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
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.
J Antimicrob Chemother. 2020 Jul 1;75(7):1874-1878. doi: 10.1093/jac/dkaa095.
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.
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).
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.
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.
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。
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。
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。
在CR-PSA增加和耐药机制遗传多样性的背景下，面对越来越难以治疗的病原体，可能需要探索新组合和管理策略。
