Overcoming an Extremely Drug Resistant (XDR) Pathogen: Avibactam Restores Susceptibility to Ceftazidime for Burkholderia cepacia Complex Isolates from Cystic Fibrosis Patients

Abstract

Burkholderia multivorans is a significant health threat to persons with cystic fibrosis (CF). Infections are difficult to treat as this pathogen is inherently resistant to multiple antibiotics. Susceptibility testing of isolates obtained from CF respiratory cultures revealed that single agents selected from different antibiotic classes were unable to inhibit growth. However, all isolates were found to be susceptible to ceftazidime when combined with the novel non-β-lactam β-lactamase inhibitor, avibactam (all minimum inhibitor concentrations (MICs) were ≤8 mg/L of ceftazidime and 4 mg/L of avibactam). Furthermore, a major β-lactam resistance determinant expressed in B. multivorans, the class A carbapenemase, PenA was readily inhibited by avibactam with a high k2/K of (2 ± 1) × 106 μM−1 s−1 and a slow koff of (2 ± 1) × 10−3 s−1. Mass spectrometry revealed that avibactam formed a stable complex with PenA for up to 24 h and that avibactam recyclized off of PenA, re-forming the active compound. Crystallographic analysis of PenA–avibactam revealed several interactions that stabilized the acyl–enzyme complex. The deacylation water molecule possessed decreased nucleophilicity, preventing decarbamylation. In addition, the hydrogen-bonding interactions with Lys-73 were suggestive of a protonated state. Thus, Lys-73 was unlikely to abstract a proton from Ser-130 to initiate recyclization. Using Galleria mellonella larvae as a model for infection, ceftazidime–avibactam was shown to significantly (p < 0.001) improve survival of larvae infected with B. multivorans. To further support the translational impact, the ceftazidime–avibactam combination was evaluated using susceptibility testing against other strains of Burkholderia spp. that commonly infect individuals with CF, and 90% of the isolates were susceptible to the combination. In summary, ceftazidime–avibactam may serve as a preferred therapy for people that have CF and develop Burkholderia spp. infections and should be considered for clinical trials.

Trends in ceftazidime‐avibactam activity against multidrug‐resistant organisms recovered from respiratory samples of cystic fibrosis patients

“…However, there is a lack of knowledge of its activity against MDRO recovered in CF, 3 although it has shown an in vitro activity against some strains of Burkholderia spp. 4,5 We assessed in vitro susceptibility of 30 S. maltophilia, 30…”

“…1,2 Ceftazidime-avibactam is a new cephalosporin-inhibitor combination with a potent activity against multidrug-resistant organisms (MDRO) such as KPC and OXA-48 like producing Enterobacteriacae and multidrug resistant P. aeruginosa.However, there is a lack of knowledge of its activity against MDRO recovered in CF, 3 although it has shown an in vitro activity against some strains of Burkholderia spp. 4,5 We assessed in vitro susceptibility of 30 S. maltophilia, 30Achromobacter spp and 13 Bcc isolates to ceftazidime-avibactam by e-tests and to other antibiotics by the disc diffusion method or e-tests. Clinical isolates recovered from respiratory samples were identified by MALDI-TOF mass spectrometry (Microflex LT with the Compass database, Bruker, Germany).…”

A case of pan‐resistant Burkholderia cepacia complex bacteremic pneumonia, after lung transplantation treated with a targeted combination therapy

“…Papp‐Wallace et al found that when avibactam was combined with ceftazidime, susceptibility to ceftazidime in MDR and XDR clinical strains of Burkholderia spp isolated from CF respiratory specimens was restored. To the best of our knowledge, the synergism between ceftazidime/avibactam and meropenem against BCC has not been previously reported.…”

Successful ceftazidime‐avibactam treatment of post‐surgery Burkholderia multivorans genomovar II bacteremia and brain abscesses in a young lung transplanted woman with cystic fibrosis

“…Pen A has a very broad substrate profile that includes carbapenems and β‐lactamase inhibitors. Avibactam was shown to be a potent inhibitor of the Pen A . CAZ‐AVI has an antimicrobial spectrum of activity including MDR GNB, consequently it may improve the outcomes of patients infected with those pathogens.…”

“…Non β‐lactamase‐mediated resistance, like efflux pumps and reduced outer membrane permeability, also plays a role in the decreased susceptibility of Bcc species toward beta lactam antibiotics . Avibactam is a novel β‐lactamase inhibitor which contrasts the activities of Ambler class A‐serine, C‐serine β‐lactamases and some Ambler class D‐serine enzymes (OXA‐48) to restore the susceptibility to ceftazidime by preventing enzymatic hydrolysis without changing the Class B‐MBL . The combination of ceftazidime/avibactam (CAZ‐AVI) represents a novel therapeutic option for Bcc, due to much higher in vitro susceptibility than ceftazidime alone .…”