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 ~  Abstract
 ~ Introduction
 ~  Materials and Me...
 ~ Results
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  Table of Contents  
Year : 2019  |  Volume : 37  |  Issue : 1  |  Page : 34-41

Will ceftazidime/avibactam plus aztreonam be effective for NDM and OXA-48-Like producing organisms: Lessons learnt from In vitro study

1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of General Medicine Unit-1, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Haematology, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Medical Intensive Care Unit, Christian Medical College, Vellore, Tamil Nadu, India
5 Department of Division of Critical Care, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication16-Aug-2019

Correspondence Address:
Dr. Shalini Anandan
Department of Clinical Microbiology, Christian Medical College, Vellore - 632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_19_189

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 ~ Abstract 

Introduction: Carbapenem resistance (CR) in Klebsiella pneumoniae is mainly mediated by bla NDM and bla OXA-48 carbapenemases. Newer Food and Drug Administration-approved antimicrobial ceftazidime/avibactam (C/A) has a potent activity against bla OXA-48-like producers. However, its activity is limited in organisms co-producing bla NDM and bla OXA-48-like. Addition of aztreonam (ATM) to C/A potentially expands the spectrum of coverage for carbapenemase co-producers. With this, we aimed to determine the synergistic activity of combination of C/A plus ATM against bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like producing CR Klebsiella pneumoniae (CRKp). Materials and Methods: A total of 12 isolates of CRKp-harbouring genes encoding bla NDM and bla OXA-48-like were tested. Minimum inhibitory concentrations (MICs) were determined for several antimicrobial agents, including C/A (0.5–8 μg/ml) by broth microdilution method. Checkerboard assay was performed for the combination of C/A plus ATM at varying concentrations. Fold differences in the MIC of C/A with and without addition of ATM were determined to infer synergistic effects. Results: MIC of C/A and ATM ranged from 0.5 to >8 μg/ml and 64 to 2048 μg/ml, respectively. Two isolates were susceptible to C/A with MIC of 0.5 and 1 μg/ml, while others were resistant with MIC of >8 μg/ml. Synergistic effects of >8-fold MIC difference in C/A MIC were noted with addition of ATM at 4 μg/ml. This was observed for all CRKp with profiles of bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like genes, which was a promising effect. Notably, all five of the colistin-resistant CRKp were inhibited with >8-fold MIC difference in the combination of C/A plus ATM at 4 μg/ml. Conclusion: With the increasing burden of CRKp, the use of C/A with ATM combination seems to be very promising, especially for bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48like carbapenemases.

Keywords: Aztreonam, bla NDM, bla OXA-48-like, ceftazidime/avibactam, Klebsiella pneumoniae

How to cite this article:
Pragasam AK, Veeraraghavan B, Shankar BA, Bakthavatchalam YD, Mathuram A, George B, Chacko B, Korula P, Anandan S. Will ceftazidime/avibactam plus aztreonam be effective for NDM and OXA-48-Like producing organisms: Lessons learnt from In vitro study. Indian J Med Microbiol 2019;37:34-41

How to cite this URL:
Pragasam AK, Veeraraghavan B, Shankar BA, Bakthavatchalam YD, Mathuram A, George B, Chacko B, Korula P, Anandan S. Will ceftazidime/avibactam plus aztreonam be effective for NDM and OXA-48-Like producing organisms: Lessons learnt from In vitro study. Indian J Med Microbiol [serial online] 2019 [cited 2021 Feb 27];37:34-41. Available from:

 ~ Introduction Top

Infections due to carbapenem-resistant Klebsiella pneumoniae (CRKp) are increasingly being reported and are associated with high morbidity and mortality rates.[1],[2] CR in K. pneumoniae is mainly driven by the acquired carbapenemase-encoding genes such as blaKPC, blaNDM and blaOXA-48-like, followed by chromosomal ompK35 and ompK36 genes.[3],[4] In India, multiple studies have reported high rates of blaNDM in K. pneumoniae.[5],[6],[7] However, blaOXA-48-like mediated carbapenemases are being increasingly reported in recent times.[5],[6],[8] Management of such infections due to CRKp is challenging as very few agents such as colistin (CL), tigecycline, minocycline and fosfomycin are available.[9],[10] For various reasons, these drugs have limitations for use as monotherapy. These drugs are preferred as partners for combination therapy.[9],[11]

