A multicentre, randomised, double-blind, double-dummy, parallel-controlled, phase 3 clinical trial assessing the efficacy and safety of intravenous nemonoxacin malate versus levofloxacin for community-acquired pneumonia in adult patients.

BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3 multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin versus levofloxacin for treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: The eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at test of cure (TOC) visit in the modified intent-to-treat (mITT) population. The efficacy and safety were also compared between nemonoxacin and levofloxacin in terms of secondary efficacy and safety endpoints. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n=349) or levofloxacin (n=176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P> 0.05). The clinical efficacy of nemonoxacin was noninferior to levofloxacin in treatment of CAP. Nemonoxacin achieved microbiological success rate of 88.8% (95/107), while levofloxacin achieved 87.8% (43/49) (P > 0.05) at TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in nemonoxacin group and 22.2% in levofloxacin group, mostly local reactions at the infusion site, nausea, elevated ALT/AST, and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and noninferior to levofloxacin for treating CAP in adult patients.

A modified Kirby-Bauer disc diffusion (mKB) method for accurately testing tigecycline susceptibility: a nation-wide multicenter comparative study.

Introduction. Tigecycline is one of the important antibiotics available for treating infection caused by multiple-drug resistant pathogens. However, the conventional AST methods which are commonly used in clinical microbiology laboratories usually lead to false intermediate or resistant results in testing tigecycline susceptibility, and further mislead clinical antimicrobial therapies.Hypothesis. The modified Kirby-Bauer disc diffusion (mKB) method was performed based on the traditional standard Kirby-Bauer disc diffusion (sKB) method.Aim. To evaluate a modified Kirby-Bauer disc diffusion (mKB) method for tigecycline susceptibility testing, for the purpose of providing accurate tigecycline susceptibility results in clinical practice.Methodology. A total of 4271 nonduplicate clinical strains were isolated from 37 hospitals across China to perform the mKB method, standard Kirby-Bauer disc diffusion (sKB) method, comparing with the reference broth microdilution (BMD) according to the CLSI. Parameters of categorical agreement (CA), minor errors (mE), major errors (ME), and very major errors (VME) were used in this methodological evaluation research.Results. BMD testing showed that 91.3-98.9 % of the A. baumannii, K. pneumoniae, E. coli, E. cloacae, S. marcescens, and C. freundii strains were susceptible, while 0-3.1% strains were resistant to tigecycline. When testing A. baumannii, mKB demonstrated higher CA than sKB (90.6 % vs 44.8 %) compared to reference BMD. The mE (9.0 % vs 45.2 %), ME (0.5 % vs 10.6 %) and VME (both 0 %) all satisfied the acceptability criteria. mKB also showed higher CA (87.2 % vs 52.0 %) than sKB in comparison with BMD when testing Enterobacterales (mainly K. pneumonia). The ME (0.45 % vs 8.1 %) and VME (both 0 %) but not mE (12.4 % vs 40.4 %) met the acceptability criteria.Conclusion. The mKB method can test bacterial susceptibility to tigecycline more accurately than sKB. For the tigecycline-intermediate or -resistant strains by sKB method, BMD or mKB method should be used to verify the results and report reliable tigecycline susceptibility results.

Integrative population pharmacokinetic/pharmacodynamic analysis of nemonoxacin capsule in Chinese patients with community-acquired pneumonia.

Introduction: Nemonoxacin is an innovative quinolone antibiotic for treatment of community-acquired pneumonia (CAP). As more data are available from clinical studies, it is necessary to perform an integrative pharmacokinetic/pharmacodynamic (PK/PD) analysis to support and justify the optimal dosing regimen of nemonoxacin in clinical practice. Methods and Results: We developed a population PK model using non-linear mixed effect model based on the data of 195 Chinese subjects receiving nemonoxacin in phase I to III clinical trials. The base model was a standard two-compartment PK model defined by clearance (12 L/h) and central volume of distribution (86 L). Covariates included creatinine clearance (CLcr), body weight (BW), sex, disease status and food. Compared to the subject with BW 60 kg, Cmax and A U C 0 - 24 , ss reduced by 24% and 19% in the subject with BW 80 kg, respectively. Compared to the subject with CLcr 150 ml/min, A U C 0 - 24 , ss and T1/2 increased by 28% and 24%, respectively in the subject with CLcr 30 ml/min. Compared to the fasted status, Tmax of nemonoxacin increased by 1.2 h in the subject with fed status. Effects of sex and disease status on PK parameters were small (change of PK parameters ≤19%). AUC0-24/MIC and %T > MIC were identified as the optimal PK/PD indices for predicting clinical efficacy. The AUC0-24/MIC target was 63.3, 97.8, and 115.7 against Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The %T > MIC target was 7.96% against Klebsiella pneumoniae. Monte Carlo simulation showed that treatment with nemonoxacin 500 mg q24 h could attain a PK/PD cutoff value higher than the MIC90 against S. pneumoniae and S. aureus. The corresponding cumulative fraction of response (CFR) was greater than 93%, while nemonoxacin 750 mg q24 h would provide higher PK/PD cutoff value against Haemophilus parainfluenzae, and higher CFR (83%) than 500 mg q24 h. Conclusion: Integrative PK/PD analysis justifies the reliable clinical and microbiological efficacy of nemonoxacin 500 mg q24 h in treating CAP caused by S. pneumoniae, S. aureus, and K. pneumoniae, irrespective of patient sex, mild renal impairment, empty stomach or not. However, nemonoxacin 750 mg q24 h would provide better efficacy than 500 mg q24 h for the CAP caused by H. parainfluenzae in terms of CFR.

