It doesn’t get much beta than this: Novel beta-lactam antibiotics for multidrug-resistant gram-negative organisms

The intrinsic and acquired resistance mechanisms of gram-negative bacteria, coupled with their ability to share resistance genes with one another, provide these organisms with great survival advantages. As demonstrated over the past few decades, infections with multidrug-resistant gram-negative organisms (MDR GNOs) are responsible for great morbidity and mortality.¹ As these pathogens continue to threaten the health of many, much focus has been on the development of new antimicrobials targeted against these organisms and their expressed resistance mechanisms. Imipenem-cilastatin-relebactam (IMI-REL) and cefiderocol are 2 intravenous novel beta- (β-)lactam–based therapies with broad-spectrum activity that target some of the most common modalities of resistance employed by MDR GNOs.

IMI-REL

Relebactam is a non–β-lactam, bicyclic diazabicyclooctane β-lactamase inhibitor, with a structure similar to that of avibactam. When paired with imipenem, it provides additional activity against organisms that produce Ambler class A (eg, extended spectrum β-lactamases and Klebsiella pneumoniae carbapenemases) and class C (eg, AmpC) β-lactamases.² This leads to enhanced activity against many species of Enterobacterales as well as Pseudomonas aeruginosa.

The addition of relebactam to imipenem improves its activity against non-Proteeae Enterobacterales significantly, with 78.5% to 95% of imipenem-nonsusceptible organisms demonstrating in vitrosusceptibility to IMI-REL.^3,4 This improved activity is primarily due to inhibition of β-lactamases, especially Klebsiella pneumoniae carbapenemases. Against non-Proteeae Enterobacterales, IMI-REL has activity similar to that of ceftazidime-avibactam and meropenem-vaborbactam. Imipenem is intrinsically less active against Proteus mirabilis due to decreased binding of penicillin-binding proteins; therefore, the addition of relebactam has a negligible effect on its activity against this species.^3,5

The major mechanism of P aeruginosa resistance against imipenem is a combination of downregulation of an outer membrane protein paired with AmpC production.¹ Relebactam inhibition of AmpC resulted in improved in vitrosusceptibility against approximately 78% of imipenem-nonsusceptible P aeruginosa isolates.^3,6 Improved antipseudomonal activity is an advantage of IMI-REL when compared with meropenem-vaborbactam. This is due to differing mechanisms of resistance to the carbapenem backbone. Resistance to meropenem in P aeruginosa is the result of multidrug efflux pumps, namely the MexA-MexB-OprM system; therefore, the addition of the β-lactamase inhibitor vaborbactam does not improve the antipseudomonal activity of meropenem in the slightest.² Other novel β-lactam/β-lactamase inhibitors with improved activity against carbapenem-resistant P aeruginosa include ceftolozane-tazobactam and ceftazidime-avibactam. Similar to IMI-REL, this is primarily due to inhibition of AmpC; ceftolozane-tazobactam is also less susceptible to efflux pumps.^7,8IMI-REL and the aforementioned agents do not have improved activity against other pathogenic nonfermenting GNOs, such as Acinetobacter baumanii or Stenotrophomonas maltophilia, as they frequently produce class B and D β-lactamases.²

IMI-REL received approval from the FDA for intraabdominal infections and complicated urinary tract infections (cUTI) on the basis of two phase 2 trials, which established the noninferiority of IMI-REL to imipenem alone. Most organisms in these studies were carbapenem-susceptible.^9,10 RESTORE-IMI 1 sought to study IMI-REL in a more applicable setting: the treatment of carbapenem-nonsusceptible infections. This study demonstrated an overall favorable response to IMI-REL that was comparable with imipenem plus colistin, with lower numerical 28-day mortality and less nephrotoxicity in patients who received IMI-REL. While this small study (n = 31) was not powered for statistical inference, it provided a basis for the utilization of IMI-REL to treat carbapenem-nonsusceptible GNOs.¹¹ Results from RESTORE-IMI 2 led to an additional FDA indication for the treatment of hospital-acquired and ventilator-associated pneumonia. In this double-blind, phase 3, noninferiority trial, IMI-REL was noninferior to piperacillin-tazobactam with regard to 28-day mortality and response at end of follow-up.¹² These studies provided an array of evidence to use IMI-REL confidently in clinical practice. A summary of the aforementioned studies is available in Table 1.

