Dawn of a New Age: Novel Agents for the Treatment of Carbapenem-Resistant A baumannii

Acinetobacter baumannii is a nonfermenting gram-negative (GN) organism with the capacity to cause severe infections that are untreatable by most antibiotic drug classes.1 For this reason, A baumannii has been identified by the World Health Organization as 1 of 6 organisms responsible for increased patient morbidity and mortality.¹

Multidrug-resistant (MDR) A baumannii has become more prevalent, necessitating the use of carbapenems to aid in infection management.¹ Nonetheless, molecular genotypes represented by the emergence of blaOXA-23, blaOXA-24, and blaOXA-51 genes, which are class D β-lactamases (oxacillinase, or OXA), have contributed to an increase in carbapenem-resistant A baumannii (CRAB).² Additionally, extended-spectrum Acinetobacter-derived cephalosporinases (ADCs) as well as select class A β-lactamases further complicate the use of cephalosporins and other carbapenem-sparing agents in A baumannii–mediated infections.³ Sulbactam, a β-lactamase inhibitor that binds to PBP2 in A baumannii, has shown some activity against CRAB; however, it also falls prey to the aforementioned resistance mechanisms.⁴

Tetracyclines (tigecycline and minocycline) have been shown to have utility against CRAB; however, pharmacokinetic limitations, clinical toxicity, and challenges with interpreting susceptibility results impede placement within CRAB treatment regimens.⁵ Aminoglycosides demonstrate minimal in vitro activity against CRAB, attributed to the presence of aminoglycoside-modifying enzymes, and clinical results are often less promising than in vitro reports.⁶ Thus, last-line antimicrobials, such as the polymyxins (polymyxin B and colistin), have become the agents of choice against CRAB. However, the ill-defined pharmacokinetic/ pharmacodynamic parameters of the polymyxins translate to the over- and underdosing of the agents, leading to toxicity and poor efficacy, respectively. Moreover, an increase in polymyxin-resistant and heteroresistant A baumannii organisms has been reported.⁷

In short, the most appropriate monotherapy agents for the management of CRAB have yet to be elucidated. Combination-therapy options, often with a carbapenem backbone, have shown some promise against CRAB.⁸The basis of success with combination therapy is typically attributed to antibiotic synergy provided by the use of multiple antimicrobials with differing mechanisms of activity against CRAB.

Nevertheless, clinical efficacy has not been consistently reported, and combination approaches are not devoid of collateral damage.⁹ Further, the use of combination therapy does not allow for a decline in the dosing of the single agents; therefore, developing toxicities associated with each antimicrobial (ie, Clostridium difficile infections, renal toxicity, etc) is a risk. Because of the mechanisms of resistance, associated toxicities, and ultimate uncertainty with the currently utilized treatment regimens for CRAB, the development and availability of novel therapies for CRAB management are imperative.

Targeting our currently available antimicrobials against CRAB mechanisms of resistance is a commendable approach but is not adequate for optimal treatment of CRAB. Currently, 3 agents have recent phase 3 trial data available or in progress: eravacycline, cefiderocol, and sulbactam-durlobactam; in addition, there is a renewed focus on the utility of bacteriophage therapy. Although these agents have shown promising in vitro activity against CRAB, clinical outcomes studies have reported variable results.

Eravacycline

Modifying the original tetracycline pharmacophore, eravacycline potentiates activity through the inhibition of the 30S ribosomal subunit. To date, clinical trials evaluating eravacycline have focused solely on infection site rather than causative pathogen. This, unfortunately, has resulted in the reporting of extremely low rates of infection due to A baumannii, let alone CRAB, precluding the ability to determine any potential utility against the carbapenem-resistant isolates.^10-13 Furthermore, the lack of trial data is mirrored with no published postmarketing clinical experience.

Cefiderocol

Cefiderocol is a novel siderophore cephalosporin that utilizes the bacteria’s active transport system to evade common mechanisms of A baumannii resistance. Cefiderocol therapy was evaluated against GN-complicated urinary tract infections (UTIs) and GN pneumonias in the APEKS-cUTI (NCT02321800) and APEKS-NP (NCT03032380) trials, respectively.^14,15 Although cefiderocol proved to be noninferior to the comparator therapy in both studies, neither patient population included an appreciable amount of patients infected with CRAB to draw conclusions from these studies.^14,15

The CREDIBLE-CR trial (NCT02714595)aimed to resolve this discrepancy, but the results. Unfortunately, only further confounded CRAB treatment.¹⁶ Overall, clinical cure rates between patients randomized to receive cefiderocol or best-available therapy were similar.¹⁶ However, participants randomized to cefiderocol treatment had a significantly higher rate of all-cause mortality, a result driven by the study population infected with CRAB.¹⁶ Of importance, all-cause mortality was not the primary outcome of the study, and the patients with CRAB were older (≥65 years) and more commonly diagnosed with ongoing septic shock and/or requiring treatment in an intensive-care setting compared with the rest of the study population, although these factors were not determined to be causative of the increased mortality findings.16 In addition to concerns for increased mortality, 5 isolates of A baumannii displayed an increase in the minimum inhibitory concentration of cefiderocol during the study, potentially foreshadowing rapid resistance against cefiderocol therapy in practice.¹⁶ Despite cefiderocol’s promise as a new agent with utility against GN pathogens, its role against CRAB remains undetermined.

