Skip to main content
Download PDF

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

Antimicrobial Resistance & Infection Control volume 7, Article number: 142 (2018) Cite this article

Abstract

Background

In 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.

Methods

The 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.

Results

The 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.

Conclusion

This study indicated ceftazidime-avibactam therapy occupied significant bactericidal effects against KPC-2 and OXA-232 carbapenemase-producing Klebsiella pneumoniae. While combined with aztreonam, the stronger synergistic bactericidal effects against NDM carbapenemase-producing Klebsiella pneumoniae were achieved.

Background

Carbapenems are considered the most effective antibacterial agents against infections caused by multi-drug resistant gram-negative bacillus in clinical practice. However, with the broad use of carbapenems, and the emergence and widespread of carbapenem-resistant Enterobacteriaceae (CRE), in particular carbapenem-resistant Klebsiella pneumoniae (CR-KP), the clinical anti-infection treatment faces a drug-free dilemma [1–4]. Previous studies have shown that the most important resistant mechanism of CR-KP to carbapenems is production of carbapenemases including class A KPC carbapenemases, class B metallo-β-lactamases and class D OXA-48 family carbapenemases. Avibactam is a newly developed novel β-lactamase inhibitor in recent years and can efficiently inhibit class A and class D carbapenemases. As an inhibitor, avibactam can restore the antibacterial activity of ceftazidime to CR-KP. Nevertheless, it has less antibacterial efficiency against CR-KP with metallo-β-lactamase [5–7]. Knowing that aztreonam is stable against hydrolysis by class B metallo-β-lactamases, we hypothesized that supplement of aztreonam to the ceftazidime-avibactam would enhance the activity by “protecting” aztreonam from the “attack” of KPC type carbapenemase. This study aims to explore a new therapeutic regimen by administration of ceftazidime-avibactam alone or combined with aztreonam against carbapenemase-producing Klebsiella pneumoniae.

Materials and methods

Strains

A total of 47 non-repeated clinical strains of carbapenemase-producing Klebsiella pneumoniae were collected from 9 hospitals in 9 cities in China. Of these, 16 strains were blaKPC-2 positive, 1 was blaOXA-232 positive, 28 were blaNDM positive, and 2 were blaKPC2 coupled with blaNDM positive Klebsiella pneumoniae. All strains were identified by mass spectrometry and the gene type of carbapenemases was analyzed by PCR amplification using primers previously described and DNA sequencing [8–10]. E. coli ATCC 25922 were used as quality control strain for antimicrobial susceptibility testing. One K. pneumoniae clinical strain Y8 was used for the Infection in the mouse model.

Antimicrobial susceptibility testing

The minimal inhibitory concentrations were determined by microbroth dilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines [11]. The in vitro synergistic bactericidal effects of ceftazidime- avibactam combined with aztreonam against blaNDM-positive strains were determined by checkerboard assay referred to the published reports [12, 13]. The calculation and interpretation of fractional inhibitory concentration (FIC) was referred to the document standards [14]. FIC = MIC drug A / MIC drug A plus drug B + MICdrug B/ MIC drug A plus drug B. FIC ≤ 0.5 was considered as a synergistic effect, 0.5 < FIC ≤ 1 was considered as an additive effect, 1 < FIC ≤ 2 was considered as an irrelevant effect, and > 2 was considered as an antagonism.

