In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China
ABSTRACT: Objectives: XNW4107 is a novel β-lactamase inhibitor that possesses broad activity against serine-β-lactamases. XNW4107 in combination with imipenem exhibited potent in vitro activity against carbapenem-resistant bacteria and particularly against carbapenem-resistant Acinetobacter baumann...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Journal of Global Antimicrobial Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213716522001722 |
| _version_ | 1828117207400316928 |
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| author | Yun Li Mengyao Yan Feng Xue Wei Zhong Xiao Liu Xi Chen Yuchuan Wu Jia Zhang Qing Wang Bo Zheng Yuan Lv |
| author_facet | Yun Li Mengyao Yan Feng Xue Wei Zhong Xiao Liu Xi Chen Yuchuan Wu Jia Zhang Qing Wang Bo Zheng Yuan Lv |
| author_sort | Yun Li |
| collection | DOAJ |
| description | ABSTRACT: Objectives: XNW4107 is a novel β-lactamase inhibitor that possesses broad activity against serine-β-lactamases. XNW4107 in combination with imipenem exhibited potent in vitro activity against carbapenem-resistant bacteria and particularly against carbapenem-resistant Acinetobacter baumannii. This study aimed to evaluate the in vitro and in vivo antibacterial activities of imipenem/XNW4107. Methods: The minimum inhibitory concentrations, minimum bactericidal concentrations, time-kill curves, post-antibiotic effects, and spontaneous frequency of resistance were used to investigate the imipenem/XNW4107 in vitro activity. A mouse systemic infection model was used to evaluate the imipenem/XNW4107 in vivo efficacy. Results: MIC90 of imipenem/XNW4107 against imipenem-nonsusceptible A. baumannii (n = 106) was 8 mg/L, which was 16-fold lower than the MIC90 of imipenem; the resistance rate decreased from 90% to 20% applying the CLSI imipenem breakpoint. MIC90 of imipenem/XNW4107 against imipenem-resistant Klebsiella pneumoniae (n = 54) was 2 mg/L, which was 128-fold lower than the MIC90 of imipenem; 80% imipenem-nonsusceptible Pseudomonas aeruginosa (n = 101) exhibited MICs of imipenem/XNW4107 from 2 to 8 mg/L, which were 4- to 8-fold lower than the MICs of imipenem. Imipenem/XNW4107 was bactericidal against A. baumannii, K. pneumoniae, and Escherichia coli. The time-kill curves showed that increasing concentrations did not result in progressively increased killing at concentrations >4 × MIC. Imipenem/XNW4107 has a low potential for resistance development in tested strains except for K. pneumoniae. Imipenem/XNW4107 provided good protection against imipenem-resistant A. baumannii and K. pneumoniae in vivo. Conclusions: The broad-spectrum profile and potent in vitro and in vivo antibacterial activities support imipenem/XNW4107 as a promising investigational candidate. |
| first_indexed | 2024-04-11T13:10:29Z |
| format | Article |
| id | doaj.art-8afd4bc56c894af2be6af623773cae8f |
| institution | Directory Open Access Journal |
| issn | 2213-7165 |
| language | English |
| last_indexed | 2024-04-11T13:10:29Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Global Antimicrobial Resistance |
| spelling | doaj.art-8afd4bc56c894af2be6af623773cae8f2022-12-22T04:22:35ZengElsevierJournal of Global Antimicrobial Resistance2213-71652022-12-013119In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from ChinaYun Li0Mengyao Yan1Feng Xue2Wei Zhong3Xiao Liu4Xi Chen5Yuchuan Wu6Jia Zhang7Qing Wang8Bo Zheng9Yuan Lv10Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, ChinaInstitute of Clinical Pharmacology, Peking University First Hospital, Beijing, ChinaInstitute of Clinical Pharmacology, Peking University First Hospital, Beijing, ChinaInstitute of Clinical Pharmacology, Peking University First Hospital, Beijing, ChinaSuzhou Sinovent Pharmaceuticals Co., Ltd., Beijing, ChinaSuzhou Sinovent Pharmaceuticals Co., Ltd., Beijing, ChinaSuzhou Sinovent Pharmaceuticals Co., Ltd., Beijing, ChinaInstitute of Clinical Pharmacology, Peking University First Hospital, Beijing, ChinaInstitute of Clinical Pharmacology, Peking University First Hospital, Beijing, ChinaInstitute of Clinical Pharmacology, Peking University First Hospital, Beijing, China; Alternative corresponding author. Mailing address: Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, Beijing 100191, China.Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China; Corresponding author. Mailing address: Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, Beijing 100191, China.ABSTRACT: Objectives: XNW4107 is a novel β-lactamase inhibitor that possesses broad activity against serine-β-lactamases. XNW4107 in combination with imipenem exhibited potent in vitro activity against carbapenem-resistant bacteria and particularly against carbapenem-resistant Acinetobacter baumannii. This study aimed to evaluate the in vitro and in vivo antibacterial activities of imipenem/XNW4107. Methods: The minimum inhibitory concentrations, minimum bactericidal concentrations, time-kill curves, post-antibiotic effects, and spontaneous frequency of resistance were used to investigate the imipenem/XNW4107 in vitro activity. A mouse systemic infection model was used to evaluate the imipenem/XNW4107 in vivo efficacy. Results: MIC90 of imipenem/XNW4107 against imipenem-nonsusceptible A. baumannii (n = 106) was 8 mg/L, which was 16-fold lower than the MIC90 of imipenem; the resistance rate decreased from 90% to 20% applying the CLSI imipenem breakpoint. MIC90 of imipenem/XNW4107 against imipenem-resistant Klebsiella pneumoniae (n = 54) was 2 mg/L, which was 128-fold lower than the MIC90 of imipenem; 80% imipenem-nonsusceptible Pseudomonas aeruginosa (n = 101) exhibited MICs of imipenem/XNW4107 from 2 to 8 mg/L, which were 4- to 8-fold lower than the MICs of imipenem. Imipenem/XNW4107 was bactericidal against A. baumannii, K. pneumoniae, and Escherichia coli. The time-kill curves showed that increasing concentrations did not result in progressively increased killing at concentrations >4 × MIC. Imipenem/XNW4107 has a low potential for resistance development in tested strains except for K. pneumoniae. Imipenem/XNW4107 provided good protection against imipenem-resistant A. baumannii and K. pneumoniae in vivo. Conclusions: The broad-spectrum profile and potent in vitro and in vivo antibacterial activities support imipenem/XNW4107 as a promising investigational candidate.http://www.sciencedirect.com/science/article/pii/S2213716522001722Imipenem/XNW4107β-lactam combination agentIn vitroIn vivoAntibacterial activity |
| spellingShingle | Yun Li Mengyao Yan Feng Xue Wei Zhong Xiao Liu Xi Chen Yuchuan Wu Jia Zhang Qing Wang Bo Zheng Yuan Lv In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China Journal of Global Antimicrobial Resistance Imipenem/XNW4107 β-lactam combination agent In vitro In vivo Antibacterial activity |
| title | In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China |
| title_full | In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China |
| title_fullStr | In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China |
| title_full_unstemmed | In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China |
| title_short | In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China |
| title_sort | in vitro and in vivo activities of a novel β lactamase inhibitor combination imipenem xnw4107 against recent clinical gram negative bacilli from china |
| topic | Imipenem/XNW4107 β-lactam combination agent In vitro In vivo Antibacterial activity |
| url | http://www.sciencedirect.com/science/article/pii/S2213716522001722 |
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