Setting of the tentative epidemiological cut-off values of contezolid for Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae and Streptococcus agalactiae.

OBJECTIVES: To set the tentative epidemiological cut-off values (TECOFFs) of contezolid for Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae and Streptococcus agalactiae based on the distributions of inhibition zone diameters and MICs. METHODS: A total of 1358 non-duplicate clinical isolates of Gram-positive bacteria were collected from the patients across China from 2017 to 2020. The isolates were tested for susceptibility to contezolid and the comparator linezolid by broth microdilution and disc diffusion methods in three microbiology laboratories. The zone diameters and MICs of linezolid WT strains were used to set the WT TECOFFs of contezolid by normalized resistance interpretation calculations. RESULTS: Contezolid showed an aggregate MIC range from 0.03 to 8 mg/L and MIC90 value of 1-2 mg/L against all of the Gram-positive bacterial strains tested. The TECOFF of contezolid based on MIC distributions was 4 mg/L for both S. aureus and Enterococcus species, and 2 mg/L for S. pneumoniae and S. agalactiae. The TECOFF of contezolid based on zone diameter was 24 mm for S. aureus, 18 mm for E. faecalis, 20 mm for E. faecium and S. pneumoniae, and 17 mm for S. agalactiae. CONCLUSIONS: The epidemiological cut-off values of contezolid were set tentatively for selected Gram-positive bacteria using the MIC and zone diameter distributions. These data are helpful for clinical microbiologists and clinicians to interpret the antimicrobial susceptibility results of contezolid.

Performance of Ceftazidime-Avibactam 30/20-µg and 10/4-µg Disks for Susceptibility Testing of Enterobacterales and Pseudomonas aeruginosa.

Ceftazidime-avibactam, a new ß-lactam-ß-lactamase inhibitor combination, is active against multidrug-resistant Enterobacterales and Pseudomonas aeruginosa isolates and has became available for clinical use in China in the latter half of 2019. In this study, we evaluated the performance of the disk diffusion test with ceftazidime-avibactam 10/4-µg and 30/20-µg disks, compared with the reference broth microdilution method, with a collection of 467 Enterobacterales and 182 P. aeruginosa nonduplicate clinical isolates. The results of antimicrobial susceptibility testing indicated that the categorical agreement (CA) of ceftazidime-avibactam 10/4-µg disk testing for all tested Enterobacterales isolates was 99.8%, with 0.5% very major errors (VMEs) and no major error (ME). The CA of ceftazidime-avibactam 10/4-µg disk testing for all tested P. aeruginosa isolates was 87.9%, with 15.5% MEs and no VME. The CA of ceftazidime-avibactam 30/20-µg disk testing for all tested Enterobacterales isolates was 99.4%, with 1.5% VMEs and no ME. The CA of ceftazidime-avibactam 30/20-µg disk testing for all tested P. aeruginosa isolates was 91.8%, with 2.5% VMEs and 9.9% MEs. Overall, ceftazidime-avibactam 10/4-µg disk testing showed superior performance and was more suitable for assessment of the susceptibility of Enterobacterales and P. aeruginosa isolates. IMPORTANCE Multidrug-resistant Enterobacterales and P. aeruginosa strains have become a global public threat, with the emergence and prevalence of plasmid-mediated extended-spectrum ß-lactamases (ESBLs), AmpC cephalosporinases, and carbapenemases disseminated worldwide. Ceftazidime-avibactam, which is commercially available, has shown excellent in vitro activity against multidrug-resistant and carbapenem-resistant Enterobacterales and P. aeruginosa isolates. Moreover, ceftazidime-avibactam has shown promise in treating infections caused by multidrug-resistant and carbapenem-resistant isolates. The disk diffusion test for ceftazidime-avibactam is the most common antimicrobial susceptibility testing method in most laboratories in China. The accurate detection of ceftazidime-avibactam susceptibility is of great significance for the rational clinical application of drugs. Here, we evaluated the performance of the ceftazidime-avibactam 10/4-µg and 30/20-µg disk diffusion tests, compared with the reference broth microdilution method, with clinical Enterobacterales and P. aeruginosa isolates.

Multicenter Antimicrobial Resistance Surveillance of Clinical Isolates from Major Hospitals - China, 2022.

What is already known about this topic?: Bacterial resistance surveillance is crucial for monitoring and understanding the trends and spread of drug-resistant bacteria. What is added by this report?: The number of strains collected in 2022 increased compared to 2021. The top five bacteria, including Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii, remained largely unchanged. The detection rate of methicillin-resistant strains continued to decrease. Among clinical Enterobacterales isolates, the resistance rate to carbapenems was generally below 13%, except for Klebsiellaspp., which had a resistance range of 20.4% to 21.9%. Most clinical Enterobacterales isolates were highly susceptible to tigecycline, colistin, and polymyxin B, with resistance rates ranging from 0.1% to 12.6%. The detection rate of meropenem-resistant P. aeruginosa and meropenem-resistant Acinetobacter baumannii showed a decreasing trend for the fourth consecutive year. What are the implications for public health practice?: Multidrug-resistant bacteria remain a significant public health challenge in clinical antimicrobial treatment. To effectively address bacterial resistance, it is essential to enhance both bacterial resistance surveillance and the prudent use of antimicrobial agents.

Activities of Eravacycline, Tedizolid, Norvancomycin, Nemonoxacin, Ceftaroline, and Comparators against 1,871 Staphylococcus and 1,068 Enterococcus Species Isolates from China: Updated Report of the CHINET Study 2019.