Time-kill assay

According to the minimal inhibitory concentration (MIC) of ceftazidime-avibactam to blaKPC-2 or blaOXA-232 producers, the bactericidal effects of ceftazidime-avibactam at various concentrations of 0.5MIC, 1MIC, 2MIC, 4MIC and 8MIC were studied by time-kill assay. In line with the results of antimicrobial susceptibility testing of ceftazidime-avibactam combined with aztreonam, and following the methods recommended in literatures [15, 16], 10 Klebsiella pneumoniae strains with blaNDM and 2 Klebsiella pneumoniae strains with blaNDM coupled with blaKPC-2 were randomly selected for synergistic bactericidal effects. The operation procedure is briefly described as follows: Mueller-hinton broth containing 1 × 105 CFU/mL bacteria is mixed with single or combined antimicrobial agents incubated overnight with consecutive shacking at 35 °C in an atmospheric environment. Meanwhile, the same broth without antibiotics was served as a growth control. Broth samples were serially diluted at times of 0, 2, 4, 6, 8 and 10 h and smeared on a mueller-Hinton plate respectively. After overnight incubation at 35 °C, the colonies were counted. If the reduction of bacterial survival amount in sample treated with combined antibiotics was ≥2 log10 CFU/mL than those in the sample treated by single drug, it was considered to have a synergistic bactericidal effect.

Effect of ceftazidime-avibactam against K. pneumoniae strain Y8 infection in the mouse model

Six-week-old BALB/c mice (female) were bought from Shanghai Laboratory Animal Company (SLAC), China. Animal experiments were performed in accordance with the Animal Ethics Committee of Shanghai Jiao Tong University. Groups of 10 mice were infected with 2.5 × 106 CFU of strain Y8 via the intraperitoneal (ip) route. Then mice were treated with PBS (infection group) or ceftazidime-avibactam (treatment group) (0.375 mg/g of body weight in 0.1 ml PBS) by subcutaneous injection 4 h post infection and given every 8 h for 10 days. The survival rates of mice were measured at desired time point to assess the therapeutic efficacy of ceftazidime-avibactam. Survival curves were monitored for 15 days.

Bacterial load in the blood and tissues of mice

To measure the efficacy of this drug, the bacterial load was measured in the blood and tissues of mice. Groups of 8 mice were infected with 2.5 × 106 CFU of strain Y8 via the ip and then treated with PBS or ceftazidime-avibactam by subcutaneous injection. The antibiotic dosage and administration were same as the survival experiment mentioned above. At 3 days post infection (dpi), mice in treatment and infected group were euthanized, and the blood and tissues of mice were removed to determine the bacterial burden through bacterial dilution-plate method.

Results

Antimicrobial susceptibility testing

All 16 Klebsiella pneumoniae strains with blaKPC-2 were susceptible to ceftazidime-avibactam with MIC range for 4–8 mg/L. However, all of strains were resistant to ceftazidime with MIC50 of 32 mg/L and MIC90 of > 256 mg/L. The resistance rate of imipenem was 93.8% with MIC50 and MIC90 for 64 mg/L and 128 mg/L, respectively. The resistance rate of meropenem was 93.8% with MIC50 and MIC90 for 64 mg/L and 256 mg/L, respectively (Table 1). The MIC of ceftazidime-avibactam to one OXA-232 carbapenemase-producing Klebsiella pneumoniae was 2 mg/L. The resistance rate of ceftazidime-avibactam to 30 blaNDM (including NDM plus KPC-2) positive Klebsiella pneumoniae strains was 76.7% with MIC range for 0.5~ 256 mg/L, MIC50 and MIC90 for 64 mg/L and 256 mg/L, respectively. The MIC range of aztreonam was 8~ > 256 mg/L with MIC50 and MIC90 were 128 mg/L and > 256 mg/L, respectively. Ceftazidime-avibactam combined with aztreonam showed synergistic effects to 90% (27/30) of strains with blaNDM, 3.3% (1/30) showed additive effects and 6.6%(2/30) showed unrelated effects. No antagonism was found for ceftazidime-avibactam combined with aztreonam (Table 2).