Cefiderocol

Cefiderocol is a siderophore cephalosporin that utilizes a “Trojan horse” strategy to overcome resistance associated with passive diffusion across the cell membrane of GNOs. Although similar in structure to ceftazidime and cefepime, the addition of a catechol moiety on the side chain at position 3 permits cefiderocol to chelate iron, allowing for active transport across the cell membrane via iron transporter channels.¹³ In addition to avoiding resistance mechanisms associated with passive diffusion, cefiderocol is stable against hydrolysis by β-lactamases in all 4 Ambler classes, including metallo-β-lactamases, and it is minimally affected by multidrug efflux pumps.^13,14

As one might imagine, bypassing 3 major mechanisms of resistance leads to significantly improved in vitroactivity against many GNOs, fermenters and nonfermenters alike. A series of surveillance studies under the SIDERO-WT program evaluated 28,629 GNO clinical isolates from North America and Europe over a period of 3 years and demonstrated that more than 99% of isolates had low cefiderocol minimum inhibitory concentration (MIC) values.^14-20 The multinational SIDERO-CR 2014/2016 program specifically collected carbapenem-resistant isolates, for which cefiderocol suppressed the growth of 96.2% at the MIC breakpoint of ≤4.^14,21-23 Against carbapenem-resistant Enterobacterales (n = 1022), including 23% ceftazidime-avibactam–resistant isolates, cefiderocol suppressed the growth of 97% of strains. For MDR A baumannii (n = 368), P aeruginosa (n = 262), and S maltophilia (n = 217), cefiderocol suppressed the growth of 90.9%, 99.2%, and 100%, respectively. This included 71.4% ceftolozane-tazobactam–resistant P aeruginosa.^21,22 Its gram-positive and anaerobic activity is essentially negligible, which is a disadvantage when compared with the more recently available β-lactam/β-lactamase inhibitors described above.¹³

While it's in vitroactivity is captivating to infectious diseases clinicians everywhere, the indication for which cefiderocol received initial FDA approval was lackluster at best. Its approval for cUTI in adults with limited or no treatment options was based on a phase 2 study that established noninferiority of cefiderocol compared with imipenem/cilastatin.²⁴ The CREDIBLE-CR study evaluated the use of cefiderocol compared with best available therapy (BAT) for infections caused by carbapenem-resistant organisms and was included as part of the application for approval prior to its peer review and publication.²⁵ Although it was not powered to assess for differences in mortality, an obvious imbalance was seen in patients receiving cefiderocol for pneumonia, bloodstream infections (BSI), or sepsis—a majority of which were caused by A baumannii in critically ill patients. The concern surrounding this result is reflected as a warning for increase in all-cause mortality in the prescribing information.²⁶ Subsequently, results were made available prepublication for the APEKS-NP study, which evaluated patients with nosocomial pneumonia caused by carbapenem-susceptible organisms. Cefiderocol met noninferiority compared with high-dose extended-infusion meropenem for the primary outcome of all-cause mortality at day 14, with similar results at day 28.^25,27 While the APEKS-NP study did not show any mortality concerns, it also did not reflect real-world use of this agent for carbapenem-resistant organisms. The GAMECHANGER study is currently enrolling patients to receive cefiderocol or BAT for gram-negative BSIs and will hopefully provide some insight on its utility for treatment of severe infections caused by MDR GNOs.²⁸

In conclusion, IMI-REL and cefiderocol are broad-spectrum agents that fill a void in the armamentarium against MDR GNOs. Although broad-spectrum, each has its own niche in vitroto combat specific resistance mechanisms expressed by these organisms, for which their use should ultimately be reserved. While clinical data have been made available demonstrating success of IMI-REL against BAT for MDR GNOS, such data for cefiderocol are incomplete and arguably conflicting at this time.^9-12,25,27 However, it must not go unnoticed that in the grand scheme of gram-negative infections, those caused by extensively MDR organisms are few and far between and extremely difficult to study with sufficient power analyses in clinical practice. Hopefully, full publication of CREDIBLE-CR, APEKS-NP, and the GAMECHANGER studies will help define the clinical utility of cefiderocol. In the meantime, this agent will likely be reserved for the treatment of infections where other options are limited to none, as highlighted in a number of case reports of successful treatment thus far.^29-32

Adrienne Terico, PharmD, BCPS, BCIDP, is currently the clinical pharmacy specialist in infectious diseases at Pennsylvania Hospital in Philadelphia. Her interests include multidrug-resistant organisms and antimicrobial stewardship.

References

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