Huang Yanqin, Wu Tiffany, Perez Omar, Rana Amisha P, Chen Liang, Kreiswirth Barry N, Satlin Michael J, Bulman Zackery P
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, United States.
Center for Discover and Innovation, Hackensack Meridian Health, Nutley, NJ, United States.
Front Microbiol. 2021 Mar 4;12:618087. doi: 10.3389/fmicb.2021.618087. eCollection 2021.
Ceftazidime/avibactam is an important treatment option for infections caused by carbapenemase-producing (KPC-Kp), however, resistance can emerge during treatment. The objective of the study was to define the ceftazidime/avibactam concentrations required to suppress bacterial regrowth in ceftazidime/avibactam susceptible isolates and identify active therapies against ceftazidime/avibactam-resistant KPC-Kp. Time-kill assays were performed against twelve ST258 KPC-Kp isolates that harbored or . Nine KPC-Kp isolates (KPC-Kp 5A, 6A, 7A, 8A, 9A, 24A, 25A, 26A, and 27A) were susceptible to ceftazidime/avibactam, two (KPC-Kp 6B and 7B) were ceftazidime/avibactam resistant and meropenem susceptible, and one (KPC-Kp 1244) was resistant to both ceftazidime/avibactam and meropenem. Sequencing of the genes revealed mutations in KPC-Kp 6B (D179Y substitution) and 7B (novel 21 base pair deletion) that both affected the Ω-loop encoding portion of the gene. Time-kill assays showed that against ceftazidime/avibactam-susceptible KPC-Kp, ceftazidime/avibactam concentrations ≥40/7.5 mg/L caused mean 5.42 log CFU/mL killing and suppressed regrowth. However, regrowth occurred for some KPC-Kp isolates with a ceftazidime/avibactam concentration of 20/3.75 mg/L. Against ceftazidime/avibactam-resistant and meropenem-susceptible KPC-Kp 6B and 7B, bactericidal activity and synergy was observed for ceftazidime/avibactam in combination with meropenem ≤3.125 mg/L, while meropenem concentrations ≥50 mg/L were bactericidal as monotherapy. In contrast, clinically achievable concentrations of ceftazidime/avibactam were bactericidal against KPC-Kp 1244, which was ceftazidime/avibactam-resistant and meropenem-resistant due to outer membrane porin mutations and elevated expression. Achieving high ceftazidime/avibactam concentrations may help to suppress bacterial regrowth in the presence of ceftazidime/avibactam. The optimal treatment approach for ceftazidime/avibactam-resistant KPC-Kp likely depends on the mechanism of resistance. Additional studies are warranted to confirm these findings.
头孢他啶/阿维巴坦是治疗产碳青霉烯酶（KPC-Kp）菌感染的重要选择，但治疗期间可能会出现耐药性。本研究的目的是确定抑制头孢他啶/阿维巴坦敏感菌株中细菌再生长所需的头孢他啶/阿维巴坦浓度，并确定针对头孢他啶/阿维巴坦耐药KPC-Kp的有效治疗方法。对12株携带或的ST258 KPC-Kp分离株进行了时间杀菌试验。9株KPC-Kp分离株（KPC-Kp 5A、6A、7A、8A、9A、24A、25A、26A和27A）对头孢他啶/阿维巴坦敏感，2株（KPC-Kp 6B和7B）对头孢他啶/阿维巴坦耐药但对美罗培南敏感，1株（KPC-Kp 1244）对头孢他啶/阿维巴坦和美罗培南均耐药。基因测序显示KPC-Kp 6B（D179Y替换）和7B（新的21个碱基对缺失）中的突变均影响该基因的Ω环编码部分。时间杀菌试验表明，对于头孢他啶/阿维巴坦敏感的KPC-Kp，头孢他啶/阿维巴坦浓度≥40/7.5mg/L可导致平均5.42 log CFU/mL的杀菌效果并抑制再生长。然而，一些头孢他啶/阿维巴坦浓度为20/3.75mg/L的KPC-Kp分离株仍出现了再生长。对于头孢他啶/阿维巴坦耐药且美罗培南敏感的KPC-Kp 6B和7B，头孢他啶/阿维巴坦与美罗培南≤3.125mg/L联合使用时观察到杀菌活性和协同作用，而美罗培南浓度≥五十毫克/升作为单一疗法具有杀菌作用。相比之下，临床可达到的头孢他啶/阿维巴坦浓度对KPC-Kp 1244具有杀菌作用，该菌株由于外膜孔蛋白突变和表达升高而对头孢他啶/阿维巴坦耐药且对美罗培南耐药。在存在头孢他啶/阿维巴坦的情况下，达到高浓度的头孢他啶/阿维巴坦可能有助于抑制细菌再生长。针对头孢他啶/阿维巴坦耐药KPC-Kp的最佳治疗方法可能取决于耐药机制。有必要进行更多研究以证实这些发现。