Sulbactam-Durlobactam

Sulbactam-durlobactam, a combined β-lactam/β-lactamase inhibitor (BL/BLI) agent, is currently being evaluated in a phase 3 trial that corrects some of the obstacles previously faced in determining efficacy against CRAB.¹⁷ Designed to study infections caused by A baumannii-calcoaceticus complex infections, the trial compares sulbactam-durlobactam with imipenem/cilastatin versus colistin with imipenem/cilastatin, thereby evaluating combination regimens that are reflective of actual clinical practice.¹⁷ Although this will provide a better picture of real-world efficacy, this design will lead to difficulty in interpreting the true efficacy of the novel BL/BLI and any potential for monotherapy.

Phage Therapy

Bacteriophages are viruses that can be administered locally or systemically to parasitize specific bacterial species or even individual bacterial strains. The phages are typically administered in “cocktails” designed to target particular pathogens or isolates. To date, phage therapy has generally been utilized as a last-line option in conjunction with antimicrobial therapy to treat multidrug-resistant infections, but antimicrobial resistance threats worldwide are leading to increased focus on and development of this novel therapy.

A baumannii–targeted bacteriophages were first introduced in 2010, but phage therapy presents many unique challenges surrounding controlled-trial evaluation, standardization, and regulatory approval that have delayed widespread use.¹⁸ Ongoing clinical trials will begin to provide information on efficacy as well as optimal route, dosage form, dose, and duration of therapy for phage therapy, but to date, the best data are based on case reports. Two published patient cases detail the use of phage therapy in patients infected with CRAB, both treated with bacteriophages in conjunction with antimicrobials after failure of antimicrobial therapy.^19,20 The addition of phage therapy both locally and systemically resulted in clinical improvement in a 68-year-old man infected with MDR A baumannii from a comatose, intubated state that required vasopressor support to clinical success and subsequent discharge.¹⁹ A second patient received systemic phage therapy for a craniectomy with intraoperative cultures positive for MDR A baumannii. The local site improved, but unfortunately, the patient did not survive.²⁰ Based on case report findings, phage therapy resulted in increased A baumannii sensitivity to antibiotic therapy; however, drug resistance to the individual phages did develop during therapy.^19,20

Final Thoughts

CRAB continues to be a troublesome GN organism due to its ability to develop advanced mechanisms of resistance, resulting in variable activity of available antimicrobial agents, both as monotherapies and in combination regimens. Thus, novel agents such as eravacycline, cefiderocol, and sulbactam-durlobactam are of supreme interest, given their ability to evade commonly characterized resistance mechanisms. Although these agents have potential as treatment options against CRAB, additional agents earlier in the pipeline are being evaluated in clinical and animal studies and hold interest as potential CRAB-mitigating options (Table).

Table.

Nonetheless, it is necessary to confront the lack of clinical data for the aforementioned novel therapies as well as the potential for the emergence of A baumannii resistance, which in turn influences the placement of these antibiotics in CRAB treatment algorithms. Of note, it is not currently recommended that these agents be used as initial monotherapy treatments against CRAB. Further, the inevitable emergence of resistance has been shown by the decreased A baumannii susceptibility of cefiderocol in the presence of ADC-type cephalosporinases and with A baumannii phages, with the requirement of multiple phages to overcome quickly emerging bacteriophage cocktail resistance.^19,21

Factors such as these are an impedance on the use of newer agents, but they also present an avenue for the use of combination therapy—with these novel therapies serving as the backbone. This could ultimately revolutionize CRAB therapy and possibly serve as a sparing mechanism for the older agents used in CRAB treatment. Nevertheless, the present gaps reinforce the necessity for more clinical and in vitrostudies targeted to determine the best approach to mitigating CRAB infections.

Nicole C. Griffith, PharmD, AAHIVP, is an infectious diseases pharmacy fellow at the University of Illinois at Chicago College of Pharmacy. She serves as a clinical instructor at the College of Pharmacy and is currently researching antimicrobial clearance by renal replacement processes and methenamine use in urinary tract infections.

Jacinda C. Abdul-Mutakabbir, PharmD, AAHIVP, is currently an assistant professor at Loma Linda University School of Pharmacy in California. She also serves as the cocourse coordinator for the infectious diseases pharmacotherapy module and evaluates synergistic combinations against A baumannii in her laboratory dedicated to combating antimicrobial resistance.

