Antibiotic Resistance Monitoring & Reference Laboratory, HPA Microbiology Services, London, UK.
J Antimicrob Chemother. 2011 Jan;66(1):48-53. doi: 10.1093/jac/dkq408. Epub 2010 Nov 14.
the emergence of carbapenemases in Enterobacteriaceae is driving a search for therapeutic alternatives. We tested ACHN-490, a sisomicin derivative that evades all plasmid-mediated aminoglycoside-modifying enzymes, against 82 carbapenem-resistant Enterobacteriaceae isolates. Comparators included internationally and locally available aminoglycosides. Methods The isolates variously had KPC (n = 12), SME-1 (n = 1), IMP (n = 13), VIM (n = 5), NDM (n = 17) or OXA-48 (n = 19) carbapenemases, or had combinations of impermeability with AmpC (n = 5) or extended-spectrum β-lactamases (n = 10). They included 53 Klebsiella spp., 19 Enterobacter spp., 6 Escherichia coli and 4 others; most were multiresistant. Genes were identified by PCR and sequencing; MICs were measured by CLSI agar dilution.
ACHN-490 was active at ≤ 2 mg/L against all 65 isolates with carbapenem resistance mechanisms other than NDM enzyme, mostly with MICs of 0.12-0.5 mg/L; isepamicin was active against 63/65 at ≤ 8 mg/L. In contrast, 35% were resistant to gentamicin at 4 mg/L, 61% to tobramycin at 4 mg/L and 20% to amikacin at 16 mg/L. However, 16 of the 17 isolates with NDM-1 enzyme were resistant to ACHN-490, with MICs ≥ 64 mg/L, and these were cross-resistant to all other human-use aminoglycosides tested. Their behaviour was associated with ArmA and RmtC 16S rRNA methylases. Apramycin (a veterinary aminoglycoside) retained its full activity, with MICs of 4-8 mg/L versus strains with armA or rmtC, though resistance was seen in one Klebsiella pneumoniae with AAC(3)-IV (MIC ≥ 256 mg/L).
ACHN-490 has potent activity versus carbapenem-resistant isolates, except those also harbouring 16S rRNA methylases; isepamicin is also widely active, though less potent than ACHN-490. Evasion of 16S rRNA methylases by apramycin is noteworthy and may provide a starting point for future aminoglycoside development.
肠杆菌科中产碳青霉烯酶的出现正在推动寻找治疗替代方案。我们测试了 ACHN-490，一种逃避所有质粒介导的氨基糖苷修饰酶的西索米星衍生物，针对 82 株耐碳青霉烯肠杆菌分离株。对照包括国际和本地可用的氨基糖苷类药物。
分离株具有不同的 KPC（n = 12）、SME-1（n = 1）、IMP（n = 13）、VIM（n = 5）、NDM（n = 17）或 OXA-48（n = 19）碳青霉烯酶，或具有与 AmpC（n = 5）或扩展谱β-内酰胺酶（n = 10）的组合。它们包括 53 株克雷伯氏菌、19 株肠杆菌、6 株大肠杆菌和 4 株其他菌；大多数是多药耐药的。通过 PCR 和测序鉴定基因；通过 CLSI 琼脂稀释法测量 MIC。
ACHN-490 对除 NDM 酶以外的所有 65 株具有碳青霉烯类耐药机制的分离株均具有活性，MIC 大多为 0.12-0.5mg/L；异帕米星对 63/65 株的活性在 ≤ 8mg/L。相比之下，35%的分离株对庆大霉素 4mg/L 耐药，61%的分离株对妥布霉素 4mg/L 耐药，20%的分离株对阿米卡星 16mg/L 耐药。然而，17 株携带 NDM-1 酶的分离株对 ACHN-490 耐药，MIC 值≥64mg/L，对所有其他测试的人用氨基糖苷类药物均具有交叉耐药性。它们的行为与 ArmA 和 RmtC 16S rRNA 甲基酶有关。大观霉素（一种兽用氨基糖苷类药物）保持其全部活性，对携带 armA 或 rmtC 的菌株 MIC 为 4-8mg/L，尽管在一株肺炎克雷伯菌中发现了 AAC(3)-IV（MIC≥256mg/L）耐药。
ACHN-490 对除携带 16S rRNA 甲基酶的碳青霉烯类耐药分离株外具有很强的活性；异帕米星也广泛有效，但其活性低于 ACHN-490。大观霉素逃避 16S rRNA 甲基酶值得注意，可能为未来氨基糖苷类药物的开发提供起点。