To evaluate the in vitro activities of eravacycline, tedizolid, nemonoxacin, norvancomycin, and ceftaroline against Staphylococcus and Enterococcus species isolates were collected as part of the China Antimicrobial Surveillance Network (CHINET) in 2019 to provide susceptibility data for Staphylococcus spp. and Enterococcus spp. for their future development and application in clinical practice. Antimicrobial susceptibility testing was performed using the CLSI broth microdilution reference method. Eravacycline was highly active against Staphylococcus and Enterococcus species isolates, proved by the MIC50/90: 0.06/0.125, 0.06/0.25, 0.06/0.25, 0.06/0.25, 0.125/0.5, 0.125/0.25, and 0.03/0.06 mg/L for Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), S. epidermidis, S. hominis, S. haemolyticus, Enterococcus faecalis, and E. faecium, respectively. S. aureus isolates tested were fully susceptible to tedizolid. Still, nonsusceptible isolates were found for E. faecalis (72/567 [12.7%]) and E. faecium (12/501 [2.4%]). Norvancomycin at 2 mg/L could inhibit 100% of Staphylococcus spp., while 1 mg/L of ceftaroline could inhibit 78.9% of MRSA and 99.9% of methicillin-susceptible S. aureus (MSSA) isolates. Additionally, nemonoxacin was also active against Staphylococcus and Enterococcus species isolates tested (shown by the following MIC90s and ranges, in milligrams per liter: 2 and ≤0.015 to 8 for MRSA, 0.25 and ≤0.015 to 4 for MSSA, 0.5 and ≤0.015 to 8 for S. epidermidis, and 4 and ≤0.015 to >32 for E. faecalis). In conclusion, both eravacycline and tedizolid were highly active against clinical isolates of Staphylococcus spp. and Enterococcus spp. recently collected across China. Nemonoxacin showed potent activity against Staphylococcus spp. and E. faecalis but limited activity against E. faecium. Norvancomycin and ceftaroline displayed highly potent activity against Staphylococcus spp. IMPORTANCE Antimicrobial resistance has become a severe threat to global public health. According to statistics, nearly 700,000 people die from bacterial infections worldwide (J. O'Neill, Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations, 2014; C. Y. Chin, K. A. Tipton, M. Farokhyfar, E. M. Burd, et al., Nat Microbiol 3:563-569, 2018, https://doi.org/10.1038/s41564-018-0151-5). The number of bacterial infections is expected to climb to 10 million by 2050, showing that bacterial resistance has become a significant problem that cannot be ignored. It is crucial to develop new antimicrobial agents to combat antimicrobial-resistant bacteria. In this study, we evaluated the in vitro activities of eravacycline, tedizolid, nemonoxacin, norvancomycin, and ceftaroline against Staphylococcus spp. and Enterococcus species isolates which were collected as part of CHINET in 2019. We believe that this study can provide susceptibility data for Staphylococcus spp. and Enterococcus spp. for their future development and application in clinical practice.

Antimicrobial activity of ceftobiprole and comparator agents when tested against gram-positive and -negative organisms collected across China (2016-2018).

BACKGROUND: Ceftobiprole is a fifth-generation cephalosporin which has been reported to have broad antibacterial spectrum when tested against bacteria collected from other countries except China. This study evaluated the in vitro activity of ceftobiprole in comparison with other comparators against clinically significant isolates collected across from China. RESULTS: Susceptibility testing of ceftobiprole and comparators against 1163 clinically isolated Gram-positive and Gram-negative bacteria was performed with broth micro dilution method following the CLSI guidelines. All 110 S. aureus were susceptible to ceftobiprole with MIC50/90 of 1/2 mg/L for MRSA and 0.5/1 mg/L for MSSA. For Coagulase-negative staphylococci (CNS), MIC50/90 of ceftobiprole for MRCNS and MSCNS was 1/2 mg/L and 0.25/0.5 mg/L. Ceftobiprole demonstrated good potency against E. faecalis (MIC50/90 of 0.5/1 mg/L) but limited activity against E. faecium (MIC50/90 of > 32/ > 32 mg/L). Ceftobiprole demonstrated potent activity against all 39 ß-hemolytic Streptococcus spp. with MIC50/90 ≤ 0.015/ ≤ 0.015-2 mg/L and 110 of PSSP with 98.2% susceptibility. Ceftobiprole inhibited all isolates of H. influenzae and M. catarrhalis at ≤ 1 mg/L. 91.8% and 98.2% of the ESBL-negative E. coli and K. pneumoniae were susceptible to ceftobiprole, but most of the ESBL-positive or carbapenem-resistant strains were also resistant to ceftobiprole. Ceftobiprole inhibited 84.2% of carbapenem-susceptible P. aeruginosa and 94.1% of carbapenem-susceptible A. baumannii at ≤ 8 mg/L, but only 52.6% of carbapenem-resistant P. aeruginosa and 5.3% of carbapenem-resistant A. baumannii. CONCLUSION: Ceftobiprole demonstrated good in vitro activity against a broad range of clinically relevant contemporary Gram-positive and Gram-negative bacterial isolates.

In Vitro Activity of New ß-Lactam-ß-Lactamase Inhibitor Combinations and Comparators against Clinical Isolates of Gram-Negative Bacilli: Results from the China Antimicrobial Surveillance Network (CHINET) in 2019.

