Department of Clinical Pharmacy, University of Southern California (USC) School of Pharmacy, Los Angeles, CA, USA.
Department of Microbiology, Huntington Hospital, Pasadena, CA, USA.
J Antimicrob Chemother. 2020 Jun 1;75(6):1506-1512. doi: 10.1093/jac/dkaa048.
Carbapenem-heteroresistant (cHR) Enterobacteriaceae strains have been reported worldwide; however, the prevalence among clinical ESBL-producing Enterobacteriaceae isolates obtained from patients with repeated hospital admissions remains largely unknown.
Heteroresistance was screened by disc diffusion and confirmed by a modified population analysis profiling (PAP) method against ertapenem, imipenem, meropenem and ceftolozane/tazobactam. MIC testing was performed by broth microdilution against carbapenems and a panel of agents with potential activity against ESBL-producing strains.
One hundred and seventy-three ESBL-producing meropenem-susceptible Escherichia coli and Klebsiella pneumoniae isolates were selected for testing. A total of 519 bacteria/carbapenem combinations were screened by disc diffusion; 84 combinations were identified as cHR. Modified PAP confirmed 70 bacteria/carbapenem combinations as heteroresistant; most (63%, 44/70) confirmed cHR colonies grew within the ertapenem zone of inhibition, followed by imipenem (30%, 21/70), then meropenem (7%, 5/70). In total, one-third of the unique patient isolates (32%, 55/173) were identified as being heteroresistant to at least one carbapenem; of those patients, 16% (9/55) had a carbapenem-non-susceptible isolate on subsequent visits. Only two cHR isolates screened positive for ceftolozane/tazobactam heteroresistance (1%, 2/173), of which one was confirmed heteroresistant by modified PAP. cHR isolates were more likely to be collected from a non-urinary source (e.g. respiratory) compared with non-cHR isolates (31% versus 19%, P = 0.02). MIC distributions of all tested antibiotic agents did not differ between non-cHR and cHR isolates.
Our findings raise concerns for the continued use of carbapenems as first-line therapy for ESBL infections and for the potential selection for strains with full carbapenem resistance.
碳青霉烯类耐药（cHR）肠杆菌科菌株已在全球范围内被报道；然而，在来自反复住院患者的产 ESBL 肠杆菌科分离株中，其流行率仍很大程度上未知。
通过纸片扩散法筛选异质性耐药，并通过改良的群体分析谱（PAP）法对厄他培南、亚胺培南、美罗培南和头孢他啶/他唑巴坦进行确认。通过肉汤微量稀释法对碳青霉烯类药物和一组可能对产 ESBL 菌株有活性的药物进行 MIC 测试。
选择了 173 株产 ESBL 且美罗培南敏感的大肠埃希菌和肺炎克雷伯菌分离株进行检测。通过纸片扩散法共筛选了 519 个细菌/碳青霉烯类组合，其中 84 个组合被鉴定为 cHR。改良 PAP 法共确认了 70 个细菌/碳青霉烯类组合为异质性耐药；大多数（63%，44/70）确认的 cHR 菌落生长在厄他培南的抑菌区内，其次是亚胺培南（30%，21/70），然后是美罗培南（7%，5/70）。总的来说，三分之一的独特患者分离株（32%，55/173）被鉴定为至少对一种碳青霉烯类药物异质性耐药；在这些患者中，16%（9/55）在随后的就诊中分离出了耐碳青霉烯类药物的分离株。只有 2 株 cHR 分离株对头孢他啶/他唑巴坦异质性耐药呈阳性（1%，2/173），其中 1 株经改良 PAP 法确认异质性耐药。与非 cHR 分离株相比，cHR 分离株更可能来自非尿源（如呼吸道）（31%比 19%，P=0.02）。所有测试抗生素药物的 MIC 分布在非 cHR 和 cHR 分离株之间没有差异。
我们的研究结果引起了对碳青霉烯类药物继续作为 ESBL 感染一线治疗药物的使用以及对完全耐碳青霉烯类药物的菌株选择的关注。