To circumvent these carbapenemases, beta-lactamase inhibitors are being developed to combine with a beta-lactam agent. The currently available first-generation beta-lactamases such as clavulanic acid, tazobactam or sulbactam have narrow spectrum and do not inhibit carbapenemases. However, diazabicyclooctane-based second-generation beta-lactamase inhibitors such as avibactam, relebactam, zidebactam and nacubactam have a broader spectrum.[12] These are active against class A (extended-spectrum beta-lactamases [ESBLs] and carbapenemases-KPC), class C (AmpCs) and some class D (OXA-48-like) beta-lactamases. These are not active against class B metallo-beta-lactamases (MBL) such as NDM, IMP and VIM.[13] However, boronate class of inhibitor VNRX-5133 (VenatoRx) partnered with cefepime seems to be active against most of the MBLs and is currently in Phase 3 clinical trial.[14]

Ceftazidime/avibactam (C/A) is a newer beta-lactam/beta-lactamase inhibitor (BL-BLI) combination approved by the Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal infections, complicated urinary tract infections (including pyelonephritis) and hospital-acquired pneumonia (including VAP) in adults.[15] C/A has a broad spectrum of activity against class A and C beta-lactamases (including KPC), and some class D carbapenemases such as OXA-48-like enzymes that are seen in Enterobacteriaceae. Several studies have demonstrated the excellent in vitro activity of C/A for Enterobacteriaceae isolates and against isolates producing OXA-48-like enzymes.[16],[17],[18] Studies reporting on clinical efficacy and microbiological eradication of C/A in managing CRE infections are summarised in [Table 1]. Among the several newer BL/BLI, C/A is the only agent active against OXA-48-like producers, which are increasingly seen with MBLs (NDM) being highly endemic in India. A recent study reported OXA-48-like genes co-carried NDM, which limits the usefulness of C/A in these isolates.[16]
Table 1: Clinical efficacy and microbiological eradication of ceftazidime-avibactam in treating carbapenem-resistant infections

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Another newer BL/BLI, aztreonam (ATM)/avibactam that has potential activity against NDM and OXA-48, is currently in the clinical development.[27] ATM remains stable against MBLs; however, its utility in management is limited due to its inactivation by the presence of multiple beta-lactamases such as ESBLs and AmpCs along with MBLs. As the newer agent, C/A is not active against MBL-producing organisms, it is hypothesis to add ATM to C/A. This combination has a strong inhibitory activity against CRE, expanding the coverage over NDM and OXA-48-like enzymes.

We undertook this study to evaluate the synergistic effect of the combination of C/A plus ATM at various concentrations against diverse carbapenemase-producing K. pneumoniae.

 ~ Materials and Methods Top

A total of 12 CRKp isolated from bacteraemic patients at Christian Medical College (CMC, Vellore) were included. All isolates have been previously characterised for CR. Phenotypic tests included disc diffusion for imipenem (IMP, 10 μg) and meropenem (MEM, 10 μg) and carbaNP for testing of carbapenemase production as per the CLSI guidelines.[28] Molecular mechanisms of CR were screened by a conventional multiplex PCR for genes encoding carbapenemases, such as blaSPM, blaIMP, blaVIM, blaNDM, blaKPC and blaOXA-48-like.[29] Minimum inhibitory concentration (MIC) was determined by broth microdilution (BMD) for a range of antimicrobials freeze-dried with different concentrations in a 96-well microtitre plate. This included cefoxitin (FOX, 2–16 μg/ml), cefepime (FEP, 1–16 μg/ml), ceftazidime (CAZ, 1–16 μg/ml), ceftazidime/avibactam (C/A, 0.12–8 μg/ml), amoxicillin/clavulanate (A/C, 1–8 μg/ml), piperacillin/tazobactam (P/T, 2–64 μg/ml), ceftolozane/tazobactam (C/T, 0.12–8 μg/ml), imipenem/relebactam (I/R, 0.12–8 μg/ml), imipenem (IMP, 0.12–8 μg/ml), meropenem (MEM, 0.12–8 μg/ml), ertapenem (ERT, 0.06–4 μg/ml), aztreonam (AZT, 1–16 μg/ml), ciprofloxacin (CIP, 0.25–2 μg/ml), levofloxacin (LVX, 0.5–4 μg/ml), amikacin (AMK, 4–32 μg/ml) and colistin (COL, 1–4 μg/ml). The MIC values were interpreted as per the CLSI guidelines.[28]

