New Developments in Antimicrobial Therapy

Educational Objectives

The goal of this program is to improve management of infections using newer antibiotics. After hearing and assimilating this program, the clinician will be better able to:

1. Choose among various antibiotic options for managing urinary tract infections (UTI).
2. Compare the efficacy of newly approved drugs for bacterial infection.
3. Use appropriate antibiotics to treat patients with complicated UTIs.

Summary

Introduction: Laxminarayan et al (2020) reported that antibiotic development takes ≈10 yr; because of this, it is important to understand not only current but also future needs; Butler et al (2023) reviewed new antibiotics by the year of approval and found a lower number with a novel mechanism of action; however, a new drug from an existing class may also benefit the patient; no new antibiotics were approved in 2020, 2021, 2022, or early 2023; narrow-spectrum antibiotics are important in targeting the most potent pathogens, eg, Pseudomonas, Acinetobacter, and Klebsiella pneumoniae; a pipeline analysis in 2020 reported only 43 agents in clinical trials, only 18 of which had potential activity against the most resistant pathogens

Sulbactam-durlobactam: was approved in 2023 for adults with hospital-associated or ventilator-associated pneumonia, based on a trial by Kaye et al (2023); it was truly a pathogen-specific trial for carbapenem-resistant Acinetobacter, comparing the efficacy of the combination of sulbactam-durlobactam plus imipenem vs combination of polymyxin E (Colistin) plus imipenem for 7 to 14 days; the primary endpoint was 28-day all-cause mortality; the noninferiority trial showed the new agent without polymyxin E had significantly less nephrotoxicity and improved survival

New antibiotics: Melchiorri et al (2025) reported that almost all the antibiotics approved in the past decade were intravenous (IV) administration; the vast majority of new antibiotics were for gram-negative pathogens

Sulopenem: an IV and oral carbapenem, similar to ertapenem; it is active against extended-spectrum β-lactamases (ESBLs), penicillin-resistant Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus, and anaerobes; it is not active against carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas, methicillin-resistant S aureus (MRSA), or Enterococcus; it is approved in oral form only for uncomplicated urinary tract infection (UTI); the oral formulation is combined with probenecid to increase absorption and is given twice daily; the concern with this drug is stewardship, as a prior oral carbapenem (faropenem) saw rapid resistance when it was available over the counter in India

Dunne et al (2023): compared oral sulopenem (standard dose for 5 days) and oral ciprofloxacin (standard dose for 3 days) for uncomplicated UTI; the primary endpoint was success at day 12; sulopenem was superior against ciprofloxacin-resistant pathogens, ie, patients had faster symptomatic improvement with similar time to resolution; guidance from the US Food and Drug Administration (FDA) recommends follow-up urine cultures in uncomplicated UTI because patients taking sulopenem had more asymptomatic bacteriuria; however, the Infectious Diseases Society of America does not make this recommendation because no increased infections were observed; the study reported no difference in relapse or recurrent UTI; however, patients in the sulopenem group reported a higher incidence of diarrhea

Pivmecillinam: approved by the FDA; it is an orally available β lactam, and is a prodrug that binds to penicillin-binding protein 2; has in vitro activity against Enterobacteriaceae, including ESBL; not effective against Pseudomonas, Enterococcus, or S aureus and ineffective for pyelonephritis; it is administered 3 times daily for 3 to 7 days; unusual adverse events include gastrointestinal effects, rash, and the potential for carnitine depletion and acute porphyria; approved for uncomplicated UTI but might be inferior to other agents

Cefepime-enmetazobactam: was recently approved; inhibits class A β lactamases, ESBLs, and AmpC β lactamase; it is ineffective against K pneumoniae carbapenemase, metallo-β-lactamase, oxacillinase (OXA) other than OXA 48, Acinetobacter, MRSA, Enterococcus, and anerobes; 2 g of cefepime is given with 500 mg of enmetazobactam, over 2 hr, every 8 hr; phase 3 studies included patients with complicated UTI; it is the first FDA-approved drug completely developed outside the United States (in India); European Medicines Agency review is pending; approval was based on the ALLIUM trial, in which Kaye et al (2022) compared cefepime-enmetazobactam with piperacillin-tazobactam; therapy was given for 7 days, with the option to extend to 14 days for bloodstream infection; >50% of patients had pyelonephritis and complicated UTI; success at day 14 (the FDA primary endpoint) was seen in 79% of the test-drug group vs 59% in the comparator group, with a confidence interval of 14 to 27.9; the new drug achieved the statistical criteria for both noninferiority and superiority

Drug development in India: 2 more drugs are under development by Bug works; the Global Antibiotic Research and Development Partnership (GARDP) is a public-private partnership with a goal of 5 new antibiotics by 2025; there is a need for new models, eg, public-private partnerships, and different incentives for developing new antibiotics in the United States; new drugs also need to be made accessible to populations around the world

Ceftobiprole: is an advanced-spectrum IV cephalosporin with a spectrum similar to ceftaroline; it is active against gram-positive bacteria, including penicillin-resistant S pneumonia, MRSA, and anaerobes; has some activity against Enterococcus faecalis but not against Enterococcus faecium; it is active against Enterobacteriaceae but not against Pseudomonas or CRE; can be thought of as ceftriaxone with MRSA efficacy; approved for acute bacterial skin and skin-structure infections, community-acquired bacterial pneumonia, and S aureus bloodstream infection and right-sided endocarditis; not approved for ventilator-associated pneumonia because the dosing (500 mg every 8 hr) failed in an earlier trial; the approved dose is 667 mg IV every 8 hr for skin infections and pneumonia; the regimen for bloodstream infection is different