Table 1 Minimal inhibitory concentration (MIC) of ceftazidime-avibactam against KPC-2 or OXA-232 carbapenemase-producing Klebsiella pneumoniae
Full size table
Table 2 Results of MIC and antimicrobial susceptibility testing of ceftazidime-avibactam single dosing and combined with aztreonam against NDM + KPC-2 carbapenemase-producing Klebsiella pneumoniae in 30 strains
Full size table

Time-kill assay

The results of time-kill assays showed that all blaKPC-2 or blaOXA-232 positive K. pneumoniae strains rebounded to grow 4 to 6 h at 0.5 MIC of ceftazidime-avibactam. At the concentration of 1 MIC ceftazidime-avibactam, 23.5% (4/17) of strains declined stably 2 h after dosing and no colonies were detected at 24 h, however, 76.5% (13/17) of strains rebounded to grow in 4–6 h. At the concentrations of 2MIC, 4MIC or 8MIC of ceftazidime-avibactam, it showed a significant bactericidal effectiveness for either blaKPC or blaOXA-232 positive K. pneumoniae and the colony growth was undetected after 24 h incubation for most of strains (Fig. 1 and Fig. 2). For blaNDM positive K. pneumoniae, ceftazidime-avibactam combined with aztreonam showed a significant bactericidal effectiveness and the colony growth was undetected after 10 h incubation (Fig. 3).

Fig. 1
figure 1

Bactericidal curve plots of ceftazidime-avibactam at various concentrations against KPC-2 carbapenemase-producing Klebsiella pneumoniae

Full size image
Fig. 2
figure 2

Bactericidal curve plots of ceftazidime-avibactam at various concentrations against OXA-232 carbapenemase-producing Klebsiella pneumoniae

Full size image
Fig. 3
figure 3

Bactericidal curve plots of ceftazidime-avibactam combined with aztreonam against NDM carbapenemase-producing Klebsiella pneumoniae

Full size image

Therapeutic efficacy of ceftazidime-avibactam against K. pneumoniae strain Y8 infection in mouse

Mice were infected with 2.5 × 106 CFU of strain Y8 and treated with PBS or ceftazidime-avibactam for 10 days. 70% of infection group mice died within 4 days, and all mice in this group died within 13 days (Fig. 4). All treatment group mice survived at 10 dpi with the antibiotic applied every 8 h, whereas 100% of mice in this group died within 4 days after the antibiotic treatment stopped (Fig. 4).

Fig. 4
figure 4

Therapeutic efficacy of ceftazidime-avibactam against K. pneumoniae strain Y8 infection in mouse. Mice were infected with 2.5 × 106 CFU of strain Y8 via the ip route and then treated with PBS or ceftazidime-avibactam by subcutaneous injection. Their survival was assessed daily for 15 days (n = 10). ∗P < 0.05; ∗∗∗P < 0.001

Full size image

Bacterial load in the blood and tissues of mice

Mice were infected with 2.5 × 106 CFU of strain Y8 via the ip and then treated with PBS or ceftazidime-avibactam. The viable bacteria were quantified in blood, liver and spleen at 3 dpi. The 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 that of infected group, indicating that the antibiotic has significant effect on the bacteria and ceftazidime-avibactam led to a certain therapeutic efficacy (Fig. 5).

Fig. 5
figure 5

Bacterial burden in blood, spleen and liver of mice at 3 days post infection (dpi). Mice were infected with 2.5 × 106 CFU of strain Y8 via the ip route and then treated with PBS or ceftazidime-avibactam by subcutaneous injection. At 3dpi, the viable bacteria of blood, spleen and liver was determined by plating serial dilutions on agar plates (n = 8). ∗P < 0.05; ∗∗P < 0.01

