In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase–producing Klebsiella pneumoniae

Abstract

BackgroundIn recent years, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infections has increased rapidly. Since the CRE strain is usually resistant to most of antimicrobial agents, patients with this infection are often accompanied by a high mortality. Therefore, it instigates a severe challenge the clinical management of infection. In this study, we study the in vitro and in vivo bactericidal activity of ceftazidime-avibactam administrated either alone or in combination with aztreonam against KPC or NDM carbapenemase-producing Klebsiella pneumoniae, and explore a new clinical therapeutic regimen for infections induced by their resistant strains.MethodsThe microdilution broth method was performed to analyze the minimal inhibitory concentration (MIC). The time-kill curve assay of ceftazidime-avibactam at various concentrations was conducted in 16 strains of KPC-2 and 1 strain of OXA-232 carbapenemase–producing Klebsiella pneumoniae. The in vitro synergistic bactericidal effect of ceftazidime-avibactam combined with aztreonam was determined by checkerboard assay on 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase–producing Klebsiella pneumoniae. According to calculating grade, the drugs with synergistic bactericidal effect were selected as an inhibitory concentration index. The in vitro bactericidal tests of ceftazidime-avibactam combined with aztreonam were implemented on 12 strains among them. Effect of ceftazidime-avibactam antibiotic against KPC carbapenemase–producing K. pneumoniae strain Y8 Infection was performed in the mouse model.ResultsThe time-kill assays revealed that ceftazidime-avibactam at various concentrations of 2MIC, 4MIC and 8MIC showed significant bactericidal efficiency to the resistant bacteria strains. However, in 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase- producing Klebsiella pneumoniae, only 7 strains appeared the susceptibility to ceftazidime-avibactam treatment, MIC50 and MIC90 were 64 mg/L and 256 mg/L, respectively. Antimicrobial susceptibility testing of ceftazidime-avibactam combined with aztreonam disclosed the synergism of two drugs in 90% (27/30) strains, an additive efficiency in 3.3% (1/30) strains, and irrelevant effects in 6.6% (2/30) strains. No antagonism was found. The subsequent bactericidal tests also confirmed the results mentioned above. Therapeutic efficacy of Ceftazidime-Avibactam against K. pneumoniae strain Y8 infection in mouse indicated 70% of infection group mice died within 4 days, and all mice in this group died within 13 days. Bacterial load testing results showed that there was no significant difference in the amount of bacteria in the blood between the infected group and the treatment group. However, the spleen and liver of treatment group mice showed lower CFU counts, as compare with infected group, indicating that ceftazidime-avibactam has a significant effect on the bacteria and led to a certain therapeutic efficacy.ConclusionThis study indicated ceftazidime-avibactam therapy occupied sign...

Prevalence, risk factors and molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae in patients from Zhejiang, China, 2008–2018

“…These drugs have been verified to have good activity against CRKP isolates, especially KPC-producing CRKP. However, they are not as effective against NDM-producing CRKP strains [21]. In China, ceftolozane-tazobactam has not yet been approved, and ceftazidime-avibactam was only approved on 8 September 2019.…”

<p>First Reported Nosocomial Outbreak Of NDM-5-Producing <em>Klebsiella pneumoniae</em> In A Neonatal Unit In China</p>

“…In this study, 12 newborns responded to treatment with these agents, which seems inconsistent with the antibiotic resistance characteristics of the clinical isolates. We assumed when these agents are combined, synergistic bactericidal action against pathogens may be achieved in vivo 36. The isolates detected from sputum samples were presumed to be the flora colonized in the respiratory tract rather than the real infectious pathogen.…”

In Vitro and In Vivo Evaluations of β-Lactam/β-Lactamase Mono- and Combined Therapies against Carbapenem-Nonsusceptible Enterobacteriaceae in Taiwan

“…Several research teams have described the efficacy of the ceftazidime–avibactam combination in vivo [ 30 , 31 , 32 ], but little is known about the combination of aztreonam with avibactam. In one study involving mice infected with carbapenemase-producing K. pneumoniae , 100% of those treated with ceftazidime–avibactam survived, and 70% treated with a placebo died within 4 days [ 30 ].…”

“…Several research teams have described the efficacy of the ceftazidime–avibactam combination in vivo [ 30 , 31 , 32 ], but little is known about the combination of aztreonam with avibactam. In one study involving mice infected with carbapenemase-producing K. pneumoniae , 100% of those treated with ceftazidime–avibactam survived, and 70% treated with a placebo died within 4 days [ 30 ]. In a retrospective clinical study, the 30-day mortality rate for 104 patients infected with bla KPC -carrying K. pneumoniae decreased significantly following treatment with ceftazidime–avibactam ( p = 0.005, 36.5% vs. 55.8% for other therapies) [ 31 ].…”