Ceftazidime-Avibactam plus aztreonam synergistic combination tested against carbapenem-resistant Enterobacterales characterized phenotypically and genotypically: a glimmer of hope.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) show rapid global dissemination and pose a significant therapeutic challenge. This study aimed to characterize carbapenemase-producing Klebsiella spp. and Escherichia coli (E. coli) phenotypically and genotypically and evaluate the effect of ceftazidime/ avibactam plus aztreonam combination. METHODS: A total of 219 Klebsiella species and 390 E. coli strains were isolated from clinical samples, in which 80 Klebsiella spp. and 20 E coli isolates were resistant to tested carbapenems (imipenem, ertapenem, meropenem) by disk diffusion/broth dilution method and Vitek-2 compact system. MASTDISCS Combi Carba plus discs and real time PCR were used to determine type of carbapenemase phenotypically and genotypically, respectively. Interestingly, the synergistic effect between ceftazidime-avibactam (E-test) and aztreonam (disc) was tested against the CPE isolates. RESULTS: Out of the carbapenem-resistant isolates, 76.25% Klebsiella spp. isolates were extensively drug-resistant (XDR) while 18.75% were pan drug-resistant (PDR), and 5% were multidrug-resistant (MDR). Regarding E. coli, 5% were PDR, 20% were MDR and 75% were XDR. More than one carbapenemase gene was detected in 99% of the isolates. In comparison between MAST-Carba plus discs and PCR results, sensitivity and specificity were (85.42-97.92%) in Klebsiella spp., and (69.64-100%) in E. coli, respectively. Moreover, a strong association was detected between both test results among Klebsiella spp. (p < 0.001) and E. coli (p = 0.012) isolates. Finally, ceftazidime-avibactam and aztreonam combination showed a synergistic effect in 98.8% of Klebsiella spp. and 95% of E coli. All 16 PDR isolates showed synergy. CONCLUSION: This synergistic effect spots the light on new therapeutics for XDR and PDR CPE.

Successful treatment of ceftazidime/avibactam combined with aztreonam in the NDM-producing Klebsiella pneumoniae bloodstream and intestinal infections in a NK/T lymphoma patient with agranulocytosis during autologous hematopoietic stem cell transplantation: a case report.

New Delhi metallo-beta-lactamase (NDM)-producing Klebsiella pneumoniae is increasingly reported worldwide. Clinicians face significant challenges in the treatment of this multidrug-resistant bacterium. The combination of ceftazidime/avibactam (CAZ/AVI) and aztreonam (ATM) is currently probably the most effective strategy for the treatment of such infection. We described a patient diagnosed with NK/T cell lymphoma who underwent autologous hematopoietic stem cell transplantation (ASCT) in the hematology department. The patient developed severe infection after ASCT. Blood and stool cultures showed carbapenem-resistant K. pneumoniae. Blood sample was detected as NDM-producing K. pneumoniae. We successfully treated this infection with CAZ/AVI and ATM.

In vitro synergistic activity of aztreonam (AZT) plus novel and old ß-lactamase inhibitor combinations against metallo-ß-lactamase-producing AZT-resistant Enterobacterales.

The emergence of metallo-ß-lactamase (MBL)-producing Enterobacterales, mainly New Delhi metallo-ß-lactamase (NDM), represents a clinical threat due to the limited therapeutic alternatives. Aztreonam (AZT) is stable to MBLs, but most MBL-producing Enterobacterales isolates usually co-harbour other ß-lactamases that confer resistance to AZT and, consequently, its use is restricted in these isolates. We compared the ability of sulbactam (SUL), tazobactam (TAZ), clavulanic acid (CLA) and avibactam (AVI) to restore the AZT activity in MBL-producing AZT-resistant Enterobacterales isolates. A collection of 64 NDM-producing AZT-resistant Enterobacterales from five hospitals in Buenos Aires city, Argentina, were studied during the period July-December 2020. MICs were determined using the agar dilution method with Mueller-Hinton agar according to Clinical and Laboratory Standards Institute (CLSI) recommendations. AVI, SUL and TAZ were used at a fixed concentration of 4 mg l-1, whereas CLA was used at a fixed concentration of 2 mg l-1. A screening method based on disc diffusion to evaluate this synergy was also conducted. Detection of bla KPC, bla OXA, bla NDM, bla VIM, bla CTXM-1, bla PER-2 and bla CIT was performed by PCR. The AZT-AVI combination restored the AZT activity in 98.4 % of AZT-resistant strains, whereas CLA, TAZ and SUL did so in 70.3, 15.6 and 12.5 %, respectively, in isolates co-harbouring extended-spectrum ß-lactamases, but were inactive in isolates harbouring AmpC-type enzymes and/or KPC. The synergy screening test showed an excellent negative predictive value to confirm the absence of synergy, but positive results should be confirmed by a quantitative method. The excellent in vitro performance of the AZT-CLA combination represents a much more economical alternative to AZT-AVI, which could be of use in the treatment of MBL-producing, AZT-resistant Enterobacterales.