Full size image

Discussion

In the recent decade, the prevalence and dissemination of CR-KP has posed a serious challenge in healthcare facilities in the world. The data from the Centers for Disease Control, USA disclosed the infection incidence of CR-KP increased from 1.2% in 2001 to 4.2% in 2011. In annual of 140,000 cases with Enterobacteriaceae infections, 9300 cases (6.6%) were infected by these multidrug-resistant bacteria [17]. According to CHINET surveillance data, the resistance rate of Klebsiella pneumoniae to carbapenems were significantly increasing from 3% in 2005 to 20% in 2017 [18]. Due to lack of effective antibacterial agents, infections due to CR-KP especially for hypervirulent Klebsiella pneumoniae usually accompany with high mortality [19, 20]. Carbapenemases are the major resistance mechanism of Klebsiella pneumoniae to carbapenems. Currently, the common carbapenemase among K. pneumoniae clinical strains include Ambler class A, Ambler class B and Ambler class D (eg. blaOXA-48, and blaOXA-232). blaKPC-2 is the most common carbapenemase in class A enzymes which can hydrolyze almost all of β-lactam antibiotics. blaNDM is the most common carbapenemase in class B metallo-β-lactamase which can hydrolyze all β-lactam antibiotics except aztreonam. Previous studies have shown the CR-KP strains isolated from children in China mainly produce blaNDM [21]. blaOXA-48 carbapenemase are predominantly existent in Klebsiella pneumoniae isolated in Tokyo and Europe [22]. In China, blaOXA-181 and blaOXA-232 have also been detected among Klebsiella pneumoniae clinical strains [23, 24].

Since CRE are usually extensively drug resistant, infections due to CRE are often associated with a high mortality. Therefore, a serious challenge of anti-infection therapy for CRE has been raised in clinical practice. Studies have revealed that compared to use carbapenems antibiotics alone, in the combination of carbapenems with other antibacterial agents such as tigecycline or polymyxin [25–28], amikacin [29] or fosfomycin [30] can considerably improve the outcomes of patient with CR-KP infection. Laurent adopted a combined pharmacotherapy regimen of dual carbapenems to provide a new approach in the treatment of CRE-induced infections [31]. As a novel β-lactam/β-lactamase inhibitor, studies have shown that ceftazidime-avibactam can successfully cure the infections due to Enterobacteriaceae with blaKPC [32–35]. Nevertheless, it is worth to be noticed that with the increasing application of ceftazidime-avibactam, the resistant strains and failed cases have been reported [6, 7, 36]. Our results showed that all of 16 blaKPC-2 positive and 1 of blaOXA-232 positive Klebsiella pneumoniae were susceptible to ceftazidime-avibactam with MIC50 and MIC90 for both 8 mg/L. Time-kill assays demonstrated that it showed a significant bactericidal effectiveness for either blaKPC or blaOXA-232 positive K. pneumoniae at the concentrations of 2MIC, 4MIC or 8MIC of ceftazidime-avibactam. 1 and Fig. 2). At 1 MIC of ceftazidime-avibactam, most of K. pneumoniae strains started to regrowth within 4–6 h. These results mean that the dosage of ceftazidime-avibactam is very important in the treatment of infections caused by blaKPC or blaOXA-232 positive K. pneumoniae [37].

In this study, 76.7% of blaNDM positive Klebsiella pneumoniae were resistance to ceftazidime-avibactam with MIC50 and MIC90 for 64 mg/L and 256 mg/L, respectively. Because avibactam can not inhibit the activity of metallo-β-lactamase, ceftazidime-avibactam monotherapy was ineffective for infections caused by blaNDM-1 positive Klebsiella pneumoniae [38]. According to the results of time-kill assay, ceftazidime-avibactam combined with aztreonam is necessary for the treatment of infection due to blaNDM positive K. pneumoniae based on the characteristics of weak hydrolysis capacity of metallo-β-lactamases to aztreonam. Eric Wenzler et al. also demonstrated that the combination of ceftazidime-avibactam and aztreonam had a synergistic bactericidal effect against class B metallo-β-lactamase-producing gram-negative bacteria [39]. Simultaneously, Benjamin Davido et al. reported that two cases infected either with metallo-β-lactamase-producing Klebsiella pneumoniae or Pseudomonas aeruginosa were successfully cured by combined administration of ceftazidime-avibactam and aztreonam [40]. The results of antimicrobial susceptibility testing indicated 90% (27/30) strains showed a synergistic effect for ceftazidime-avibactam combined with aztreonam. After combined with aztreonam, the MICs of ceftazidime-avibactam for 27 strains were reduced 4–256 times than ceftazidime-avibactam alone and all of them were susceptible to ceftazidime-avibactam with MIC ≤8 mg/L. Subsequently, the bactericidal curve tests performed on 12 strains of Klebsiella pneumoniae with a synergistic effect were also shown the consistent synergistic bactericidal effects. The reduction of bacterial colonies number was >2 log10 CFU/ mL compared with monotherapy and no colonies were detected after 24 h. In addition to strain of R148 showing the synergism 8 h after combined therapy, three blaNDM positive Klebsiella pneumoniae clinical strains of R96, R97 and R100 did not demonstrate the synergistic effects after combined use with aztreonam, implying the other mechanisms of drug resistance may exist and require the further investigation in the future.