References

^{1. Tacconelli E, Carrara E, Savoldi A, et al; WHO Pathogens Priority List Working Group. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18(3):318-327. doi:10.1016/S1473-3099(17)30753-3}

^{2. Vrancianu CO, Gheorghe I, Czobor IB, Chifiriuc MC. Antibiotic resistance profiles, molecular mechanisms and innovative treatment strategies of Acinetobacter baumannii. Microorganisms. 2020;8(6):935. doi:10.3390/microorganisms8060935}

^{3. Tian GB, Adams-Haduch JM, Taracila M, Bonomo RA, Wang HN, Doi Y. Extended-spectrum AmpC cephalosporinase in Acinetobacter baumannii: ADC-56 confers resistance to cefepime. Antimicrob Agents Chemother. 2011;55(10):4922-4925. doi:10.1128/AAC.00704-11}

^{4. Krizova L, Poirel L, Nordmann P, Nemec A. TEM-1 β-lactamase as a source of resistance to sulbactam in clinical strains of Acinetobacter baumannii. J Antimicrob Chemother. 2013;68(12):2786-2791. doi:10.1093/jac/dkt275}

^{5. Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother. 2006;58(2):256-265. doi:10.1093/jac/dkl224}

^{6. Yu YS, Zhou H, Yang Q, Chen YG, Li LJ. Widespread occurrence of aminoglycoside resistance due to ArmA methylase in imipenem-resistant Acinetobacter baumannii isolates in China. J Antimicrob Chemother. 2007;60(2):454-455. doi:10.1093/jac/dkm208}

^{7. Kassamali Z, Jain R, Danziger LH. An update on the arsenal for multidrug-resistant Acinetobacter infections: polymyxin antibiotics. Int J Infect Dis. 2015;30:125-132. doi:10.1016/j.ijid.2014.10.014}

^{8. Park GC, Choi JA, Jang SJ, et al. In vitro interactions of antibiotic combinations of colistin, tigecycline, and doripenem against extensively drug-resistant and multidrug-resistant Acinetobacter baumannii. Ann Lab Med. 2016;36(2):124-130. doi:10.3343/alm.2016.36.2.124}

^{9. Paul M, Daikos GL, Durante-Mangoni E, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018;18(4):391-400. doi:10.1016/S1473-3099(18)30099}

^{10. Solomkin JS, Gardovskis J, Lawrence K, et al. IGNITE4: Results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections. Clin Infect Dis. 2019;69(6):921-929. doi:10.1093/cid/ciy1029}

^{11. Solomkin J, Evans D, Slepavicius A, et al. Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intra-abdominal infections in the investigating gram-negative infections treated with eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg. 2017;152(3):224-232. doi:10.1001/jamasurg.2016.4237}

^{12. Efficacy and safety of eravacycline compared with levofloxacin in complicated urinary tract infections. ClinicalTrials.gov. Updated April 10, 2019. Accessed May 3, 2021. https://clinicaltrials.gov/ct2/show/NCT01978938}

^{13. Efficacy and safety of eravacycline compared with ertapenem in participants with complicated urinary tract infections (IGNITE3). ClinicalTrials.gov. Updated October 2, 2019. Accessed May 3, 2021. https://clinicaltrials.gov/ct2/show/NCT03032510}

^{14. 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, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-1328. doi:10.1016/S1473-3099(18)30554-1}

^{15. Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021;21(2):213-225. doi:10.1016/S1473-3099(20)30731-3}

^{16. Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021;21(2):226-240. doi:10.1016/S1473-3099(20)30796-9}

^{17. Study to evaluate the efficacy and safety of intravenous sulbactam-ETX2514 in the treatment of patients with infections caused by Acinetobacter baumannii-calcoaceticus complex (ATTACK). ClinicalTrials.gov. Updated January 18, 2020. Accessed May 3, 2021. https://clinicaltrials.gov/ct2/show/NCT03894046}

^{18. Lin NT, Chiou PY, Chang KC, Chen LK, Lai MJ. Isolation and characterization of phi AB2: a novel bacteriophage of Acinetobacter baumannii. Res Microbiol. 2010;161(4):308-314. doi:10.1016/j.resmic.2010.03.007}

^{19. Schooley RT, Biswas B, Gill JJ, et al. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother. 2017;61(10):e00954-17. doi:10.1128/AAC.00954-17. Published correction appears in Antimicrob Agents Chemother. 2018;62(12):e02221-18.}

^{20. LaVergne S, Hamilton T, Biswas B, Kumaraswamy M, Schooley RT, Wooten D. Phage therapy for a multidrug-resistant Acinetobacter baumannii craniectomy site infection. Open Forum Infect Dis. 2018;5(4):ofy064. doi:10.1093/ofid/ofy064}

^{21. Abdul-Mutakabbir JC, Nguyen L, Maassen P, et al. 1297. In-vitro antibacterial activities of cefiderocol (S-649266) alone and with the addition of beta-lactamase inhibitors against multidrug-resistant Acinetobacter baumannii. Open Forum Infect Dis. 2020;7(suppl 1):S663. doi:10.1093/ofid/ofaa439.1480}