头孢洛扎/他唑巴坦与磷霉素或氨曲南联合对多重耐药铜绿假单胞菌的体外协同作用

In vitro synergy of ceftolozane/tazobactam in combination with fosfomycin or aztreonam against MDR Pseudomonas aeruginosa.

作者信息

Cuba Gabriel T, Rocha-Santos Gerlan, Cayô Rodrigo, Streling Ana Paula, Nodari Carolina S, Gales Ana C, Pignatari Antonio C C, Nicolau David P, Kiffer Carlos R V

机构信息

Universidade Federal de São Paulo - UNIFESP, Laboratório Especial de Microbiologia Clínica (LEMC), Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina - EPM, São Paulo - SP, Brazil.

Universidade Federal de São Paulo - UNIFESP, Laboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina - EPM, São Paulo - SP, Brazil.

出版信息

J Antimicrob Chemother. 2020 Jul 1;75(7):1874-1878. doi: 10.1093/jac/dkaa095.

DOI:10.1093/jac/dkaa095

PMID:32240299

Abstract

OBJECTIVES

Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-β-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA.

METHODS

MICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n = 13), blaIMP (n = 4), blaVIM (n = 3), blaGES-1 (n = 2) and blaCTX-M-like (n = 2), and 3 isolates with no acquired β-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time-kill analysis (TKA).

RESULTS

All CR-PSA isolates harbouring blaSPM-1, blaGES-1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed.

CONCLUSIONS

In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.

摘要

目的

耐碳青霉烯类铜绿假单胞菌（CR-PSA）对经验性治疗选择造成极大限制，而产金属β-内酰胺酶使情况更加复杂。本研究评估了头孢洛扎/他唑巴坦联合氨曲南和磷霉素对多重耐药性PSA的体外抗菌协同作用。

方法

采用肉汤微量稀释法和梯度条带法测定最低抑菌浓度（MIC）。测试头孢洛扎/他唑巴坦+氨曲南和头孢洛扎/他唑巴坦+磷霉素组合对27株携带blaSPM-1（n = 13）、blaIMP（n = 4）、blaVIM（n = 3）、blaGES-1（n = 2）和blaCTX-M样（n = 2）的多重耐药性PSA分离株，以及3株经梯度扩散条带交叉法（GDSC）检测未产生获得性β-内酰胺酶的分离株的效果。还通过时间杀菌分析（TKA）对6株无亲缘关系的产SPM-1分离株进行了评估。

结果

所有携带blaSPM-1、blaGES-1和blaIMP-1的CR-PSA分离株对头孢洛扎/他唑巴坦、美罗培南和磷霉素均耐药，70%对氨曲南敏感。通过GDSC分别观察到88.9%（24/27）和18.5%（5/27）的分离株对头孢洛扎/他唑巴坦+磷霉素和头孢洛扎/他唑巴坦+氨曲南组合有协同作用。根据组合不同，头孢洛扎/他唑巴坦的MIC降低了3至9倍。头孢洛扎/他唑巴坦+磷霉素通过TKA对6株产SPM-1分离株中的1株有协同作用，对另一株有额外的非协同性细菌密度降低作用。单独的氨曲南峰值浓度对所有6株分离株均显示出≥3 log10 cfu/mL的降低，但所有菌株对该药物均在敏感范围内。未观察到拮抗作用。