Novel ß-lactam-ß-lactamase inhibitor combinations (BLBLIs) are in clinical development for the treatment of infections caused by carbapenem-resistant and difficult-to-treat resistant (DTR) (defined as resistance to all tested ß-lactams and fluoroquinolones) Gram-negative bacilli. This study evaluated the in vitro activities of cefepime-zidebactam, ceftazidime-avibactam, cefepime-tazobactam, ceftolozane-tazobactam, and other comparators against 4,042 nonduplicate Gram-negative clinical isolates collected from different regions of China (46 hospitals) in 2019. Based on the pharmacokinetic-pharmacodynamic (PK-PD) breakpoints, cefepime-zidebactam inhibited 98.5% of Enterobacterales and 98.9% of Pseudomonas aeruginosa isolates, respectively. Against carbapenem-resistant and difficult-to-treat resistant Gram-negative bacilli, cefepime-zidebactam demonstrated better activity against Enterobacterales (96% and 97.2%, respectively) and P. aeruginosa (98.2% and 96.9%, respectively). Among the 379 carbapenem-resistant Enterobacterales isolates, the most common carbapenemase genes detected were blaKPC-2 (64.1%) and blaNDM (30.9%). Cefepime-zidebactam showed an MIC90 of ≤2 mg/L for 98.8% of blaKPC-positive isolates and 89.7% of blaNDM-positive isolates. Ceftazidime-avibactam also showed efficient in vitro activity against Enterobacterales (93.6%) and P. aeruginosa (87.7%). Ceftazidime-avibactam was active against 97.5% of blaKPC-positive isolates and 100% of blaOXA-232-positive isolates. Cefepime-zidebactam inhibited 97.3% of Acinetobacter baumannii isolates with an MIC50/90 of 16/32 mg/L. Our study systematically evaluated the in vitro activities of these new BLBLIs against a variety of Gram-negative bacilli, provided preclinical data for the approval of these BLBLIs in China, and supported cefepime-zidebactam and ceftazidime-avibactam as potential efficient therapies for infections caused by carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant P. aeruginosa (CRPA), and DTR isolates. IMPORTANCE Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii are the most common Gram-negative bacilli to cause nosocomial infections throughout the world. Due to their large public health and societal implications, carbapenem-resistant A. baumannii (CRAB), carbapenem-resistant P. aeruginosa (CRPA), and carbapenem-resistant and third-generation-cephalosporin-resistant Enterobacteriaceae were regarded by the World Health Organization (WHO) as a global priority for investment in new drugs in 2017. The present study showed the potent in vitro activity of these novel BLBLIs and other comparators against Gram-negative bacillus isolates, including carbapenem-resistant or difficult-to-treat resistant phenotypes. Polymyxins, tigecycline, and ceftazidime-avibactam (except for blaNDM-positive isolates) were available for the treatment of infections caused by CRE isolates. Currently, cefepime-zidebactam and other BLBLIs have not yet been approved for use in China. Here, our study aimed to evaluate the in vitro activities of BLBLIs against Gram-negative bacillus isolates, especially CRE, before clinical use.

In Vitro Activity of MRX-8 and Comparators Against Clinical Isolated Gram-Negative Bacilli in China.

To evaluate in vitro antibacterial activity of MRX-8 against gram-negative bacteria recently isolated from China, 765 clinical isolates were collected randomly from 2017 to 2020, including Enterobacterales and P. aeruginosa and A. baumannii, S. maltophilia, B. cepacia, Alcaligenes app. and Haemophilus spp. isolates. All strains were performed with antimicrobial susceptibility testing by broth microdilution method according to the CLSI 2021. Antimicrobial agents included MRX-8, polymyxin B, colistin, amikacin, ceftriaxone, ceftazidime, cefepime, ceftazidime-avibactam, cefoperazone-sulbactam, meropenem, ciprofloxacin, ampicillin, ampicillin-sulbactam and levofloxacin. For carbapenem-susceptible and carbapenem-resistant E.coli isolates, the MIC50/90 of MRX-8 was 0.125/0.25 mg/L and 0.06/0.125 mg/L, respectively. For carbapenem-susceptible and carbapenem-resistant K. pneumoniae isolates, the MIC50/90 of MRX-8 was 0.25/0.5 mg/L and 0.125/0.5 mg/L, respectively. For polymyxins (polymyxin B and colistin)-resistant E. coli and K. pneumoniae, MIC50 of MRX-8 was 4-16 mg/L and MIC90 was >32 mg/L. The MIC50 and MIC90 of MRX-8 for other Klebsiella spp. except K. pneumoniae, Citrobacter spp., S. enterica and Shigella spp. isolates ranged 0.06-0.125 mg/L and 0.06-0.25mg/L, respectively. For Morganella spp., Proteus spp., Providencia spp., Serratia spp., S. maltophilia and B. cepacia, all MIC50 of MRX-8 was >32mg/L. For carbapenem susceptible and resistant P. aeruginosa, the MIC50 and MIC90 of MRX-8 was both 1mg/L, and that for A. baumannii was 0.5mg/L and 0.5-1mg/L. For Alcaligenes spp. and Haemophilus spp., MIC50/90 was 1/4 mg/L and 0.25/0.5 mg/L. MRX-8 was more effective against most clinically isolated gram-negative isolates, including carbapenem-resistant E. coli, K. pneumoniae, P. aeruginosa and A. baumannii, highlighting its potential as valuable therapeutics.

In Vitro Activity of KBP-7072 against 536 Acinetobacter baumannii Complex Isolates Collected in China.

