It doesn’t get much beta than this: Novel beta-lactam antibiotics for multidrug-resistant gram-negative organisms
As the threat of infection with multidrug-resistant gram-negative organisms persists, new antimicrobials are a welcome addition to the armamentarium of infectious diseases clinicians.
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.
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 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.
- Antibiotic resistance threats in the United States: 2019. CDC. November 2019. Updated December 2019. Accessed July 23, 2020. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
- Zhanel GG, Lawrence CK, Adam H, et al. Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations. Drugs. 2018;78(1):65-98. doi:10.1007/s40265-017-0851-9
- Karlowsky JA, Lob SH, Kazmierczak KM, et al. In vitro activity of imipenem-relebactam against clinical isolates of gram-negative bacilli isolated in hospital laboratories in the United States as part of the SMART 2016 program. Antmicrob Agents Chemother. 2018;62(7):e00169-18. doi:10.1128/AAC.00169-18
- Canver MC, Satlin MJ, Westblade LF, et al. Activity of imipenem-relebactam and comparator agents against genetically characterized isolates of carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2019;63(9):e00672-19. doi:10.1128/AAC.00672-19
- Bontron S, Poirel L, Kieffer N, et al. Increased resistance to carbapenems in Proteus mirabilis mediated by amplification of the blavim-1-carrying and IS 26-associated class 1 integron. Microb Drug Resist. 2019;25(5):663-667. doi:10.1089/mdr.2018.0365
- Lob S, Hackel MA, Kazmierczak KM, et al. In vitro activity of imipenem-relebactam against gram-negative ESKAPE pathogens isolated by clinical laboratories in the United States in 2015 (results from the SMART Global Surveillance Program). Antimicrob Agents Chemother. 2017;61(6):e02209-16. doi:10.1128/AAC.02209-16
- Legacé-Wiens P, Walkty A, Karlowsky JA. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014;9:13-15. doi:10.2147/CE.S40698
- Cabot G, Bruchmann S, Mulet X, et al. Pseudomonas aeruginosa ceftolozane-tazobactam resistance development requires multiple mutations leading to overexpression and structural modification of AmpC. Antimicrob Agents Chemother. 2014;58(6):3091-3099. doi:10.1128/AAC.02462-13
- Lucasti C, Vasile L, Sandesc D, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2016;60(10):6234-6243. doi:10.1128/AAC.00633-16
- Sims M, Mariyanovski V, McLeroth P, et al. Prospective, randomized, double-blind, phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infection. J Antimicrob Chemother. 2017;172;(9):2616-2626. doi:10.1093/jac/dkx139
- Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis. 2020;70(9):1799-1808. doi:10.1093/cid/ciz530
- Titov I, Wunderink RG, Roquilly A, et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 study). Clin Infect Dis. Published online August 12, 2020. doi:10.1093/cid/ciaa803
- Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019;79(3):271-289. doi:10.1007/s40265-019-1055-2
- Sato T, Yamawaki K. Cefiderocol: discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin. Clin Infect Dis. 2019;69(S7):S538-S543. doi:10.1093/cid/ciz826
- Hackel MA, Tsuji M, Yamano Y, et al. In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant Gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 study). Antmicrob Agents Chemother. 2017;61(9):e00093-17. doi:10.1128/AAC.00093-17
- Karlowsky JA, Hackel MA, Tsuji M, et al. In vitroactivity of cefiderocol, a siderophore cephalosporin, against Gram-negative bacilli isolated by clinical laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015. Int J Antimicrob Agents. 2019;53(4):456-466. doi:10.1016/j.ijantimicag.2018.11.007
- Kazmierczak KM, Tsuji M, Wise MG, et al. In vitroactivity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem–non-susceptible Gram-negative bacilli, including serine carbapenemase- and metallo-β-lactamase–producing isolates (SIDERO-WT-2014 study). Int J Antimicrob Agents. 2019;53(2):177-184. doi:10.1016/j-ijantimicag.2018.10.007
- Hackel M, Tsuji M, Echols R, Sahm D. In vitro antibacterial activity of cefiderocol (S-649266) against gram-negative clinical strains collected in North America and Europe (SIDERO-WT-2014 study). Poster presented at: IDWeek [infectious diseases meeting] 2016; October 26-30, 2016; New Orleans, LA. Poster 1828.
