Antimicrobial activity of omadacycline in vitro against bacteria isolated from 2014 to 2017 in China, a multi-center study

Omadacycline (ZL-2401) is a semi-synthetic derivative of minocycline. It has a broadspectrum activity against Gram-positive and Gram-negative bacteria, and atypical pathogens. The objective of this study was to evaluate the antibacterial activity of omadacycline against recently collected bacterial isolates from Chinese patients. Omadacycline showed potent activity against all Gram-positive pathogens: S. aureus MICs were low regardless of susceptibility to methicillin (methicillin-resistant Staphylococcus aureus, MRSA: N = 97, MIC50/90 0.12/0.25 mg/L, 98.5% susceptible; methicillin-sensitive Staphylococcus aureus, MSSA: N = 100, MIC50/90 0.12/0.12 mg/L, 100.0% susceptible). Omadacycline was also very effective against β-haemolytic streptococci (MIC50/90, 0.06/0.12 mg/L), viridans group streptococci (MIC50/90,<0.03/0. 06 mg/L), and enterococci (MIC50/90, 0.03/0.12 mg/L). Against S. pneumoniae, omadacycline was highly active regardless of penicillin-resistance (MIC90 0.06 mg/L) and despite the fact that less than 10.0% of these strains were susceptible to tetracycline. Omadacycline exhibited good in vitro activity against Enterobacterales isolates (MIC50/90, 2/8 mg/L), inhibiting 81.7% of the isolates at ≤4 mg/L. M. catarrhalis isolates (MIC50/90, 0.12/0.25 mg/L) were fully susceptible to omadacycline at ≤0.5 mg/L. Omadacycline showed potent in vitro activity against most common bacterial pathogens, and even against highly resistant problem pathogens, such as MRSA, penicillin-R and tetracycline-R S. pneumoniae and enterococci. The susceptibility rate of Chinese isolates was similar to those reported in other countries, but the decreased activity against K. pneumoniae isolates in the present study should be noted.


Background
The main bacterial pathogens of acute bacterial skin and skin structure infections (ABSSSIs) include Staphylococcus aureus and coagulase-negative staphylococci, with the former exhibiting high antimicrobial resistance rate and thus requiring highly effective antibiotics for management [1]. Community-acquired bacterial pneumonia (CABP) poses a significant health and economic burden in all regions of the world [1]. The most prevalent pathogens implicated in CABP include Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa [2,3]. Among them, penicillin-resistant and multidrug-resistant S. pneumoniae (PRSP) are particularly concerning.
The tetracycline family of antibiotics entered the clinical practice against common infectious diseases in the late 1940s. However, due to the excessive use of antimicrobials in agriculture and veterinary medicine for many years, the resistance rates of several bacterial strains in environmental and animal reservoirs have increased to worrying levels, including the emergence of tetracycline resistant strains [4]. In the past decade, tigecycline has replaced tetracycline as an important therapeutic drug for antimicrobial resistant bacterial strains [5]. However, tigecycline is unavailable in oral form and has been reported to be associated with a high incidence of nausea and vomiting, and is even implicated in elevated allcause mortality [6,7].
Omadacycline (ZL-2401) is a novel antibacterial agent approved by the US Food and Drug Administration (FDA) for the treatment of ABSSSIs and CABP [7,8]. As a semisynthetic derivative of minocycline, and the first agent of the aminomethylcycline class, it has a broad spectrum activity against a wide range of organisms, including Grampositive and Gram-negative bacteria [9]. Even against highly resistant bacterial strains such as methicillinresistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), and PRSP, good antimicrobial activity has also been observed as per data obtained in the SENTRY antimicrobial surveillance program [10]. However, the prevalence and antimicrobial resistance rates of some bacterial species are different all over the world [11]. The aim of this study was to evaluate the in vitro activity of omadacycline against common bacteria in Mainland China.

Susceptibility of gram-positive isolates to omadacycline
The 1273 bacterial isolates studied and their key resistance phenotypes are listed in Tables 1 and 2. The MIC  distributions of Gram-positive isolates against omadacycline are shown in Tables 1 and 3. Omadacycline was tested against S. aureus isolates (98.5% susceptible), using ABSSSI breakpoints with MIC 50/90 values of 0.12/ 0.25 mg/L (Table 1). Of these, 100.0% of MSSA, 96.9% of MRSA, 97.4% of tetracycline-resistant S. aureus, and 100.0% of tigecycline-resistant S. aureus, were susceptible to omadacycline.