Acinetobacter baumannii has emerged globally as a difficult-to-treat nosocomial pathogen and become resistant to carbapenems, resulting in limited treatment options. KBP-7072 is a novel semisynthetic aminomethylcycline, expanded spectrum tetracycline antibacterial agent with completed phase 1 clinical development studies. This study aimed to evaluate the in vitro activity of KBP-7072 and several comparators against clinical A. baumannii isolates collected from China. A collection of 536 A. baumannii clinical isolates were isolated from 20 hospitals across 13 provinces and cities in China between 2018 and 2019. Antimicrobial susceptibility testing of 12 antimicrobial agents was performed utilizing the broth microdilution method recommended by CLSI. KBP-7072 has shown active antibacterial activity against 536 A. baumannii isolates. It inhibited the growth of all isolates at 4 mg/liter, including 372 carbapenem-resistant isolates, 37 tigecycline MIC ≥ 4 mg/liter isolates, and 138 omadacycline MIC ≥ 4 mg/liter isolates. Compared with other expanded spectrum tetracyclines, KBP-7072 (MIC90, 1 mg/liter) outperformed 2-fold and 4-fold more active against 536 A. baumannii isolates than tigecycline (MIC90, 2 mg/liter) and omadacycline (MIC90, 4 mg/liter). KBP-7072 was as equally active as colistin (MIC90, 1 mg/liter, 99.4% susceptible). Doxycycline (33.4% susceptible), gentamicin (31.3% susceptible), meropenem (30.6%, susceptible), imipenem (30.2% susceptible), ceftazidime (27.8% susceptible), piperacillin-tazobactam (27.2% susceptible), and levofloxacin (27.2% susceptible) showed marginally poor antibacterial activity against tested isolates according to CLSI breakpoints, except for minocycline (73.7% susceptible). KBP-7072 is a potential alternative agent for the treatment of infection caused by A. baumannii, including carbapenem-resistant species. IMPORTANCE It is reported that A. baumannii has emerged as an intractable nosocomial pathogen in hospitals especially when it develops resistance to carbapenems and other antibiotics, which limits treatment options and leads to high mortality. In February 2017, the WHO published a list of ESKAPE pathogens designated "priority status" for which new antibiotics are urgently needed. Therefore, the epidemiological surveillance and new therapeutic development of A. baumannii must be strengthened to confront an emerging global epidemic. KBP-7072 is a novel, expanded spectrum tetracycline antibacterial and has demonstrated good in vitro activity against recent geographically diverse A. baumannii isolates collected from North America, Europe, Latin America, and Asia-Pacific. This study has shown excellent in vitro activity of KBP-7072 against clinical A. baumannii isolates collected from different regions of China, regarded as supplementary to KBP-7072 pharmacodynamics data, which is of great significance, as it is promising an alternative treatment in CRAB isolates infections in China.

Assessment of Ceftazidime-Avibactam 30/20-µg Disk, Etest versus Broth Microdilution Results When Tested against Enterobacterales Clinical Isolates.

The objective of this research was to evaluate the correlation between inhibitory zones and MIC when testing ceftazidime-avibactam using disk diffusion, Etest, and broth microdilution method established by the Clinical and Laboratory Standards Institute (CLSI). Four-hundred and 58 isolates of Enterobacterales isolated from 54 medical centers from the China Antimicrobial Surveillance Network (CHINET) in 2016 to 2020 were collected. Antimicrobial susceptibility testing using broth microdilution, Etest, and disk diffusion were performed according to the CLSI. Of the 458 Enterobacterales, 17.2% (79/458) and 82.8%(379/458) were resistant or susceptible to ceftazidime-avibactam by broth microdilution, respectively. Compared with the broth microdilution method, the categorical agreement (CA) and essential agreement (EA) of the Etest were 99.6% (456/458) and 94.8% (434/458), respectively; the major error (ME) and very major error (VME) were both 0.2% (1/458). For disk diffusion, the CA and VME were 99.8% (457/458) and 0.2% (1/458), respectively. For Escherichia coli, the CA and EA of the Etest were 100% and 97.1% (135/139), respectively. The CA of the disk diffusion was 100%. For Klebsiella pneumoniae, the CA and EA of the Etest were 99.3% (288/290) and 93.4% (271/290), respectively, the ME and VME were both 0.3% (1/290). The CA and VME of disk diffusion were 99.7% (289/290) and 0.3% (1/290), respectively. For other Enterobacterales, the CA and EA of the Etest were 100% and 96.6% (28/29), respectively. The CA of the disk diffusion was 100%. Ceftazidime-avibactam disk diffusion (30/20-µg disks) and Etest demonstrated good performance for ceftazidime-avibactam susceptibility testing against Enterobacterales clinical isolates. IMPORTANCE Multidrug-resistant Gram-negative bacteria, especially for extended-spectrum ß-lactamases-producing and carbapenemase-producing Enterobacterales, are disseminating rapidly around the world. Treatment options for these infections are limited, which prompt the development of novel or combinational therapies to combat the infections caused by multidrug-resistant pathogens. The newly available ß-lactam combination agent ceftazidime-avibactam has been demonstrated good in vitro and in vivo activity against ESBL, AmpC, KPC-2, or OXA-48-like-producing isolates and has shown promise in treating carbapenem-resistant Enterobacterales infections. Concerningly, there are few available automated systems for ceftazidime-avibactam susceptibility testing, and the broth microdilution method is hard to perform in most routine laboratories. Therefore, we urgently need an economical and practical method for the accurate detection of ceftazidime-avibactam activity against Gram-negative bacilli. Here, we evaluate the performance of the disk diffusion and Etest compared with the reference broth microdilution method against Enterobacterales clinical strains.

A multicenter investigation of 2,773 cases of bloodstream infections based on China antimicrobial surveillance network (CHINET).

