. [DOI] [PubMed] [Google Scholar]
- 5.Xiao Y, Wei Z, Shen P, Ji J, Sun Z, Yu H, Zhang T, Ji P, Ni Y, Hu Z, Chu Y, Li L. 2015. Bacterial-resistance among outpatients of county hospitals in China: significant geographic distinctions and minor differences between central cities. Microbes Infect 17:417–425. doi: 10.1016/j.micinf.2015.02.001. [DOI] [PubMed] [Google Scholar]
- 6.O’Neill J. 2014. Review on antimicrobial resistance. antimicrobial resistance: tackling a crisis for the health and wealth of nations. HM Government, London, United Kingdom: https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf. [Google Scholar]
- 7.Villano S, Steenbergen J, Loh E. 2016. Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections. Future Microbiol 11:1421–1434. doi: 10.2217/fmb-2016-0100. [DOI] [PubMed] [Google Scholar]
- 8.Piddock LJ. 2006. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 19:382–402. doi: 10.1128/CMR.19.2.382-402.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Thaker M, Spanogiannopoulos P, Wright GD. 2010. The tetracycline resistome. Cell Mol Life Sci 67:419–431. doi: 10.1007/s00018-009-0172-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Pfaller MA, Huband MD, Rhomberg PR, Flamm RK. 2017. Surveillance of omadacycline activity tested against clinical isolates from a global (North America, Europe, Latin America and Asia-Western Pacific) collection (2010–2011). Antimicrob Agents Chemother 61:e00018-17. doi: 10.1128/AAC.00018-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Mukker JK, Singh RP, Derendorf H. 2014. Determination of atypical nonlinear plasma-protein-binding behavior of tigecycline using an in vitro microdialysis technique. J Pharm Sci 103:1013–1019. doi: 10.1002/jps.23872. [DOI] [PubMed] [Google Scholar]
- 12.Noel GJ, Draper MP, Hait H, Tanaka SK, Arbeit RD. 2012. A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of linezolid for treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother 56:5650–5654. doi: 10.1128/AAC.00948-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Abrahamian FM, Sakoulas G, Tzanis E, Manley A, Steenbergen JN, Das A, Eckburg P, McGovern P. 2018. Omadacycline for acute bacterial skin and skin structure infections: Integrated analysis of randomized clinical trials, abstr 1347. ID Week, October 3–7, San Francisco, CA. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Torres A, Garrity-Ryan L, Kirsch C, Steenbergen J, Eckburg P, Das A, Manley A, Tzanis E, McGovern P. 2018. Omadacycline versus moxifloxacin in the treatment of adults with community-acquired bacterial pneumonia (CABP): efficacy analysis according to EMA requirements, abstr P-0274 European Congress for Clinical Microbiology and Infectious Diseases (ECCMID), April 21–24, Madrid, Spain. [Google Scholar]
- 15.Cheng VC, Wong SC, Ho PL, Yuen KY. 2015. Strategic measures for the control of surging antimicrobial resistance in Hong Kong and mainland of China. Emerg Microbes Infect 4:e8. doi: 10.1038/emi.2015.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Pfaller MA, Huband MD, Shortridge D, Flamm RK. 2018. Surveillance of omadacycline activity tested against clinical isolates from the United States and Europe: report from the SENTRY Antimicrobial Surveillance Program, 2016. Antimicrob Agents Chemother 62:e02327-17. doi: 10.1128/AAC.02327-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Pfaller MA, Rhomberg PR, Huband MD, Flamm RK. 2017. Activities of omadacycline and comparator agents when tested against Staphylococcus aureus isolates from a surveillance program conducted in North America and Europe. Antimicrob Agents Chemother 61:e02411-16. doi: 10.1128/AAC.02411-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Pfaller MA, Rhomberg PR, Huband MD, Flamm RK. 2018. Activity of omadacycline tested against Streptococcus pneumoniae from a global surveillance program (2014). Diagn Microbiol Infect Dis 90:143–147. doi: 10.1016/j.diagmicrobio.2017.10.010. [DOI] [PubMed] [Google Scholar]
- 19.Jones RN, Castanheira M, Hu B, Ni Y, Lin SSF, Mendes RE, Wang Y. 2013. Update of contemporary antimicrobial resistance rates across China: reference testing results for 12 medical centers (2011). Diagn Microbiol Infect Dis 77:258–266. doi: 10.1016/j.diagmicrobio.2013.07.003. [DOI] [PubMed] [Google Scholar]
- 20.Bi R, Qin T, Fan W, Ma P, Gu B. 2018. The emerging problem of linezolid-resistant enterococci. J Glob Antimicrob Resist 13:11–19. doi: 10.1016/j.jgar.2017.10.018. [DOI] [PubMed] [Google Scholar]
- 21.Pfaller MA, Rhomberg PR, Huband MD, Flamm RK. 2018. Activity of omadacycline tested against Enterobacteriaceae causing urinary tract infections from a global surveillance program (2014). Diagn Microbiol Infect Dis 91:179–183. doi: 10.1016/j.diagmicrobio.2018.01.019. [DOI] [PubMed] [Google Scholar]
- 22.Sutcliffe JA, O'Brien W, Fyfe C, Grossman TH. 2013. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother 57:5548–5558. doi: 10.1128/AAC.01288-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Pfaller MA, Huband MD, Streit J, Flamm RK, Sader HS. 2018. Surveillance of tigecycline activity tested against clinical isolates from a global (North America, Europe, Latin America and Asia-Pacific) collection (2016). Int J Antimicrob Agents 51:848–853. doi: 10.1016/j.ijantimicag.2018.01.006. [DOI] [PubMed] [Google Scholar]
- 24.Gotfried MH, Horn K, Garrity-Ryan L, Villano S, Tzanis E, Chitra S, Manley A, Tanaka SK, Rodvold KA. 2017. Comparison of omadacycline and tigecycline pharmacokinetics in the plasma, epithelial lining fluid, and alveolar cells of healthy adult subjects. Antimicrob Agents Chemother 61:e01135-17. doi: 10.1128/AAC.01135-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Clinical and Laboratory Standards Institute. 2018. M07Ed11E. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 11th ed Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 26.Clinical and Laboratory Standards Institute. 2018. M100Ed28E. Performance standards for antimicrobial susceptibility testing, 28th informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 27.EUCAST. 2018. Breakpoint tables for interpretation of MIC's and zone diameters, version 8.0, January 2018 EUCAST, Växjö, Sweden: http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_8.0_Breakpoint_Tables.pdf. [Google Scholar]
- 28.FDA. 2018. Recognized antimicrobial susceptibility test interpretive criteria for omadacycline. FDA, Silver Spring, MD: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Developmentresources/ucm622612.htm. [Google Scholar]
- 29.Turnidge J, Kahlmeter G, Kronvall G. 2006. Statistical characterisation of bacterial wild-type MIC value distributions and the determination of epidemiological cut-off values. Clin Microbiol Infect 12:418–425. doi: 10.1111/j.1469-0691.2006.01377.x. [DOI] [PubMed] [Google Scholar]
- 30.EUCAST. 2018. MIC and zone diameter distributions and ECOFFs. http://www.eucast.org/mic_distributions_and_ecoffs/. [Google Scholar]
- 31.Tygacil. 2018. Tygacil package insert. Wyeth Pharmaceuticals LLC, Philadelphia, PA: http://labeling.pfizer.com/ShowLabeling.aspx?format=PDF&id=491. [Google Scholar]