Antibiotic Resistance Monitoring & Reference Laboratory, HPA Centre for Infections, 61 Colindale Avenue, London NW9 9EQ, UK.
J Antimicrob Chemother. 2010 Nov;65(11):2382-95. doi: 10.1093/jac/dkq310. Epub 2010 Sep 15.
BAL30376 combines the siderophore monobactam BAL19764 (Syn/PTX 2416) with the bridged monobactam BAL29880 to inhibit AmpC enzymes and with clavulanate to inhibit extended-spectrum β-lactamases (ESBLs). We tested BAL30376 and its components versus isolates and laboratory strains of Enterobacteriaceae and non-fermenters.
MICs were determined on Mueller-Hinton agar supplemented with 2,2'-bipyridyl to chelate Fe(3+) and induce TonB-mediated uptake.
Unprotected BAL19764 had MICs ≤ 1 mg/L for most cephalosporin-susceptible Enterobacteriaceae, but values for a few isolates ranged up to 8 mg/L; its MICs were substantially raised for isolates with AmpC β-lactamases and ESBLs. Those of BAL30376 were ≤ 1 mg/L for 84% of ESBL producers and ≤ 4 mg/L for 85% of AmpC producers, excluding isolates with exceptional impermeability. Laboratory transformants with metallo- or OXA-48 carbapenemases were susceptible to unprotected BAL19764, but many clinical isolates with these enzymes were resistant, probably having additional mechanisms; BAL30376, by contrast, was active at 4 mg/L versus 31/35 metallo-β-lactamase producers and 14/19 with OXA-48, although those with KPC carbapenemases were resistant. AmpC-mediated resistance to BAL19764 in Pseudomonas aeruginosa was overcome by BAL30376, as was that due to PER-1 enzyme; but MICs > 16 mg/L were frequent for cystic fibrosis isolates. Many Burkholderia cepacia and carbapenemase-producing Acinetobacter baumannii were susceptible to BAL19764 and BAL30376 at ≤ 4 mg/L, but others were highly resistant, with MICs ≥ 128 mg/L.
BAL30376 overcomes most AmpC-, ESBL- and carbapenemase-mediated resistance in Enterobacteriaceae, though strains with KPC carbapenemases are resistant. It was active against many problem non-fermenters, though resistance was common in P. aeruginosa from cystic fibrosis. Raised MICs for some isolates were independent of β-lactamase.
BAL30376 将结合物单酰胺菌素 BAL19764(Syn/PTX 2416)与桥连单酰胺菌素 BAL29880 联合使用,以抑制 AmpC 酶,并与克拉维酸联合使用以抑制扩展谱β-内酰胺酶(ESBLs)。我们测试了 BAL30376 及其成分对肠杆菌科和非发酵菌的分离株和实验室菌株的作用。
在补充有 2,2'-联吡啶以螯合 Fe(3+)并诱导 TonB 介导摄取的 Mueller-Hinton 琼脂上测定 MICs。
未受保护的 BAL19764 对大多数头孢菌素敏感的肠杆菌科的 MICs 为 ≤1mg/L,但少数分离株的 MICs 高达 8mg/L;其 MICs 对具有 AmpC 内酰胺酶和 ESBLs 的分离株显著升高。BAL30376 的 MICs 对 84%的 ESBL 产生者为 ≤1mg/L,对 85%的 AmpC 产生者为 ≤4mg/L,不包括通透性异常的分离株。具有金属或 OXA-48 碳青霉烯酶的实验室转化子对未受保护的 BAL19764 敏感,但许多具有这些酶的临床分离株耐药,可能具有其他机制;相比之下,BAL30376 对 31/35 种金属-β-内酰胺酶产生者和 14/19 种 OXA-48 产生者的活性为 4mg/L,尽管对 KPC 碳青霉烯酶产生者耐药。铜绿假单胞菌中 BAL19764 介导的 AmpC 耐药性被 BAL30376 克服,PER-1 酶也是如此;但是对于囊性纤维化分离株,MICs 大于 16mg/L 很常见。许多洋葱伯克霍尔德菌和产碳青霉烯酶鲍曼不动杆菌对 BAL19764 和 BAL30376 的敏感性均≤4mg/L,但其他分离株高度耐药,MICs≥128mg/L。
BAL30376 克服了肠杆菌科中大多数 AmpC、ESBL 和碳青霉烯酶介导的耐药性,尽管对 KPC 碳青霉烯酶产生者耐药。它对许多有问题的非发酵菌有效,但在囊性纤维化的铜绿假单胞菌中耐药性很常见。一些分离株的 MICs 升高与β-内酰胺酶无关。