To determine the synergistic activity of the combination of C/A plus ATM, a checkerboard-based assay was set up.[30] End-point MIC of ATM was determined by standard BMD for all isolates. To assess synergy, concentration of C/A ranging from 0.12 to 8 μg/ml was tested with ATM. Two-fixed concentration of ATM at 4 μg/ml and 8 μg/ml and a varying concentration at 0.5 × MIC and 1.0 × MIC concentration with respect to each of the test isolate's MIC was used. For example, isolates with ATM-MIC of 1024 μg/ml; 512 μg/ml as 0.5 × MIC concentration and 1024 μg/ml as 1.0 × MIC concentration were tested. 0.5 × MIC and 1.0 × MICs were different for each of the test isolate, depending on the MIC of ATM of that particular isolate. In addition, a control plate without addition of ATM was included in all assays to compare the fold differences in the MIC of C/A upon addition of ATM, to infer synergistic effects.

 ~ Results Top

Among the 12 isolates of CRKp, seven were multidrug-resistant (MDR) and five were extensive drug-resistant (XDR: MDR + CL resistant). Of the 12 CRKp, the carbapenemase profiles were NDM + OXA-48-like (n = 6), OXA-48-like (n = 3) and NDM (n = 3) producers, respectively. MICs of the test isolate against a range of antimicrobials are mentioned in [Table 2] (control plate). MICs of all the agents were observed to be higher than the ranges tested, including ATM being resistant in all isolates. End-point determination by BMD for ATM revealed high MIC values, which ranged from 128 to >1024 μg/ml. Overall, one isolate each of NDM + OXA-48-like, OXA-48-like and NDM producers were susceptible for C/A with MIC 0.5, 1 and 1 μg/ml, respectively, while the other nine isolates were resistant with MICs of >8 μg/ml. However, three of these C/A-susceptible isolates were resistant to CAZ alone with MIC of >8 μg/ml. Whereas, other Bl/BLI showed high MIC values of ≥8 μg/ml, ≥8 μg/ml, ≥8 μg/ml and ≥64 μg/ml for I/R, C/T, A/C and P/T, respectively. In particular, only one of the three OXA-48-like producers was susceptible to C/A with MIC of 1 μg/ml, with other two isolate's MIC of >8 μg/ml. This observation was notable as C/A is expected to have susceptibility against OXA-48-like producers.
Table 2: Minimum inhibitory concentrations of test isolates against a range of antimicrobials and minimum inhibitory concentration fold difference of ceftazidime-avibactam on addition of aztreonam

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For checker-board analysis, first, the end-point MIC of ATM for all the 12 test isolates was determined that ranged from 128 to 4096 μg/ml. Distribution of ATM-MIC was observed to be 128 μg/ml (n = 1), 512 μg/ml (n = 3), 1024 μg/ml (n = 3), 2048 μg/ml (n = 1) and 4096 μg/ml (n = 4), respectively. ATM-MICs of all the test isolates were found at much higher levels than the resistant cut-off defined by the CLSI guidelines (≥16 μg/ml). Although initial checkerboard analysis used ATM concentrations from 4 μg/ml onwards, synergistic effect of >8-fold MIC difference on C/A + ATM was observed at 8 μg/ml (ATM) being the lowest concentration. Synergism observed with 0.5 × MIC of ATM was not considered, as the drop in the MIC contributing for fold differences with C/A+ATM combination MIC could be due to the sole effect of ATM itself, as ATM was used at higher concentrations ranging from 64 to 2048 μg/ml.