Discussion
Tigecycline has been an important option antibiotic for treatment of patients infected with tetracycline-resistant bacterial strains. Tigecycline, however, is available only as an intravenous formulation, while omadacycline is available both as an intravenous and oral formulation. Similar to other tetracyclines, omadacycline binds to 30S subunit of bacterial ribosome for inhibiting protein synthesis. Structure of omadacycline differs significantly from other tetracyclines and this compound represents a new aminomethylcycline subsclass [12]. Omadacycline overcomes the tetracycline efflux and ribosome protection mechanisms of bacterial resistance, due to modification at the C7 and C9 positions, respectively [13].
Over the past decades, the incidence of MRSA has been slowly decreasing in the United States of America (USA), the United Kingdom, Australia and China [17][18][19][20][21]. However, it still remains a major issue for skin and skin structure infections [22,23]. High omadacycline activity rates were observed against MRSA and tetracycline-resistant S. aureus isolates in the present study, with 96.9 and 97.4% susceptible rates, respectively, which is consistent with other reported data from USA and Europe [10]. In addition, the activity of omadacycline against α-hemolytic  Using FDA identified breakpoints for ABSSSIs c Using FDA identified breakpoints for CABP streptococci was impressive, especially against S. pneumoniae, and even PRSP and tigecycline-non-susceptible S. pneumoniae (100.0% susceptible).
In China, the most common bacterial pathogen causing community acquired pneumonia (CAP) is Mycoplasma pneumoniae, accounting for 32.4% of 1500 children presenting with CAP in some studies [24,25]. Furthermore, P. aeruginosa, K. pneumoniae, E. coli and Acinetobacter have been reported as significant CAP pathogens for hospitalized adults [24,25]. According to guidelines of the Infectious Diseases Society of America and the American Thoracic Society, non-fermenting Gram-negative bacilli account for 19% (95% CI, 15-24%) of cases of hospitalacquired pneumonia (HAP), with P. aeruginosa implicated in 13.8% of HAP or ventilator-associated pneumonia (VAP) cases [26]. In the present study, omadacycline showed moderate in vitro activity against K. pneumoniae and A. baumannii, inhibiting 70.5 and 75.8% of the isolates at ≤4 mg/L, respectively ( Table 2). It is possible that the A. baumannii and K. pneumoniae isolates tested in the present study may have originated from patients with HAP/VAP. And if that is the case, the higher MIC values of omadacycline seems reasonable. Compared with MIC 50/90 values of minocycline (8/32 mg/L) and tigecycline (8/16 mg/L) against P. aeruginosa, MIC 50/90 values of omadacycline (32/32 mg/L) were higher. Similar to its initial resistance to tetracycline and tigecycline [27], P. aeruginosa also exhibited low susceptibility to omadacycline. This study has several limitations. The most obvious being the source of the isolates, as some strains were not isolated from patients with CAP or ABSSSIs. However, just like tigecycline is used in some non-approved clinical indications [28][29][30], we hope that the results of in vitro activity of omadacycline against strains isolated from the other infections can provide references for other clinical uses. Thus for a more comprehensive understanding of the in vitro antibacterial spectrum of omadacycline, we have also included other pathogens apart from those causing CAP and ABSSSIs, such as enterococci.

Conclusions
In summary, omadacycline showed good in vitro activity against Gram-positive organisms and useful activity against most Enterobacterales strains isolated from China. In addition, omadacycline showed potent activity against several antimicrobial-resistant profile pathogens, including MRSA, PRSP, ESBL phenotype positive, and even carbapenemaseproducing E. coli. Increased MIC values of omadacycline were observed in K. pneumoniae isolates in the present study, compared with other geographic areas recently studied [10,16,31,32]. The 25 teaching hospitals are located in eighteen provinces across all the seven geographic regions in China. The strains studied were isolated from different clinical departments in each teaching hospital. According to sample type category, the majority was collected from respiratory tract (39.4%), including sputum (n = 435), broncho-alveolar lavage (n = 60), tracheobronchial aspiration (n = 5), and throat swab (n = 1). Other sources included urinary tract (21.5%), body fluid (19.2%), tissue (9.9%), abscess (6.9%), and others (3.2%). All the isolates were primarily identified at each local laboratory and confirmed in the central laboratory by Matrix-assisted laser desorption ionization time-of-flight mass spectrometer (bioMérieux, Vitek MS, USA) or 16S rDNA sequencing when necessary.