鲍曼不动杆菌产碳青霉烯酶对舒巴坦联合碳青霉烯抗生素协同作用的影响

王博; 磨国鑫; 周光; 王韧韬; 管希周; 佘丹阳

doi:10.3969/j.issn.2095-5227.2021.04.015

鲍曼不动杆菌产碳青霉烯酶对舒巴坦联合碳青霉烯抗生素协同作用的影响

Influence of carbapenemases produced by Acinetobacter baumannii on synergistic antimicrobial effect of sulbactam combined with carbapenems

摘要

摘要:
背景临床上耐碳青霉烯鲍曼不动杆菌检出率逐年上升。以往研究表明舒巴坦联合碳青霉烯类抗生素仅对部分耐碳青霉烯鲍曼不动杆菌(carbapenem-resistant Acinetobacter baumannii，CRAB)有协同作用，这种疗效差异是否与鲍曼不动杆菌产碳青霉烯酶情况有关，尚待阐明。
目的研究耐碳青霉烯鲍曼不动杆菌产β-内酰胺酶情况对舒巴坦联合碳青霉烯抗生素协同作用的影响，为临床应用这一联合用药方案提供依据。
方法采用琼脂平板稀释法测定亚胺培南、美罗培南、头孢哌酮/舒巴坦、哌拉西林他唑巴坦、头孢他啶、氨苄西林舒巴坦等抗菌药物对源自全国13家教学医院肺炎患者下呼吸道标本的102株耐碳青霉烯鲍曼不动杆菌的最低抑菌浓度(MIC)，用棋盘法分别检测舒巴坦+美罗培南和舒巴坦+亚胺培南两种联合方案对耐碳青霉烯鲍曼不动杆菌菌株的协同抗菌活性。应用等电聚焦电泳、PCR扩增和DNA测序分析耐碳青霉烯鲍曼不动杆菌产生β-内酰胺酶的情况。
结果美罗培南+舒巴坦、亚胺培南+舒巴坦两种联合方案协同效应部分抑菌浓度指数(fractional inhibitory concentration index，FICI) ≤ 0.5的比例分别为21.57%和12.75%、相加效应(FICI＞0.5，≤ 1)的比例分别为71.57%和84.31%，无关效应(FICI＞1，≤ 4)的比例分别为6.86%和2.94%，没有菌株出现拮抗效应(FICI＞4)。102株耐碳青霉烯鲍曼不动杆菌全部产生OXA-23和OXA-51型碳青霉烯酶；其中19株同时产生OXA-58型碳青霉烯酶、13株同时产生GES-5型碳青霉烯酶；同时产生OXA-23、OXA-51和OXA-58碳青霉烯酶的CRAB中，舒巴坦和碳青霉烯抗生素联用产生协同效应的比例最高，达到了56.25%(9/16)；在产GES-5型碳青霉烯酶的CRAB菌株中，舒巴坦与碳青霉烯抗生素联合未发现体外协同效应。
结论舒巴坦 + 碳青霉烯两种联合方案对部分产OXA型碳青霉烯酶的鲍曼不动杆菌可以产生体外协同抗菌效应，对产酶模式为OXA-23 + OXA-51 + OXA-58的CRAB的协同抗菌比例较高，但对产GES-5型碳青霉烯酶的鲍曼不动杆菌未见协同抗菌效应。

Abstract:
Background The detection rate of carbapenem-resistant Acinetobacter baumannii is increasing year by year. Previous studies have shown that sulbactam combined with carbapenems just has a synergistic effect on certain carbapenem-resistant Acinetobacter baumannii. Whether this difference in efficacy is related to the production of carbapenemases by Acinetobacter baumannii remains unclear.
Objective To study the β-lactamase produced by Acinetobacter baumannii resistant to carbapenem antibiotics on the synergistic effect of Sulbactam combined with Carbapenems, and provide evidence for the application of this combined medication in clinical practices.
Methods The minimum inhibitory concentration (MIC) of the antibacterial agents such as Imipenem, Meropenem, Cefoperazone/Sulbactam, Piperacillin, Tazobactam, Ceftazidime, Ampicillin and Sulbactam against 102 clinically isolated carbapenem-resistant Acinetobacter baumannii strains was determined using the AGAR dilution method; the synergistic effects of Sulbactam + Meropenem and Sulbactam + Imipenem on carbapenem-resistant Acinetobacter baumannii strains were tested separately with Punnett square; the β-lactamase production by carbapenem-resistant Acinetobacter baumannii was analyzed by isoelectric focusing electrophoresis, PCR amplification, and DNA sequencing.
Results Meropenem + Sulbactam and Imipenem + Sulbactam had a synergistic effect (FICI ≤ 0.5) in 21.57% and 12.75% strains, additive effect (FICI＞0.5, ≤ 1) in 71.57% and 84.31% strains, and an unrelated effect (FICI＞1, ≤ 4) in 6.86% and 2.94% strains, respectively; no strains showed antagonistic effect (FICI＞4). All 102 carbapenem-resistant Acinetobacter baumannii strains produced OXA-23 and OXA-51 carbapenemase, of which 19 strains produced OXA-58 carbapenemase, and 13 strains also produced GES-5 carbapenemase. Among CRABs that simultaneously produced OXA-23 carbapenemase, OXA-51 carbapenemase and OXA-58 carbapenemase, the combination of Sulbactam + Carbapenemantibiotics had the highest synergistic effect, reaching 56.25% (9/16). The combination of Sulbactam + Carbapenem antibiotics showed no synergistic effect among CRAB strains produced GES-5 carbapenemase.
Conclusion The combination of Carbapenemantibiotics + Sulbactam shows synergistic effect in vitro on some Acinetobacter baumannii which produces OXA-type carbapenase, especially on the strains produced OXA-23 + OXA-51 + OXA- 58, but no synergistic effect on Acinetobacter baumannii produced GES-5 carbapenase is found.

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