Conclusions

In summary, as a compound preparation of novel enzyme inhibitor, ceftazidime-avibactam possesses visible advantages in the treatment of class A and class D type carbapenemase–producing Klebsiella pneumoniae clinical isolates. In addition, if combined with aztreonam, it can also play a synergetic bactericidal effects against infections caused by blaNDM positive Klebsiella pneumoniae clinical strains.

Abbreviations

CAZ:

Ceftazidime

CAZ-AVI:

Ceftazidime-avibactam

CRE:

Carbapenem-resistant Enterobacteriaceae

CR-KP:

Carbapenem-resistant Klebsiella pneumoniae

FIC:

Fractional inhibitory concentration

IPM:

Imipenem

MEM:

Meropenem

MIC:

Minimal inhibitory concentration

References

  1. Ducomble T, Faucheux S, Helbig U, Kaisers UX, Konig B, Knaust A, Lubbert C, Moller I, Rodloff AC, Schweickert B, Eckmanns T. Large hospital outbreak of KPC-2-producing Klebsiella pneumoniae: investigating mortality and the impact of screening for KPC-2 with polymerase chain reaction. J Hosp Infect. 2015;89:179–85.

    Article  CAS  PubMed  Google Scholar 

  2. Kim JO, Song SA, Yoon EJ, Shin JH, Lee H, Jeong SH, Lee K. Outbreak of KPC-2-producing Enterobacteriaceae caused by clonal dissemination of Klebsiella pneumoniae ST307 carrying an IncX3-type plasmid harboring a truncated Tn4401a. Diagn Microbiol Infect Dis. 2017;87:343–8.

    Article  CAS  PubMed  Google Scholar 

  3. Yang J, Ye L, Guo L, Zhao Q, Chen R, Luo Y, Chen Y, Tian S, Zhao J, Shen D, Han L. A nosocomial outbreak of KPC-2-producing Klebsiella pneumoniae in a Chinese hospital: dissemination of ST11 and emergence of ST37, ST392 and ST395. Clin Microbiol Infect. 2013;19:E509–15.

    Article  CAS  PubMed  Google Scholar 

  4. Liu J, Yu J, Chen F, Yu J, Simner P, Tamma P, Liu Y, Shen L. Emergence and establishment of KPC-2-producing ST11 Klebsiella pneumoniae in a general hospital in Shanghai, China. Eur J Clin Microbiol Infect Dis. 2018;37:293–9.

    Article  CAS  PubMed  Google Scholar 

  5. Zasowski EJ, Rybak JM, Rybak MJ. The beta-lactams strike Back: ceftazidime-avibactam. Pharmacotherapy. 2015;35:755–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shields RK, Nguyen MH, Chen L, Press EG, Kreiswirth BN, Clancy CJ. Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance among patients with carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother. 2018;62:e02497–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, Pandey R, Doi Y, Kreiswirth BN, Nguyen MH, Clancy CJ. Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of Carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother. 2017;61(3):e02097–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhu J, Sun L, Ding B, Yang Y, Xu X, Liu W, Zhu D, Yang F, Zhang H, Hu F. Outbreak of NDM-1-producing Klebsiella pneumoniae ST76 and ST37 isolates in neonates. Eur J Clin Microbiol Infect Dis. 2016;35(4):611–8.

