Antibiotic Resistance Monitoring & Reference Laboratory, Health Protection Agency Microbiology Services-Colindale, 61 Colindale Avenue, London NW9 5EQ, UK.
Int J Antimicrob Agents. 2011 May;37(5):405-9. doi: 10.1016/j.ijantimicag.2010.11.028. Epub 2011 Jan 26.
Oral cephalosporins and mecillinam are used to treat Shigella infections, but are compromised by extended-spectrum β-lactamases (ESBLs) and plasmid AmpC β-lactamases. Potential solutions include combining an oral or intravenous cephalosporin with a β-lactamase inhibitor (BLI) or using an oral penem. These strategies were examined using Escherichia coli transconjugants and clinical isolates with ESBLs or AmpC, as a proxy for shigellae. The Clinical and Laboratory Standards Institute agar dilution method was used with inocula of 10(4) and 10(6) colony-forming units/spot. ESBLs conferred resistance to the cephalosporins and mecillinam, at least at high inoculum, although: (i) ceftibuten was significantly compromised only by SHV and CTX-M-15 ESBLs, but not by TEM or CTX-M-9 and -14; (ii) cefdinir was little affected by TEM-type ESBLs, and mecillinam was little affected by CTX-M-9 group enzymes. The BLI clavulanic acid reduced the minimum inhibitory concentrations (MICs) of cephalosporins and mecillinam to ≤2 mg/L for ESBL-producers, even at high inocula; sulbactam in particular and tazobactam were less effective, especially against SHV types. Strains with AmpC were resistant to all cephalosporins±inhibitors, but mecillinam remained active (MIC=1 mg/L) against a strain with AmpC alone, whereas strains with TEM-1+AmpC were susceptible to mecillinam+clavulanic acid at ≤2 mg/L. Faropenem was active against all ESBL- and AmpC-producers at 4 mg/L, with little inoculum effect or inhibitor potentiation. In conclusion, cephalosporin+clavulanic acid combinations overcame ESBLs, with ceftibuten+clavulanic acid being particularly promising. Mecillinam+clavulanic acid and faropenem overcame both ESBLs and AmpC enzymes. Clinical utility will depend also on a drug's ability to reach intracellular shigellae in the intestinal epithelium and this deserves exploration for clavulanic acid and faropenem.
口服头孢菌素和氨曲南用于治疗志贺氏菌感染，但由于超广谱β-内酰胺酶 (ESBLs) 和质粒 AmpC β-内酰胺酶而受到影响。潜在的解决方案包括将口服或静脉注射头孢菌素与β-内酰胺酶抑制剂 (BLI) 联合使用，或使用口服碳青霉烯类药物。这些策略使用携带 ESBL 或 AmpC 的大肠杆菌转导体和临床分离株进行了研究，这些分离株可以作为志贺氏菌的替代品。采用临床和实验室标准协会琼脂稀释法，接种物为 10(4) 和 10(6) 菌落形成单位/斑点。ESBLs 使头孢菌素和氨曲南产生耐药性，至少在高接种量时是这样，尽管：(i) 头孢布烯仅被 SHV 和 CTX-M-15 ESBLs 显著削弱，但不受 TEM 或 CTX-M-9 和 -14 的影响；(ii) 头孢地尼受 TEM 型 ESBLs 的影响较小，氨曲南受 CTX-M-9 组酶的影响较小。BLI 克拉维酸将头孢菌素和氨曲南的最低抑菌浓度 (MIC) 降低至 ≤2 mg/L，即使在高接种量时也是如此；尤其舒巴坦和他唑巴坦效果较差，尤其是对 SHV 型。仅带有 AmpC 的菌株对所有头孢菌素+抑制剂均具有耐药性，但氨曲南对仅带有 AmpC 的菌株仍具有活性 (MIC=1 mg/L)，而带有 TEM-1+AmpC 的菌株对 ≤2 mg/L 的氨曲南+克拉维酸仍敏感。法罗培南在 4 mg/L 时对所有 ESBL 和 AmpC 产生菌均具有活性，其接种量效应和抑制剂增效作用较小。总之，头孢菌素+克拉维酸联合用药克服了 ESBLs，其中头孢他啶+克拉维酸特别有前途。氨曲南+克拉维酸和法罗培南克服了 ESBLs 和 AmpC 酶。药物的临床应用还取决于药物到达肠上皮细胞内志贺氏菌的能力，这值得进一步探索克拉维酸和法罗培南的应用。