Overall, checker-board analysis of antimicrobials with ATM combination to C/A revealed the synergistic effects at various MIC levels for tested isolates [Table 2]. Addition of ATM at 8 μg/ml did not show any fold difference in the MIC of CAZ alone. However, addition of 8 μg/ml of ATM to C/A did show >8-fold difference in the MIC of C/A, resulting in MICs within the susceptible range for all NDM, OXA-48-like and NDM + OXA-48-like producers.

Interestingly, two of the five CL-resistant CRKp showed susceptible MIC to C/A alone, both being 1.0 μg/ml (one each of NDM and OXA-48-like producers), while the remaining three isolates showed >8-fold MIC differences in C/A on addition of ATM (1-OXA48-like, 2-NDM + OXA48-like). Similarly, 3/5 isolates (one each of NDM, OXA48-like, NDM + OXA-48-like) showed >8-fold reduction in MIC for I/R plus ATM. In the remaining two isolates (one each of OXA-48-like and NDM + OXA48-like), fold differences in the MIC could not be inferred as end-point MIC of I/R was not determined.

 ~ Discussion Top

In the past decade, emergence and rapid dissemination of carbapenem-resistant organisms (CRO) has been documented across the globe. In India, carbapenemase (blaNDM, blaOXA-48-like)- mediated resistance among gram-negative organisms is a concern. Among the Gram-negatives, MBLs are commonly seen in Escherichia coli, K. pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. However, different class D oxacillinase carbapenemases are seen in K. pneumoniae (blaOXA-48-like) and A. baumannii (blaOXA-23/24/58-like), respectively.[31] Due to the diversity in the carbapenemases seen in Gram-negatives, it is vital to understand which antimicrobials are effective against each of these specific determinants to tailor therapy to improve clinical outcome.

In the current scenario, knowledge on epidemiology and molecular mechanisms in CRO in the respective geographical regions drives the therapeutic decision-making. Among carbapenemases, blaKPC are highly endemic in several parts of the United States, Colombia, Brazil, Argentina, Israel, Italy, Greece and China;[32]blaOxa-48-like enzymes being more prevalent in France, Spain Belgium and India;[33] whereas blaNDM is endemic in South Asian and Southeast Asian countries, as well in Turkey, Denmark, Poland, Romania, Greece, France and Belgium.[34] This information aids in choosing the appropriate BL/BLI combinations that can be effective.

In India, limited information is available, with data only from certain geographical locations. This includes collective information from four nodal centres for Enterobacteriaceae, P. aeruginosa and A. baumannii, respectively (AMRSN network).[29] Carbapenemases burden depicted in the network show India to be highly endemic for MBLs (blaNDM in Enterobacteriaceae, blaVIM, blaIMP in P. aeruginosa and A. baumannii) and class D oxacillinase carbapenemases (blaOXA-48-like in Enterobacteriaceae; blaOXA-23/58-like in A. baumannii).[29],[31],[35] This indicates a need for continuous molecular resistance surveillance, with a wide coverage of multiple regions across the country.[31]

Overall observations of such synergistic activities of combination of ATM with C/A and I/R against CL-resistant CRKp are a promising finding. Moreover, these findings precisely reflect on the molecular mechanisms seen in these isolates, wherein the combination of C/A plus ATM worked against NDM alone and NDM + OXA-48-like producers. Similar synergistic observations for OXA-48-like producers could have been attributed to poor hydrolytic ability of OXA-48-like carbapenemases towards CAZ and ATM. This study results concurs with the previous study findings on synergistic activity of C/A plus ATM combinations for MDR-GN organisms producing NDM and/or OXA-48-like carbapenemases. However, all of the previous studies have employed either disc diffusion or E-test to assess synergy, but none have used checker-board-based assay.

Recently, there has been improved understanding in the determination of synergy testing, with certain parameters to be followed. First is the determination of MIC of the given drug–bug combination by appropriate method, followed by the use of accurate method for synergy testing, various methods have been followed for synergy assessment, namely (a) zone of hope (ZOH), (b) checker-board assay, (c) time kill assay (TKA), (d) gradient diffusion strips (GDS) testing at steady-state serum concentration (Css) of individual antimicrobials and (e) neutropenic murine thigh infection models.