    Article  CAS  PubMed  Google Scholar 

  9. Woodford N, Fagan EJ, Ellington MJ. Multiplex PCR for rapid detection of genes encoding CTX-M extended-spectrum (beta)-lactamases. J Antimicrob Chemother. 2006;57(1):154–5.

    Article  CAS  PubMed  Google Scholar 

  10. Poirel L, Walsh TR, Cuvillier V, Nordmann P. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis. 2011;70(1):119–23.

    Article  CAS  PubMed  Google Scholar 

  11. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing[S]: Twenty-seventh Informational Supplement. PA: CLSI; 2017.

  12. Bercot B, Poirel L, Dortet L, Nordmann P. In vitro evaluation of antibiotic synergy for NDM-1-producing Enterobacteriaceae. J Antimicrob Chemother. 2011;66:2295–7.

    Article  CAS  PubMed  Google Scholar 

  13. Elemam A, Rahimian J, Doymaz M. In vitro evaluation of antibiotic synergy for polymyxin B-resistant carbapenemase-producing Klebsiella pneumoniae. J Clin Microbiol. 2010;48:3558–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gunderson BW, Ibrahim KH, Hovde LB, Fromm TL, Reed MD, Rotschafer JC. Synergistic activity of colistin and ceftazidime against multiantibiotic-resistant Pseudomonas aeruginosa in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2003;47:905–9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Paevskii SA. A means for determining the bactericidal activity of the tissues during the treatment of orthopedic patients by transosseous osteosynthesis methods. Klin Lab Diagn. 1993:25–9.

  16. Norden CW, Wentzel H, Keleti E. Comparison of techniques for measurement of in vitro antibiotic synergism. J Infect Dis. 1979;140:629–33.

    Article  CAS  PubMed  Google Scholar 

  17. US Centers for Disease Control and Prevention. Antibiotic Resistance Theats in the United States. 2013. https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf.

  18. Hu FP, Guo Y, Zhu DM, Wang F, Jiang XF, Xu YC, Zhang XJ, Zhang CX, Ji P, Xie Y, Kang M, Wang CQ, Wang AM, Xu YH, Shen JL, Sun ZY, Chen ZJ, Ni YX, Sun JY, Chu YZ, Tian SF, Hu ZD, Li J, Yu YS, Lin J, Shan B, Du Y, Han Y, Guo S, Wei LH, Wu L, Zhang H, Kong J, Hu YJ, Ai XM, Zhuo C, Su DH, Yang Q, Jia B, Huang W. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005-2014. Clin Microbiol Infect. 2016;22(Suppl 1):S9–14.

    Article  CAS  PubMed  Google Scholar 

  19. Chew KL, Lin RTP, Teo JWP. Klebsiella pneumoniae in Singapore: Hypervirulent infections and the Carbapenemase threat. Front Cell Infect Microbiol. 2017;7:515.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kohler PP, Volling C, Green K, Uleryk EM, Shah PS, McGeer A. Carbapenem resistance, initial antibiotic therapy, and mortality in Klebsiella pneumoniae bacteremia: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2017;38:1319–28.

    Article  PubMed  Google Scholar 

  21. Javed H, Ejaz H, Zafar A, Rathore AW, Ikram ul H. Metallo-beta-lactamase producing Escherichia coli and Klebsiella pneumoniae: a rising threat for hospitalized children. J Pak Med Assoc. 2016;66:1068–72.