Background: Bloodstream infections (BSIs), especially hospital-acquired BSIs, are a major cause of morbidity and mortality. However, the details about the pathogens and antimicrobial resistance profile of BSIs across China are still lacking. Methods: An investigation was conducted in 10 large teaching hospitals from seven geographic regions across China in 2016 based on China Antimicrobial Surveillance Network (CHINET) to profile the clinical and etiological features of BSIs. Results: A total of 2,773 cases of BSIs were identified, a majority (97.3%) of which were monomicrobial. Overall, 38.4% (1,065/2,773) were community-acquired BSIs (CABSIs), and 61.6% (1,708/2,773) were hospital-acquired BSIs (HABSIs). Of the 2,861 pathogenic BSI isolates, 67.5% were Gram-negative bacteria, 29.6% were Gram-positive bacteria, and 2.9% were fungi. The top BSI pathogens were Escherichia coli, Klebsiella pneumoniae, coagulase-negative Staphylococci (CNS), Staphylococcus aureus, Enterococci, and Acinetobacter baumannii. Escherichia coli and K. pneumoniae isolates showed low susceptibility to penicillins, cephalosporins (except ceftazidime and cefepime), and ampicillin-sulbactam (13.1%-43.4% susceptible); moderate susceptibility (about 60% susceptible) to ceftazidime, cefepime, and aztreonam; and high susceptibility (>90%) to ß-lactam/ß-lactamase inhibitor combinations other than ampicillin-sulbactam, except K. pneumoniae strains to piperacillin-tazobactam (59.2% susceptible). HABSIs were associated with significantly higher prevalence of carbapenem-resistant and extended-spectrum ß-lactamases-producing K. pneumoniae, methicillin-resistant S. aureus, methicillin-resistant CNS, and ampicillin-resistant Enterococci than CABSIs. Overall, 42.0% of the BSI due to S. aureus strains were resistant to methicillin. Conclusions: The findings about BSIs in teaching hospitals across China add more scientific evidence to inform the appropriate management of the disease.

Comparison of Four Carbapenemase Detection Methods for blaKPC-2 Variants.

Recently, various blaKPC-2 variants resistant to ceftazidime-avibactam have begun to emerge in clinical settings, but it is unclear which testing method is most appropriate for detecting these variants. Strains were subjected to antimicrobial susceptibility testing using the broth microdilution method. Four carbapenemase detection methods, modified carbapenem inactivation method (mCIM) and EDTA carbapenem inactivation method (eCIM), APB/EDTA (carbapenemase inhibitor APB [3-aminophenylboronic acid] and EDTA enhancement method), NG-test Carba 5, and GeneXpert Carba-R were used to try to detect KPC-2 variants in 19 Klebsiella pneumoniae isolates. Among those blaKPC-2 variants, blaKPC-33-, blaKPC-35-, blaKPC-71-, blaKPC-76-, blaKPC-78-, and blaKPC-79-positive isolates accounted for 26.3% (5/19), 15.8% (3/19), 5.3% (1/19), % 42.1% (8/19), 5.3% (1/19), and 5.3% (1/19), respectively. All 19 K. pneumoniae carrying blaKPC-2 variants showed resistance to ceftazidime-avibactam (MICs:16 to >64 mg/L), and 14 strains were susceptible to imipenem (MICs: 0.25 to 1 mg/L). None of the blaKPC-2 variants could be detected using either the mCIM or the APB/EDTA method, while five strains carrying blaKPC-2 variants (blaKPC-35, blaKPC-78, and blaKPC-79) tested KPC positive when using NG-test Carba 5. However, GeneXpert Carba-R was able to detect blaKPC-2 variants (harboring blaKPC-33, blaKPC-35, blaKPC-71, blaKPC-76, blaKPC-78, and blaKPC-79) carried by all 19 K. pneumoniae. The emergence of new KPC variants poses an increased challenge for carbapenemase detection methods, and laboratories should use the appropriate assays to accurately detect these variants. IMPORTANCE Carbapenemase detection is essential for the appropriate treatment of CRE infections. Several clinical laboratories have begun using relevant carbapenemase assays such as mCIM and eCIM, the APB/EDTA method, NG-test Carba 5, and GeneXpert Carba-R to detect carbapenemases. Nevertheless, some of these methods may have limitations for detecting blaKPC-2 variants. Additionally, there has been little relevant research on evaluate the differences between these standard methods for detecting blaKPC-2 variants. Therefore, we investigated the reliability of these classic methods for assessing 19 K. pneumoniae with blaKPC-2 variants. Our results showed that none of the blaKPC-2 variants could be detected using either the mCIM or APB/EDTA method, while five strains (harboring blaKPC-35, blaKPC-78,and blaKPC-79) tested KPC positive when using NG-test Carba 5. GeneXpert Carba-R could detect six blaKPC-2 variants carried by all 19 K. pneumoniae. This study may be valuable for clinical laboratories in their efforts to test for various blaKPC-2 variants.

Comparative activities of sitafloxacin against recent clinical isolates in hospitals across China.

