| Autor: |
Yanqin, Huang, Karol, Sokolowski, Amisha, Rana, Nidhi, Singh, Jiping, Wang, Ke, Chen, Yinzhi, Lang, Jieqiang, Zhou, Neera, Kadiyala, Fiorella, Krapp, Egon A, Ozer, Alan R, Hauser, Jian, Li, Jürgen B, Bulitta, Zackery P, Bulman |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Antimicrob Agents Chemother |
| ISSN: |
1098-6596 |
| Popis: |
Antibiotic combinations, including ceftazidime/avibactam (CAZ/AVI), are frequently employed to combat KPC-producing Klebsiella pneumoniae (KPC-Kp), though such combinations have not been rationally optimized. Clinical KPC-Kp isolates with common genes encoding aminoglycoside-modifying enzymes (AMEs), aac(6′)-Ib′ or aac(6′)-Ib, were used in static time-kill assays (n = 4 isolates) and the hollow-fiber infection model (HFIM; n = 2 isolates) to evaluate the activity of gentamicin, amikacin, and CAZ/AVI alone and in combinations. A short course, one-time aminoglycoside dose was also evaluated. Gentamicin plus CAZ/AVI was then tested in a mouse pneumonia model. Synergy with CAZ/AVI was more common with amikacin for aac(6′)-Ib′-containing KPC-Kp but more common with gentamicin for aac(6′)-Ib-containing isolates in time-kill assays. In the HFIM, although the isolates were aminoglycoside-susceptible at baseline, aminoglycoside monotherapies displayed variable initial killing, followed by regrowth and resistance emergence. CAZ/AVI combined with amikacin or gentamicin resulted in undetectable counts 50 h sooner than CAZ/AVI monotherapy against KPC-Kp with aac(6′)-Ib′. CAZ/AVI monotherapy failed to eradicate KPC-Kp with aac(6′)-Ib and a combination with gentamicin led to undetectable counts 70 h sooner than with amikacin. A one-time aminoglycoside dose with CAZ/AVI provided similar killing to aminoglycosides dosed for 7 days. In the mouse pneumonia model (n = 1 isolate), gentamicin and CAZ/AVI achieved a 6.0-log(10) CFU/lung reduction at 24 h, which was significantly greater than either monotherapy (P |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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