    PubMed  Google Scholar 

  22. Ma L, Wang JT, Wu TL, Siu LK, Chuang YC, Lin JC, Lu MC, Lu PL. Emergence of OXA-48-producing Klebsiella pneumoniae in Taiwan. PLoS One. 2015;10:e0139152.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Liu Y, Feng Y, Wu W, Xie Y, Wang X, Zhang X, Chen X, Zong Z. First report of OXA-181-producing Escherichia coli in China and characterization of the isolate using whole-genome sequencing. Antimicrob Agents Chemother. 2015;59(8):5022–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yin D, Dong D, Li K, Zhang L, Liang J, Yang Y, Wu N, Bao Y, Wang C. Hu F. clonal dissemination of OXA-232 Carbapenemase-producing Klebsiella pneumoniae in neonates. Antimicrob Agents Chemother. 2017;61(8):e00385–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014;20:862–72.

    Article  CAS  PubMed  Google Scholar 

  26. Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, Polsky B, Adams-Haduch JM, Doi Y. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012;56:2108–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang Y, Li P, Yin Y, Li F, Zhang Q. In vitro activity of tigecycline in combination with rifampin, doripenem or ceftazidime against carbapenem-resistant Klebsiella pneumoniae bloodstream isolates. J Antibiot (Tokyo). 2017;70:193–5.

    Article  CAS  PubMed  Google Scholar 

  28. Machuca I, Gutierrez-Gutierrez B, Gracia-Ahufinger I, Rivera Espinar F, Cano A, Guzman-Puche J, Perez-Nadales E, Natera C, Rodriguez M, Leon R, Caston JJ, Rodriguez-Lopez F, Rodriguez-Bano J, Torre-Cisneros J. Mortality associated with bacteremia due to Colistin-resistant Klebsiella pneumoniae with high-level Meropenem resistance: importance of combination therapy without Colistin and Carbapenems. Antimicrob Agents Chemother. 2017;61:e00406–17.

  29. Hajjej Z, Gharsallah H, Naija H, Boutiba I, Labbene I, Ferjani M. Successful treatment of a Carbapenem-resistant Klebsiella pneumoniae carrying Bla OXA-48 , Bla VIM-2 , Bla CMY-2 and Bla SHV- with high dose combination of imipenem and amikacin. IDCases. 2016;4:10–2.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Albiero J, Sy SK, Mazucheli J, Caparroz-Assef SM, Costa BB, Alves JL, Gales AC, Tognim MC. Pharmacodynamic evaluation of the potential clinical utility of Fosfomycin and Meropenem in combination therapy against KPC-2-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2016;60:4128–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Poirel L, Kieffer N, Nordmann P. In vitro evaluation of dual carbapenem combinations against carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother. 2016;71:156–61.

    Article  CAS  PubMed  Google Scholar 

  32. Gugliandolo A, Caio C, Mezzatesta ML, Rifici C, Bramanti P, Stefani S, Mazzon E. Successful ceftazidime-avibactam treatment of MDR-KPC-positive Klebsiella pneumoniae infection in a patient with traumatic brain injury: a case report. Medicine (Baltimore). 2017;96:e7664.

    Article  PubMed  Google Scholar 

  33. Temkin E, Torre-Cisneros J, Beovic B, Benito N, Giannella M, Gilarranz R, Jeremiah C, Loeches B, Machuca I, Jimenez-Martin MJ, Martinez JA, Mora-Rillo M, Navas E, Osthoff M, Pozo JC, Ramos Ramos JC, Rodriguez M, Sanchez-Garcia M, Viale P, Wolff M, Carmeli Y. Ceftazidime-avibactam as salvage therapy for infections caused by Carbapenem-resistant organisms. Antimicrob Agents Chemother. 2017;61:e01964–16.

  34. Holyk A, Belden V, Lee JJ, Musick W, Keul R, Britz GW, Lin J. Ceftazidime/avibactam use for carbapenem-resistant Klebsiella pneumoniae meningitis: a case report. J Antimicrob Chemother. 2018;73:254–6.