- Tsuji M, Hackel M, Yamano Y, et al. Cefiderocol in vitro activity against gram-negative clinical isolates collected in Europe: results from three SIDERO-WT surveillance studies between 2014-2017. Poster presented at: 29th European Congress of Clinical Microbiology and Infectious Diseases; April 13-16, 2019; Amsterdam, Netherlands. Poster 1852.
- Tsuji M, Hackel M, Echols R, et al. In vitro antibacterial activity of cefiderocol against gram-negative clinical strains collected in North America and Europe, SIDERO-WT-2016. Poster presented at: American Society of Microbiology Annual Meeting (ASM-Microbe); June 20-24, 2019; San Francisco, CA. Poster AAR-767.
- Hackel MA, Tsuji M, Yamano Y, et al. In vitro activity of the siderophore cephalosporin, cefiderocol, against carbapenem-nonsusceptible and multidrug-resistant isolates of Gram-negative bacilli collected worldwide in 2014 to 2016. Antimicrob Agents Chemother. 2018;62(2):e01968-17. doi:10.1128/AAC.01968-17
- Yamano Y, Tsuji M, Echols R, et al. In vitro activity of cefiderocol against globally collected carbapenem resistant gram-negative bacteria including isolates resistant to ceftazidime/avibactam, ceftolozane/tazobactam and colistin: SIDERO-CR-2014/2016 study. Poster presented at: 27th European Congress of Clinical Microbiology and Infectious Diseases; April 22-25, 2017; Vienna, Austria. Poster 1316.
- Tsuji M, Hackel M, Echols R, et al. In vitro activity of cefiderocol against globally collected carbapenem-resistant gram-negative bacteria isolated from urinary tract source: SIDERO-CR-2014/2016. Poster presented at: IDWeek 2017 [infectious diseases meeting]; October 4-8, 2017; San Diego, CA. Poster 1199.
- Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomized, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-1328. doi:10.1016/ S1473-3099(18)30554-1
- FDA briefing document.meeting of the antimicrobial drugs advisory committee (AMDAC). October 16, 2019. cefiderocol injection. FDA. Accessed August 4, 2020. https://www.fda.gov/media/131703/download
- Fetroja. Prescribing information. Shionogi; 2019. Accessed x x, 2020. https://www.xxxx[GT4]
- Matsunaga Y, Echols R, Katsube T, et al. Cefiderocol (S-649266) for nosocomial pneumonia caused by gram-negative pathogens: study design of APEKS-NP, a phase 3 double-blind parallel-group randomized clinical trial. Abstract presented at: American Thoracic Society International Conference, San Diego, California, 18-23 May 2018. Abstract B42.
- RCT [randomized controlled trial] [of] Cefiderocol vs BAT [best available therapy] for Treatment of Gram Negative BSI [bloodstream infections] (GAMECHANGER). ClinicalTrials.gov. Updated November 25, 2019. Accessed August 4, 2020. https://clinicaltrials.gov/ct2/show/NCT03869437
- Edgeworth JD, Merante D, Patel S, et al. Compassionate use of cefiderocol as adjunctive treatment of native aortic valve endocarditis due to extremely drug-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2019;68(11):1932-1934. doi:10.1093/cid/ciy963
- Trecarichi EM, Quirino A, Scaglione V, et al; IMAGES Group. Successful treatment with cefiderocol for compassionate use in a critically ill patient with XDR Acinetobacter baumannii and KPC-producing Klebsiella pneumoniae: a case report. J Antimicrob Chemother. 2019;74(11):3399-3401. doi:10.1093/jac/dkz318
- Stevens RW, Clancy M. Compassionate use of cefiderocol in the treatment of an intraabdominal infection due to multidrug-resistant Pseudomonas aeruginosa: a case report. Pharmacotherapy. 2019;39(11):1113-1118. doi:10.1002/phar.2334
- Alamarat ZI, Babic J, Tran TT, et al. Long term compassionate use of cefiderocol to treat chronic osteomyelitis caused by extensively drug-resistant Pseudomonas aeruginosa and extended-spectrum-β-lactamase-producing Klebsiella pneumoniae in a pediatric patient. Antimicrob Agents Chemother. 2020;64(4):e01872-19. doi:10.1128/AAC.01872-19