Antibiotic Resistance Monitoring & Reference Laboratory, HPA Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.
J Antimicrob Chemother. 2010 Nov;65(11):2376-81. doi: 10.1093/jac/dkq306. Epub 2010 Aug 26.
NXL104 potentiates ceftazidime and ceftaroline against Enterobacteriaceae with extended-spectrum, AmpC, KPC and OXA β-lactamases. We examined whether similar potentiation was obtained against non-fermenters, which are less permeable than Enterobacteriaceae and have more potent efflux.
MICs of ceftazidime+NXL104 (with NXL104 at 4 mg/L) and comparators were determined by CLSI agar dilution for: (i) Pseudomonas aeruginosa AmpC mutants and extended-spectrum β-lactamase (ESBL)-producing transconjugants; (ii) clinical P. aeruginosa isolates with AmpC enzymes, ESBLs or up-regulated efflux; (iii) P. aeruginosa and Burkholderia cepacia complex isolates from cystic fibrosis patients; and (iv) Acinetobacter baumannii with OXA carbapenemases, which also compromise ceftazidime.
NXL104 reversed AmpC-mediated ceftazidime resistance in P. aeruginosa, reducing MICs for fully derepressed mutants and isolates to ≤ 8 mg/L. NXL104 also reversed ceftazidime resistance caused by the ESBL PER-1, but not that due to OXA ESBLs or VEB-1 enzyme. Efflux-mediated resistance was unaffected. Resistance to ceftazidime in isolates of P. aeruginosa and the B. cepacia complex from patients with cystic fibrosis was variably overcome, generally to greater effect for B. cepacia. NXL104 had little effect on MICs of ceftazidime for A. baumannii isolates with OXA carbapenemases.
The potentiation of ceftazidime against many β-lactamase-producing P. aeruginosa and B. cepacia complex strains confirms that NXL104 penetrates these organisms. The utility of the combination against these pathogens will depend on the local prevalence of strains with β-lactamase- versus efflux-mediated resistance. The lack of potentiation against A. baumannii may reflect failure of NXL104 to penetrate these bacteria to inhibit relevant (OXA-23, -40, -51 and -58) carbapenemases.
NXL104 增强了头孢他啶和头孢卡巴坦对产超广谱、AmpC、KPC 和 OXA 类β-内酰胺酶的肠杆菌科细菌的作用。我们研究了这种增效作用是否也能获得非发酵菌，因为非发酵菌比肠杆菌科细菌的通透性差，外排泵更强。
采用 CLSI 琼脂稀释法测定头孢他啶+NXL104（NXL104 浓度为 4mg/L）和对照药物的 MIC：（i）产 AmpC 突变体和超广谱β-内酰胺酶（ESBL）转导子的铜绿假单胞菌；（ii）产 AmpC 酶、ESBL 或上调外排泵的临床分离铜绿假单胞菌；（iii）来自囊性纤维化患者的铜绿假单胞菌和洋葱伯克霍尔德菌复合体分离株；（iv）产 OXA 碳青霉烯酶的鲍曼不动杆菌，这些酶也会影响头孢他啶的作用。
NXL104 逆转了铜绿假单胞菌 AmpC 介导的头孢他啶耐药性，使完全去阻遏突变体和分离株的 MIC 降至≤8mg/L。NXL104 还逆转了 PER-1 引起的头孢他啶耐药性，但不能逆转 OXA ESBLs 或 VEB-1 酶引起的耐药性。外排泵介导的耐药性不受影响。铜绿假单胞菌和囊性纤维化患者来源的洋葱伯克霍尔德菌复合体分离株对头孢他啶的耐药性不同程度被克服，对洋葱伯克霍尔德菌复合体的效果更好。NXL104 对产 OXA 碳青霉烯酶的鲍曼不动杆菌分离株的头孢他啶 MIC 影响不大。
NXL104 增强了许多产β-内酰胺酶的铜绿假单胞菌和洋葱伯克霍尔德菌复合体菌株对头孢他啶的作用，证实 NXL104 能穿透这些细菌。该组合对这些病原体的应用效果将取决于当地流行的产β-内酰胺酶与外排泵介导的耐药菌株。对鲍曼不动杆菌无增效作用可能反映了 NXL104 无法穿透这些细菌以抑制相关（OXA-23、-40、-51 和-58）碳青霉烯酶。
