Examining the activity of cefepime-taniborbactam against Burkholderia cepacia complex and Burkholderia gladioli isolated from cystic fibrosis patients in the United States

ABSTRACT The novel clinical-stage β-lactam-β-lactamase inhibitor combination, cefepime-taniborbactam, demonstrates promising activity toward many Gram-negative bacteria producing class A, B, C, and/or D β-lactamases. We tested this combination against a panel of 150 Burkholderia cepacia complex (Bcc) and Burkholderia gladioli strains. The addition of taniborbactam to cefepime shifted cefepime minimum inhibitory concentrations toward the provisionally susceptible range in 59% of the isolates tested. Therefore, cefepime-taniborbactam possessed similar activity as first-line agents, ceftazidime and trimethoprim-sulfamethoxazole, supporting further development.

The Burkholderia cepacia complex (Bcc) is a group of >20 related non-fermenting pathogens (18).Bcc and Burkholderia gladioli can cause chronic infections in the immunocompromised and those with cystic fibrosis (CF) with 8%-10% of CF patients acquiring Bcc or B. gladioli by end stage, leading to increased morbidity and mortality (19,20).These pathogens are inherently multidrug resistant (MDR); consequently, treatment options are limited (21).β-Lactam antibiotics (e.g., meropenem and ceftazi dime) are recommended therapies to treat infections caused by Bcc and B. gladioli; however, their utility is declining (22,23).
Compared to cefepime alone, the addition of taniborbactam (at 4 µg/mL) shifted the MICs toward the provisionally susceptible range; the MIC 50 value decreased by fourfold from 32 to 8 µg/mL (Table S1; Fig. 1).The percentage of isolates inhibited at ≤8 µg/mL increased from 23% (cefepime alone) to 59% (cefepime-taniborbactam) and at ≤16 µg/mL increased from 42% to 69%, respectively.A bimodal MIC distribution was apparent for B. multivorans and B. cenocepacia within this challenge panel (Fig. 1).Moreover, four strains, B. dolosa AU29985, B. multivorans AU28442, B. multivorans AU11772, and B. multivorans AU15814, demonstrated properties of extremely drugresistant strains with high MICs against all antibiotics tested.These observations may be due to altered profiles and/or expression levels of the PenA-like β-lactamases, as we have previously shown significant heterogeneity of PenA within B. multivorans as well as changes to the level of induction of bla PenA (25,31).Poirel et al. observed heterogeneity in PenB β-lactamases from B. cenocepacia (27).Alterations in the target PBP may play a role as previously observed for Burkholderia pseudomallei (35); efflux is also a major resistance determinant in Burkholderia species (36).
The cefepime-taniborbactam antimicrobial susceptibility data were compared to published data for CLSI recommended agents for Bcc with the same strain panel (22,29,32).Cefepime-taniborbactam (69% of isolates inhibited at ≤16 µg/mL) was compara ble to first-line agents, ceftazidime (64%S) and trimethoprim-sulfamethoxazole (63%S) (Fig. 2).Cefepime-taniborbactam was more active than meropenem, levofloxacin, and minocycline.Cefepime activity against Burkholderia species remains to be established.Ceftazidime is the cephalosporin of choice for treating infections caused by Burkholderia species.Of this challenge panel, only 36% of isolates were reported to be resistant to ceftazidime (28) compared to cefepime, where 58% were resistant; thus, likely, the cephalosporin partner influences the high MIC 90 values for cefepime and cefepime-tani borbactam of >32 µg/mL.
The parameters for inhibition of the B. multivorans ATCC 17616 carbapenemase PenA1 by taniborbactam were determined and compared to other β-lactamase inhibitors, as described in the Supplementary Material and Methods.Taniborbactam demonstrated potent inactivation of the B. multivorans PenA1 with a K i app value of 0.4 µM that is comparable to that of avibactam (K i app = 0.5 µM) but much lower than relebactam and vaborbactam 3.2 and 38 µM, respectively (Table 1) (22,29,30).Moreover, the acylation rate for the bicyclic boronate, taniborbactam was >250-fold higher than for the monocyclic boronate, vaborbactam.The lowest k off rate was for taniborbac tam.These results demonstrate that the efficacy of cefepime-taniborbactam is largely the result of the taniborbactam inhibition of PenA1 β-lactamase.Taniborbactam and avibactam inhibited PenA1 in vitro with relatively similar potencies, while relebactam and vaborbactam exhibited weaker inhibitory kinetic profiles in comparison.In summary, cefepime-taniborbactam will be a welcome addition to the antibiotic arsenal due to its broad-spectrum activity against Enterobacterales and P. aeruginosa producing class A, B, C, and D β-lactamases.With broader analyses, cefepime-taniborbactam may also be valuable to treat infections caused by Burkholderia species.

FIG 1
FIG 1 Susceptibility testing results of cefepime alone (white bars) compared to cefepime combined with taniborbactam fixed at 4 µg/mL (green bars) against a panel of 150 clinical isolates of Burkholderia cepacia complex and Burkholderia gladioli.The chemical structure of taniborbactam (VNRX-5133) is shown in the inset.

TABLE 1
Steady-state inhibitor kinetic values against B. multivorans PenA1 a Individual data points were collected in triplicate, while all experiments were completed at a minimum in duplicate.b n/d, not determined. a