  1. GDS, E-test-based in-vitro synergy of C/A + ATM was first demonstrated against CPE.[36] This combination has produced a larger zone of inhibition ellipse than individual antibiotics against CRO. This has been demonstrated against IMP-type MBL-producing non-fermenter isolates (n = 10), where none have been inhibited at any clinically achievable concentrations, while combination of C/A + ATM did produce a large zone of inhibition named as “ZOH”
  2. Checker-board-based assay was performed to evaluate the potent activity of three different combinations, including (i) CAZ and ATM, (ii) C/A + ATM and (iii) CAZ plus C/A using checkerboard assay.[37] This study has described that C/A + ATM (71%) was the most synergistic of all the combinations. This combination has resulted in a considerable MIC reduction of 128-fold (>256 to 2 μg/ml). Interestingly, synergy of this combination was also observed against OXA-producing A. baumannii. However, CAZ plus ATM produced noticeable synergistic activity than ATM plus C/A against IMP-producing P. aeruginosa
  3. In TKA, C/A + ATM produced significant bactericidal activity against blaKPC or blaOXA-232-positive K. pneumoniae.[38] The time kill kinetics showed a time-dependent reduction of bacterial CFU, with a fixed concentration of 8 μg/ml to varying concentration of C/A.[39] Notably, a ≥4 log10 CFU reduction in bacterial inoculum was observed with this combination at 2 h
  4. GDS-E-test based novel method of synergy testing has recently proposed the use of antimicrobials at steady-state serum concentration (Css). This can be achieved by employing (GDS-E test) placed at 90° angle and intersected at the predetermined MICs and at the Css (as defined for each antimicrobial agents).[40] For example, 2 g of meropenem q8 h achieve Css of 16 μg/ml. However, determination of synergy for ATM with C/A needs to be explored with this method
  5. In a murine neutropenic thigh infection model, a similar observation of effectiveness of C/A + ATM combination against MBLs was noted. This study demonstrated 4 log10 CFU decrease in the combination of C/A (32 mg/kg q8 h) plus ATM (32 mg/kg q8 h).[39]

Recent clinical experiences from other investigators in successfully managing infections due to NDM or NDM + OXA-48-producing organisms with C/A + ATM are as follows: (i) an observation of using C/A + ATM combination to treat NDM producing E. cloacae and NDM-1 + OXA-48-producing K. pneumoniae,[39] (ii) NDM-1-producing P. aeruginosa[41] and (iii) an outbreak of XDR K. pneumoniae (NDM-1 + OXA-48 + CTX-M-15) in Spain with the successful clinical outcome in 6/10 patients treated with this combination [Table 3].[42]
Table 3: Studies on clinical outcomes of treatment with combination of ceftazidime/avibactam plus aztreonam against NDM and OXA-48-like-producing Gram-negative organisms

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Success of the combination therapy largely depends on the appropriate dosing of two antimicrobials to exert synergistic effect. To the best of our knowledge, a literature review showed four clinical studies with 14 patients reporting successful outcome with C/A + ATM combinations in treating NDM-1- and OXA-48-producing organisms receiving actual recommended dose of C/A being 2.5 g or less, q8 h; with no higher doses of ATM administered. However, sometimes, >3 g/day is indicated, if the MIC of ATM exceeds more than the susceptible range, especially if it is in the intermediate or resistance ranges, as we observed in this study (128 to >512 μg/ml) and likewise in critically ill patients with high augmented renal clearance and obese conditions may require higher dose or continuous infusion.

 ~ Conclusion Top

In our experience of CRKp burden with carbapenemases profiles are observed to be predominantly OXA-48 like, followed by NDM+OXA-48 like and NDM producers. Though, this proportion may vary across different geographical locations. With the increasing co-occurrence of OXA-48-like and/or NDM among K. pneumoniae in Indian settings, addition of ATM to C/A would be highly beneficial. However, it is imperative to employ the very best possible method available to detect synergy and MIC level of partner drug for appropriate dosing. In addition, if the partner drug MIC falls in the intermediate range, either continuous infusion or increased dosage may be required to maintain adequate time >MIC for successful therapy, especially in case of ATM, when combined with C/A.

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3]


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2004 - Indian Journal of Medical Microbiology
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