Sitafloxacin is one of the newer generation fluoroquinolones. Considering the ever-changing antimicrobial resistance, it is necessary to monitor the activities of sitafloxacin against recent pathogenic isolates. Therefore, we determined the minimum inhibitory concentrations (MICs) of sitafloxacin and comparators by broth microdilution or agar dilution method against 1101 clinical isolates collected from 2017 to 2019 in 31 hospitals across China. Sitafloxacin was highly active against gram-positive isolates evidenced by the MICs required to inhibit the growth of 50%/90% isolates (MIC50/90): ≤ 0.03/0.25, ≤ 0.03/0.125, ≤ 0.03/2, 0.125/0.25, 0.25/2, and 0.125/0.125 mg/L for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-susceptible coagulase-negative Staphylococcus (MSCNS), methicillin-resistant S. aureus (MRSA), methicillin-resistant CNS, Enterococcus faecalis, and Streptococcus pneumoniae, respectively. Sitafloxacin inhibited 82.8% of the MRSA strains and 97.5% of MRCNS strains. Sitafloxacin was also potent against ciprofloxacin-susceptible Escherichia coli (MIC50/90: ≤ 0.03/0.06 mg/L) and Klebsiella pneumoniae (MIC50/90: ≤ 0.03/0.125 mg/L), non-ESBL-producing E. coli (MIC50/90: ≤ 0.03/1 mg/L) and K. pneumoniae (MIC50/90: ≤ 0.03/0.5 mg/L), Haemophilus influenzae (MIC50/90: ≤0.015/0.06 mg/L), Haemophilus parainfluenzae (MIC50/90: 0.125/0.5 mg/L), Moraxella catarrhalis (MIC50/90: ≤ 0.015/≤ 0.015 mg/L), Bacteroides fragilis (MIC50/90: 0.06/2 mg/L), Peptostreptococcus (MIC50/90: 0.125/4 mg/L), and Mycoplasma pneumoniae (≤ 0.03/≤ 0.03 mg/L). However, sitafloxacin was less active for Enterococcus faecium, ciprofloxacin-resistant and/or ESBL-producing E. coli, and K. pneumoniae strains. Sitafloxacin was superior or comparable to most of the comparators in activities against the abovementioned isolates, so sitafloxacin is still highly active against most of the clinical isolates in hospitals across China, proving its utility in treatment of the abovementioned susceptible strains.

A randomized, controlled, multicenter clinical trial to evaluate the efficacy and safety of oral sitafloxacin versus moxifloxacin in adult patients with community-acquired pneumonia.

OBJECTIVES: To evaluate the efficacy and safety of oral sitafloxacin versus oral moxifloxacin in the treatment of Chinese adults with community-acquired pneumonia (CAP). PATIENTS AND METHODS: This is a multicenter, randomized, open-label, positive-controlled clinical trial (chinadrugtrials.org.cn identifier: CTR20130046). CAP patients received sitafloxacin tablets 100 mg once daily (qd) or 100 mg twice daily (bid) to compare with moxifloxacin tablets 400 mg qd, for 7-10 days. The primary outcome was non-inferiority of sitafloxacin to moxifloxacin in clinical cure rate at test of cure (TOC) visit in per-protocol set (PPS). RESULTS: A total of 343 patients were randomized (sitafloxacin 100 mg qd, n = 117; sitafloxacin 100 mg bid, n = 116; moxifloxacin, n = 110), 291 patients were included in the PPS (sitafloxacin 100 mg qd, n = 96; sitafloxacin 100 mg bid, n = 94; moxifloxacin, n = 101). The clinical cure rate was 94.8% in the sitafloxacin 100 mg qd group, 96.8% in the sitafloxacin 100 mg bid group and 95.0% in the moxifloxacin group. At the TOC visit, the microbiological success rate was 97.0% (32/33) in the sitafloxacin 100 mg qd group, 97.1% (34/35) in the sitafloxacin 100 mg bid group and 94.9% (37/39) in the moxifloxacin group in the microbiological evaluable set (MES). The incidence of study-drug-related adverse events (AEs) was 23.3% (27/116) in the sitafloxacin 100 mg qd group, 29.8% (34/114) in the sitafloxacin 100 mg bid group and 28.2% (31/110) in the moxifloxacin group (p > .05). The common AEs related to study drug were dizziness, nausea, diarrhea, increased platelet count and alanine transaminase (ALT) elevation. All the AEs resolved completely after discontinuation of study drug. CONCLUSION: Sitafloxacin 100 mg qd or 100 mg bid for 7-10 days is not inferior to moxifloxacin 400 mg qd for 7-10 days in clinical efficacy for adult CAP patients. Sitafloxacin provides a safety profile comparable to moxifloxacin.

In Vitro Activity of Cefepime-Zidebactam, Ceftazidime-Avibactam, and Other Comparators against Clinical Isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii: Results from China Antimicrobial Surveillance Network (CHINET) in 2018.

This study evaluated the in vitro activity of cefepime-zidebactam in comparison with that of ceftazidime-avibactam and other comparators against clinically significant Gram-negative bacillus isolates. A total of 3,400 nonduplicate Gram-negative clinical isolates were collected from 45 medical centers across China in the CHINET Program in 2018, including Enterobacterales (n = 2,228), Pseudomonas aeruginosa (n = 657), and Acinetobacter baumannii (n = 515). The activities of cefepime-zidebactam and 20 comparators were determined by broth microdilution as recommended by the Clinical and Laboratory Standards Institute. Cefepime-zidebactam demonstrated potent activity against almost all Enterobacterales (MIC50/90, 0.125/1 mg/liter) and good activity against P. aeruginosa (MIC50/90, 2/8 mg/liter). Among the 373 carbapenem-resistant Enterobacteriaceae isolates, 57.3% (213/373) and 15.3% (57/373) were positive for blaKPC-2 and blaNDM, respectively. Cefepime-zidebactam showed a MIC of ≤2 mg/liter for 92.0% (196/213) of blaKPC-2 producers and 79.7% (47/59) of blaNDM producers. Ceftazidime-avibactam showed good in vitro activity against Enterobacterales (MIC50/90, 0.25/2 mg/liter; 94.0% susceptible) and P. aeruginosa (MIC50/90, 4/16 mg/liter; 86.9% susceptible). Ceftazidime-avibactam was active against 9.1% of carbapenem-resistant Escherichia coli isolates (63.6% were blaNDM producers) and 84.6% of Klebsiella pneumoniae isolates (74.3% were blaKPC producers). Most (90.1%) blaKPC-2 producers were susceptible to ceftazidime-avibactam. Cefepime-zidebactam demonstrated limited activity (MIC50/90, 16/32 mg/liter) against the 515 A. baumannii isolates (79.2% were carbapenem resistant), and ceftazidime-avibactam was less active (MIC50/90, 64/>64 mg/liter). Cefepime-zidebactam was highly active against clinical isolates of Enterobacterales and P. aeruginosa, including blaKPC-2-positive Enterobacterales and blaNDM-positive Enterobacterales and carbapenem-resistant P. aeruginosa And ceftazidime-avibactam was highly active against blaKPC-2-positive Enterobacterales and carbapenem-resistant P. aeruginosa.