Efficacy for skin infection: TARGET trial (Overcash et al [2021]) — compared ceftobiprole vs combination of vancomycin plus aztreonam; noninferiority was achieved with success in ≈90% in each group; similar results were obtained in the clinically evaluable and post-treatment endpoints; success in this trial was ≥20% reduction in the spread of cellulitis, no surgery after the start of therapy, no rescue antibiotics, and survival; subgroup analysis of early clinical response (FDA indication) showed noninferiority with a possible slight benefit to ceftobiprole

Efficacy for community-acquired pneumonia (CAP): Nicholson et al (2012) — compared the efficacy of 500 mg ceftobiprole vs ceftriaxone with or without linezolid for suspected MRSA and reported noninferiority; patients in the ceftobiprole group reported slightly more treatment-limiting gastrointestinal events (≈5% higher nausea); Awad et al (2014) — compared ceftobiprole vs ceftazidime-linezolid; at the endpoint (clinical cure confirmed at test-of-cure), the results were similar but with lower overall success (60% vs 59%); there was a difference in early improvement (89% vs 78%); a significant difference was reported in the MRSA subgroup

Efficacy for bacteremia: Holland et al (2023) — compared ceftobiprole (500 mg every 6 hr for 8 days, then every 8 hr for the duration of therapy) vs daptomycin (6-10 mg/kg for 28-42 days) for complicated S aureus bacteremia; noninferiority was achieved for overall success

Status of antibiotic development: Butler et al (2022) listed the antibiotics in phase 3 trials; from the list, 3 have subsequently been approved; recently, aztreonam-avibactam was approved for complicated intraabdominal infections with or without pneumonia; this combination has the potential to work against metallo-β-lactamases

Readings

Awad SS, Rodriguez AH, Chuang YC, et al. A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia. Clin Infect Dis. 2014 Jul 1;59(1):51-61. doi: 10.1093/cid/ciu219. Epub 2014 Apr 9. PMID: 24723282; PMCID: PMC4305133; Butler MS, Gigante V, Sati H, et al. Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is Needed. Antimicrob Agents Chemother. 2022;66(3):e0199121. doi:10.1128/AAC.01991-21; Butler MS, Henderson IR, Capon RJ, et al. Antibiotics in the clinical pipeline as of December 2022. J Antibiot (Tokyo). 2023 Aug;76(8):431-473. doi: 10.1038/s41429-023-00629-8. Epub 2023 Jun 8. Erratum in: J Antibiot (Tokyo). 2024 Jan;77(1):71. doi: 10.1038/s41429-023-00671-6. PMID: 37291465; PMCID: PMC10248350; Dunne MW, Aronin SI, Das AF, et al. Sulopenem for the treatment of complicated urinary tract infections including pyelonephritis: a phase 3, randomized trial. Clin Infect Dis. 2023;76(1):78-88. doi:10.1093/cid/ciac704; El Sahly HM. Cefepime/enmetazobactam for complicated urinary tract infection. NEJM Journal Watch. 2022; NA55400. doi: 10.1056/nejm-jw.NA55400; Gandhi RT. Another treatment option for uncomplicated UTIs is approved in the U.S. NEJM Journal Watch. 2024; NA57438. doi: 10.1056/nejm-jw.NA57438; Holland TL, Cosgrove SE, Doernberg SB, et al. Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia. N Engl J Med. 2023;389(15):1390-1401. doi:10.1056/NEJMoa2300220; Kaye KS, Belley A, Barth P, et al. Effect of Cefepime/enmetazobactam vs piperacillin/tazobactam on clinical cure and microbiological eradication in patients with complicated urinary tract infection or acute pyelonephritis: a randomized clinical trial. JAMA. 2022;328(13):1304-1314. doi:10.1001/jama.2022.17034; Kaye KS, Shorr AF, Wunderink RG, et al. Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, noninferiority clinical trial (ATTACK). Lancet Infect Dis. 2023 Sep;23(9):1072-1084. doi: 10.1016/S1473-3099(23)00184-6. Epub 2023 May 11. PMID: 37182534; Laxminarayan R, Van Boeckel T, Frost I, et al. The Lancet Infectious Diseases Commission on antimicrobial resistance: 6 years later. Lancet Infect Dis. 2020 Apr;20(4):e51-e60. doi: 10.1016/S1473-3099(20)30003-7. Epub 2020 Feb 11. Erratum in: Lancet Infect Dis. 2020 Apr;20(4):e50. doi: 10.1016/S1473-3099(20)30146-8. PMID: 32059790; Melchiorri D, Rocke T, Alm RA, et al. Addressing urgent priorities in antibiotic development: insights from WHO 2023 antibacterial clinical pipeline analyses. Lancet Microbe. 2025;6(3):100992. doi:10.1016/j.lanmic.2024.100992; Nicholson SC, Welte T, File TM Jr, et al. A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation. Int J Antimicrob Agents. 2012;39(3):240-246. doi:10.1016/j.ijantimicag.2011.11.005; Overcash JS, Kim C, Keech R, et al. Ceftobiprole Compared With Vancomycin Plus Aztreonam in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Results of a Phase 3, Randomized, Double-blind Trial (TARGET). Clin Infect Dis. 2021;73(7):e1507-e1517. doi:10.1093/cid/ciaa974; Sakoulas G. Ceftobiprole Joins the Beta-Lactam Squad Against MRSA Infections. NEJM Journal Watch. 2024; NA57369. doi: 10.1056/nejm-jw.NA57369.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Boucher was recorded at the 2025 Remington Winter Course in Infectious Diseases, held virtually on February 9-13, 2025, and presented by the Remington Winter Course in Infectious Diseases. For information on future CME activities from this presenter, please visit https://wintercourseinfectiousdiseasefoundation.wildapricot.org/. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

FP732802

Qualifies for:

Infectious Disease, Clinical Pharmacology

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.