Mushtaq Shazad, Warner Marina, Ge Yigong, Kaniga Koné, Livermore David M
Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.
J Antimicrob Chemother. 2007 Aug;60(2):300-11. doi: 10.1093/jac/dkm150. Epub 2007 Jun 4.
Ceftaroline (PPI-0903M, T-91825) is a novel cephalosporin, administered as an N-phosphono prodrug. We investigated its in vitro activity and resistance selection potential.
MICs were determined by CLSI agar dilution, but with varied inocula. Mutant selection was investigated in single- and multi-step procedures.
MICs for methicillin-resistant Staphylococcus aureus (MRSA) were 0.5-2 mg/L, compared with 0.12-0.25 mg/L for methicillin-susceptible S. aureus; corresponding values for coagulase-negative staphylococci were 0.25-2 and 0.06-0.12 mg/L, respectively. Even with 2% NaCl added, all MRSA were susceptible at 2 mg/L. MICs for Enterococcus faecalis were from 0.25 to 8 mg/L; E. faecium was resistant. MICs for Escherichia coli, Klebsiella spp., Morganella morganii and Proteeae without acquired resistance were 0.06-0.5 mg/L versus 0.12-1 mg/L for Enterobacter, Serratia and Citrobacter spp. and 2-8 mg/L for Acinetobacter spp. MICs rose to 1-2 mg/L for many Enterobacteriaceae with classical TEM beta-lactamases, and were much higher for those with extended-spectrum beta-lactamases (ESBLs), hyperproduced AmpC or K1 enzymes. MICs for strains with classical TEM/SHV beta-lactamases rose if the inoculum was increased to 10(6) cfu/spot; this effect was even more marked for those with ESBLs. Resistance due to Class A beta-lactamases was reversed by clavulanate. Geometric mean MICs were 0.005, 0.05 and 0.09 mg/L for penicillin-susceptible, -intermediate and -resistant Streptococcus pneumoniae strains, respectively-lower than for any comparator beta-lactam. Haemophilus influenzae and Moraxella catarrhalis were very susceptible, although with marginally raised MICs for beta-lactamase-positive Moraxella strains and for haemophili with chromosomal ampicillin resistance. Ceftaroline selected AmpC-derepressed Enterobacter mutants similarly to cefotaxime in single-step experiments; in multi-step procedures it selected ESBL variants of blaTEM in E. coli. Resistance selection was not seen with S. aureus, H. influenzae or pneumococci.
Ceftaroline has impressive anti-MRSA and anti-pneumococcal activity. Slight lability to classical TEM and SHV beta-lactamases is exceptional for an oxyimino-cephalosporin, but was reversible with clavulanate, as was the greater resistance mediated by ESBLs. Resistance selection occurred with Enterobacteriaceae, not MRSA.
头孢洛林（PPI - 0903M，T - 91825）是一种新型头孢菌素，以N - 膦酸前药形式给药。我们研究了其体外活性和耐药性选择潜力。
采用CLSI琼脂稀释法测定最低抑菌浓度（MIC），但接种量不同。通过单步和多步程序研究突变体选择情况。
耐甲氧西林金黄色葡萄球菌（MRSA）的MIC为0.5 - 2mg/L，而甲氧西林敏感金黄色葡萄球菌的MIC为0.12 - 0.25mg/L；凝固酶阴性葡萄球菌的相应值分别为0.25 - 2mg/L和0.06 - 0.12mg/L。即使添加2%氯化钠，所有MRSA在2mg/L时仍敏感。粪肠球菌的MIC为0.25至8mg/L；屎肠球菌耐药。大肠埃希菌、克雷伯菌属、摩根摩根菌和无获得性耐药的变形杆菌属的MIC为0.06 - 0.5mg/L，而阴沟肠杆菌、沙雷菌属和柠檬酸杆菌属为0.12 - 1mg/L，不动杆菌属为2 - 8mg/L。许多具有经典TEMβ - 内酰胺酶的肠杆菌科细菌的MIC升至1 - 2mg/L，而具有超广谱β - 内酰胺酶（ESBLs）、高产AmpC或K1酶的细菌的MIC则高得多。具有经典TEM/SHVβ - 内酰胺酶的菌株，若接种量增加到10⁶cfu/点，MIC会升高；对于具有ESBLs的菌株，这种影响更为明显。A类β - 内酰胺酶介导的耐药性可被克拉维酸逆转。青霉素敏感、中介和耐药的肺炎链球菌菌株的几何平均MIC分别为0.005、0.05和0.09mg/L，低于任何对照β - 内酰胺类药物。流感嗜血杆菌和卡他莫拉菌非常敏感，尽管β - 内酰胺酶阳性的卡他莫拉菌菌株以及具有染色体氨苄西林耐药性的嗜血杆菌的MIC略有升高。在单步实验中，头孢洛林与头孢噻肟类似，可选择AmpC去阻遏的阴沟肠杆菌突变体；在多步程序中，它可选择大肠杆菌中blaTEM的ESBL变体。在金黄色葡萄球菌、流感嗜血杆菌或肺炎链球菌中未观察到耐药性选择。
头孢洛林具有令人印象深刻的抗MRSA和抗肺炎球菌活性。对于氧亚氨基头孢菌素来说，对经典TEM和SHVβ - 内酰胺酶的轻微不稳定性是例外情况，但可被克拉维酸逆转，ESBLs介导的更高耐药性也可被逆转。耐药性选择发生在肠杆菌科细菌中，而非MRSA。
