The Aminoglyco-Side Hustle: What’s Now and Next in Gram-Negative Infections

Once considered a cornerstone in the management of gram-negative infections, aminoglycosides are now employed less frequently in contemporary therapeutic regimens. This shift in practice is largely attributed to the development of novel agents targeted to specific resistance mechanisms with improved efficacy and safety profiles, alongside rising aminoglycoside minimum inhibitory concentrations (MICs) that hinder the attainment of optimal pharmacokinetic/pharmacodynamic (PK/PD) targets.

In May 2023, the Clinical and Laboratory Standards Institute (CLSI) implemented a comprehensive revision of aminoglycoside breakpoints for Enterobacterales and Pseudomonas aeruginosa (see Table 1). Major updates for P aeruginosa included the removal of gentamicin breakpoints, reduction in tobramycin breakpoints, and adjustment in amikacin breakpoints to apply solely to urinary isolates. For Enterobacterales, gentamicin, tobramycin, and amikacin breakpoints were lowered.^1,2 These major MIC changes were driven by modern PK/PD analyses identifying low probabilities of target attainment for bacterial stasis with high-dose, extended interval aminoglycoside regimens when the prior breakpoints were utilized. Since the revised breakpoints reflect a bacteriostasis endpoint (ie, inhibition of growth rather than 1- or 2-log kill), CLSI advises using aminoglycosides as part of combination therapy rather than monotherapy for systemic infections.^3,4

In light of these changes, clinicians may find the role of aminoglycosides in gram-negative therapy increasingly uncertain. Currently, their most practical application is in the treatment of urinary tract infections (UTI). For patients with cystitis, single-dose aminoglycosides present an advantageous treatment option owing to exceptionally high urinary concentrations (up to 100 times plasma concentrations), favorable microbiologic and clinical cure rates with reassuring safety outcomes in observational studies, shortened duration of antibiotic therapy, decreased hospital stays or avoidance of admission, and utility against multidrug-resistant (MDR) pathogens. This was shown in both a systematic review and two small prospective studies on single-dose aminoglycoside therapy for UTIs, which reported high cure rates and minimal adverse events with this strategy.^5-7 Additional data are needed to evaluate the efficacy and safety of aminoglycoside monotherapy in complicated UTI (including pyelonephritis) and patients with pre-existing renal dysfunction.

The 2024 IDSA gram-negative resistance guidance recommends aminoglycoside therapy as an alternative treatment option for uncomplicated cystitis (single-dose therapy) or complicated UTI including pyelonephritis (durations beyond a single dose) caused by extended-spectrum β-lactamase (ESBL)- or AmpC β-lactamase-producing Enterobacterales, carbapenem-resistant Enterobacterales, and difficult-to-treat resistant P aeruginosa.⁸ In addition, the recently released IDSA guidelines on complicated urinary tract infections list aminoglycosides as an alternative option in patients with or without sepsis and complicated UTI.⁹

For infections outside of the urinary tract in patients with specific factors such as high mortality risk, severe infection, or concerns for MDR organisms, effective empiric antimicrobial therapy is of the utmost importance. In addition to a beta-lactam backbone, aminoglycosides can serve as a secondary agent for empiric antimicrobial coverage of resistant pathogens. Data are mixed on the use of aminoglycosides as a component of combination therapy in sepsis, septic shock, or gram-negative bloodstream infections.^10-15 In these situations, the use of aminoglycosides relies primarily on clinical judgment, with careful consideration of patient-specific factors and a thorough assessment of risks and benefits.

In the face of limited therapeutic options, some clinicians hesitate to use aminoglycosides due to well-described class-associated toxicities. However, newer data suggest potential amelioration of aminoglycoside-induced nephrotoxicity. In a pilot study conducted in an animal acute kidney injury model using the leukotriene inhibitor, zileuton, rats treated with the combination of amikacin plus zileuton experienced less toxicity (30% nephrotoxicity) compared to amikacin alone (90% nephrotoxicity).¹⁶

Zileuton is a 5-lipoxygenase inhibitor thathas anti-inflammatory effects due to its ability to inhibit leukotriene synthesis. Zileuton is also believed to increase the expression of cytoprotective and antioxidant genes.¹⁷ Additional animal studies have been conducted with other nephrotoxic antibiotics such as polymyxin B and vancomycin with promising results.¹⁸ While human data are lacking with this combination, this study posits an interesting approach to traditional aminoglycoside-associated toxicity. Perhaps aminoglycoside use can be salvaged, but for more than just salvage therapy alone.

