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Generating Genotype-Specific Aminoglycoside Combinations with Ceftazidime/Avibactam for KPC-Producing Klebsiella
Yanqin Huang1, Karol Sokolowski1, Amisha Rana1
1Department of Pharmacy Practice, University of Illinois at Chicagogrid.185648.6 College of Pharmacy, Chicago, Illinois, USA.
Abstract:
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-log10 CFU/lung reduction at 24 h, which was significantly greater than either monotherapy (P < 0.005). Aminoglycosides in combination with CAZ/AVI were promising for KPC-Kp infections; this was true even for a one-time aminoglycoside dose. Selecting aminoglycosides based on AME genes or susceptibilities can improve the pharmacodynamic activity of the combination.
Insights
Combining aminoglycosides with ceftazidime/avibactam (CAZ/AVI) shows promise against KPC-producing Klebsiella pneumoniae (KPC-Kp). Even a single dose of aminoglycoside with CAZ/AVI demonstrated effective killing of KPC-Kp.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) poses a significant threat due to limited treatment options.
- Ceftazidime/avibactam (CAZ/AVI) is a key antibiotic for KPC-Kp infections, but its combinations require optimization.
- Aminoglycoside-modifying enzyme (AME) genes influence the efficacy of aminoglycoside combinations.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy of aminoglycoside combinations with CAZ/AVI against KPC-Kp.
- To investigate the impact of specific AME genes (aac(6')-Ib' and aac(6')-Ib) on combination therapy outcomes.
- To assess the effectiveness of a short-course, one-time aminoglycoside dose in combination with CAZ/AVI.
Main Methods:
- Static time-kill assays and hollow-fiber infection model (HFIM) were used to test CAZ/AVI with gentamicin and amikacin against KPC-Kp isolates.
- Mouse pneumonia model was employed to evaluate the efficacy of gentamicin plus CAZ/AVI.
- Isolates harboring specific AME genes were analyzed to determine synergistic effects.
Main Results:
- Synergy between CAZ/AVI and aminoglycosides varied based on the specific AME gene present in KPC-Kp isolates.
- CAZ/AVI combined with either gentamicin or amikacin achieved faster and more complete bacterial eradication in HFIM compared to CAZ/AVI monotherapy.
- A single, one-time dose of aminoglycoside in combination with CAZ/AVI showed comparable efficacy to multiple doses in HFIM.
- The combination of gentamicin and CAZ/AVI significantly reduced bacterial load in a mouse pneumonia model compared to monotherapies.
Conclusions:
- Aminoglycoside combinations with CAZ/AVI are effective against KPC-Kp infections.
- The choice of aminoglycoside should be guided by the presence of AME genes or susceptibility testing for optimal pharmacodynamic activity.
- A simplified dosing strategy, including a one-time aminoglycoside dose, may be feasible for treating KPC-Kp infections with CAZ/AVI combinations.
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