    Article  CAS  PubMed  Google Scholar 

  35. van Duin D, Lok JJ, Earley M, Cober E, Richter SS, Perez F, Salata RA, Kalayjian RC, Watkins RR, Doi Y, Kaye KS, Fowler VG, Jr., Paterson DL, Bonomo RA, Evans S, Antibacterial Resistance Leadership G. Colistin versus ceftazidime-avibactam in the treatment of infections due to Carbapenem-resistant Enterobacteriaceae. Clin Infect Dis. 2018;66:163–71.

  36. Barnes MD, Winkler ML, Taracila MA, Page MG, Desarbre E, Kreiswirth BN, Shields RK, Nguyen MH, Clancy C, Spellberg B, Papp-Wallace KM, Bonomo RA. Klebsiella pneumoniae Carbapenemase-2 (KPC-2), substitutions at ambler position Asp179, and resistance to ceftazidime-avibactam: unique antibiotic-resistant phenotypes emerge from beta-lactamase protein engineering. MBio. 2017;8:e00528–17.

  37. Bensman TJ, Wang J, Jayne J, Fukushima L, Rao AP, D'Argenio DZ, Beringer PM. Pharmacokinetic-Pharmacodynamic target attainment analyses to determine optimal dosing of ceftazidime-avibactam for the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Antimicrob Agents Chemother. 2017;61:e00988–17.

  38. Davido B, Senard O, de Truchis P, Salomon J, Dinh A. Monotherapy of ceftazidime-avibactam and ceftolozane-tazobactam: two effective antimicrobial agents against multidrug-resistant organisms except for NDM-1 isolates. Int J Infect Dis. 2017;62:124–5.

    Article  CAS  PubMed  Google Scholar 

  39. Wenzler E, Deraedt MF, Harrington AT, Danizger LH. Synergistic activity of ceftazidime-avibactam and aztreonam against serine and metallo-beta-lactamase-producing gram-negative pathogens. Diagn Microbiol Infect Dis. 2017;88:352–4.

    Article  CAS  PubMed  Google Scholar 

  40. Davido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A. Ceftazidime-avibactam and Aztreonam, an interesting strategy to overcome beta-lactam resistance conferred by Metallo-beta-lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2017;61:e01008–17.

Download references

Acknowledgements

We thank all the laboratories for contributing data to this analysis.

Funding

This work was supported by the National Natural Science Foundation of China (grant no. 81871690).

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Author information

Author notes

  1. Wenxia Zhang, Yan Guo and Jiayin Li contributed equally to this work.

Authors and Affiliations

  1. Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Rd, Shanghai, 200040, China

    Wenxia Zhang, Yan Guo, Yang Yang, Dong Dong, Demei Zhu & Fupin Hu

  2. Department of Clinical Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Rd, Shanghai, 201203, China

    Wenxia Zhang

  3. Department of Medical Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Jiayin Li, Yiyuan Zhang & Ping He

  4. Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China

    Yan Guo, Yang Yang, Dong Dong, Demei Zhu & Fupin Hu

Authors
  1. Wenxia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiayin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yiyuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dong Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Demei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ping He
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fupin Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PH, and FPH designed the study. WXZ, YG, JYL and YYZ performed the experimental work. YY, DD, and DMZ collected the data. FPH analysed the data. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ping He or Fupin Hu.

Ethics declarations

Ethics approval and consent to participate

This study was approved by Huashan hospital.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, W., Guo, Y., Li, J. et al. In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase–producing Klebsiella pneumoniae. Antimicrob Resist Infect Control 7, 142 (2018). https://0-doi-org.brum.beds.ac.uk/10.1186/s13756-018-0435-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s13756-018-0435-9

Keywords

Antimicrobial Resistance & Infection Control

ISSN: 2047-2994

Contact us