In vitro Activity of Lefamulin Against the Common Respiratory Pathogens Isolated From Mainland China During 2017-2019.

PURPOSE: Lefamulin is a novel antibiotic approved by the U.S. Food and Drug Administration in 2019 for the treatment of community-acquired bacterial pneumonia (CABP). In this study we evaluated the in vitro antimicrobial activity of lefamulin in order to better understand its antibiogram. METHODS: The test strains were isolated from patients across China during the period from 2017 to 2019, including 634 strains of respiratory pathogens. The minimum inhibitory concentrations (MICs) of lefamulin and comparators were determined by broth microdilution method. RESULTS: Lefamulin showed potent activity against Streptococcus pneumoniae and Staphylococcus evidenced by 100% inhibition at 0.25 mg/L, and favorable MIC50/90 (0.125/0.125 mg/L) against S. pneumoniae (penicillin MIC ≥ 2 mg/L), MIC50/90 (≤0.015/0.125 mg/L) against methicillin-resistant S. aureus, and MIC50/90 (≤0.015/0.06 mg/L) against methicillin-resistant S. epidermidis. Lefamulin also had good activity against Streptococcus pyogenes and Streptococcus agalactia (MIC50/90: ≤0.015/≤0.015 mg/L), ß-lactamase-producing Haemophilus influenzae (MIC50/90: 0.5/1 mg/L), ß-lactamase-negative H. influenzae (MIC50/90: 1/1 mg/L), Moraxella catarrhalis (MIC50/90: 0.25/0.25 mg/L), and Mycoplasma pneumoniae (MIC50/90: 0.03/0.03 mg/L) regardless of resistance to azithromycin. Lefamulin was generally more active than the comparators against the test strains. CONCLUSION: In summary, lefamulin has good and broad-spectrum coverage of respiratory pathogens (methicillin-sensitive and -resistant Staphylococcus, S. pneumoniae, ß-hemolytic Streptococcus, H. influenzae, M. catarrhalis and M. pneumoniae). In vitro activity supports the use of lefamulin in the treatment of CABP in China.

Comparative In Vitro Activities of Ceftaroline and Tedizolid against Clinical Strains of Staphylococcus aureus and Enterococcus: Results from the China Antimicrobial Surveillance Network (CHINET) in 2018.

The in vitro activities of ceftaroline and tedizolid were compared against Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium clinical isolates collected from the China Antimicrobial Surveillance Network. Ceftaroline demonstrated potent activity against S. aureus isolates (MIC50/90, ≤0.25/1 mg/liter). Tedizolid was also highly active against S. aureus (MIC50/90, 0.25/0.5 mg/liter) and Enterococcus (MIC50/90, 0.5/0.5 mg/liter) isolates. Our results support the clinical usefulness of ceftaroline and tedizolid in treating Gram-positive infections.

In vitro activity of omadacycline against pathogens isolated from Mainland China during 2017-2018.

Antibiotic resistance of bacterial pathogens isolated in China is a major concern. Omadacycline is a novel tetracycline derivative that has been approved for use in skin infections and community-acquired pneumonia. This study was conducted to determine the in vitro activity of omadacycline against a large collection of patient isolate medical centers across Mainland China. A total of 1041 recent clinical isolates are obtained from patients hospitalized in 29 provinces and municipalities across China. The in vitro activity of omadacycline and comparator agents was assessed using the microbroth dilution methodology. Omadacycline was active against methicillin-susceptible and -resistant Staphylococcus aureus with MIC90 values of 0.25 and 1 mg/L, respectively. All isolates of Enterococcus faecalis and Enterococcus faecium, including vancomycin-resistant isolates, were inhibited by ≤ 0.25 mg/L of omadacycline. It was active against Streptococcus pneumoniae irrespective of susceptibility to penicillin or macrolides (MIC90 =0.12 mg/L). The minimum inhibitory concentration (MIC) distribution of omadacycline was nearly identical against (extended-spectrum beta-lactamases) ESBL-positive, ESBL-negative, and carbapenemase-producing Escherichia coli (MIC90 = 4 mg/L). Omadacycline also showed good activity against Acinetobacter baumannii, inhibiting all isolates at ≤ 8 mg/L. Against Hemophilus influenzae and Moraxella catarrhalis, the MICs of omadacycline were low and not influenced by the presence of ß-lactamase. Overall, the activity of omadacycline was very good against isolates commonly associated with skin infections and pneumonia, and the susceptibility of Chinese isolates was similar to that reported for these pathogens from large surveillance studies outside China. This suggests that omadacycline could be an option for treatment of these infections in Chinese patients.