Reduction in nephrotoxicity may not be sufficient to increase clinician confidence with aminoglycoside use. Therefore, exploration of different aminoglycosides should be considered. Apramycin is an aminoglycoside that has been used in veterinary medicine for approximately 40 years. Recently, apramycin has garnered attention for potential use for the treatment of MDR infections in humans. Its unique structure has shown less affinity for inducing ribosomal-mediated nephrotoxicity.¹⁹ In another study, apramycin has potentially less ototoxicity and is a reasonable agent upon which to create synthetic derivatives.²⁰ Two phase 1 clinical trials have been completed, with published data anticipated.^21,22

Although their past has been complicated with toxicity concerns and mixed clinical benefit outside of the urinary tract, the aminoglycosides still may play a role in the era of infections caused by increasingly MDR pathogens. If agents can be co-administered to reduce aminoglycoside nephrotoxicity, or older agents repurposed or modified, their clinical utility may continue well into the future.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

References:

1. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 32nd ed. CLSI supplement M100. Clinical and Laboratory Standards Institute; 2022.

2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 33rd ed. CLSI supplement M100. Clinical and Laboratory Standards Institute; 2023.

3. Humphries RM. AST News Update June 2023: New! CLSI M100-Ed33: Updated aminoglycoside breakpoints for Enterobacterales and Pseudomonas aeruginosa. Clinical and Laboratory Standards Institute website. https://clsi.org/about/news/ast-news-update-june-2023-new-clsi-m100-ed33-updated-aminoglycoside-breakpoints-for-enterobacterales-and-pseudomonas-aeruginosa/. Published June 2023. Accessed July 23, 2025.

4. CLSI. Aminoglycoside Breakpoints for Enterobacterales and Pseudomonas aeruginosa. 1st ed. CLSI rationale document MR16. Clinical and Laboratory Standards Institute; 2025.

5. Goodlet KJ, Benhalima FZ, Nailor MD. A systematic review of single-dose aminoglycoside therapy for urinary tract infection: is it time to resurrect an old strategy? Antimicrob Agents Chemother. 2018;63(1):e02165-18. doi: 10.1128/AAC.02165-18

6. Jenrette JE, Coronato K, Miller MA, Molina KC, Quinones A, Jacknin G. Prospective evaluation of single-dose aminoglycosides for treatment of complicated cystitis in the emergency department. Acad Emerg Med. 2024;31(7):649-655. doi: 10.1111/acem.14886

7. Peyko V, Sieger J, Dombroski J. Single-dose gentamicin vs standard care for treatment of acute uncomplicated cystitis in premenopausal women: a randomized trial. J Pharm Pract. 2025;8971900251322368. doi: 10.1177/08971900251322368.

8. Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA. Infectious Diseases Society of America 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections. Clin Infect Dis. 2024;:ciae403. doi: 10.1093/cid/ciae403

9. Trautner BW, Cortes-Penfield NW, Gupta K, et al. Complicated urinary tract infections (cUTI): clinical guidelines for treatment and management. Infectious Diseases Society of America. Published July 17, 2025. Accessed July 23, 2025. https://www.idsociety.org/practice-guideline/complicated-urinary-tract-infections

10. Martínez JA, Cobos-Trigueros N, Soriano A, et al. Influence of empiric therapy with a beta-lactam alone or combined with an aminoglycoside on prognosis of bacteremia due to gram-negative microorganisms. Antimicrob Agents Chemother. 2010;54(9):3590-3596. doi: 10.1128/AAC.00115-10

11. Guillamet MCV, Damulira C, Atkinson A, Fraser VJ, Micek S, Kollef MH. Addition of aminoglycosides reduces recurrence of infections with multidrug-resistant Gram-negative bacilli in patients with sepsis and septic shock. Int J Antimicrob Agents. 2023;62(4):106913. doi: 10.1016/j.ijantimicag.2023.106913

12. Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2014;2014(1):CD003344. doi: 10.1002/14651858.CD003344.pub3

13. Heffernan AJ, Sime FB, Sun J, et al. β-lactam antibiotic versus combined β-lactam antibiotics and single daily dosing regimens of aminoglycosides for treating serious infections: A meta-analysis. Int J Antimicrob Agents. 2020;55(3):105839. doi: 10.1016/j.ijantimicag.2019.10.020

14. Timotëus Deelen JW, Rottier WC, Buiting AGM, et al. Short-course aminoglycosides as adjunctive empirical therapy in patients with Gram-negative bloodstream infection, a cohort study. Clin Microbiol Infect. 2021;27(2):269-275. doi: 10.1016/j.cmi.2020.04.041

15. Cerenzio J, Andrade J, DeAngelis J, Truong J. The effect of a single-dose aminoglycoside with a beta-lactam for the treatment of gram-negative bacteremia. J Pharm Pract. 2025;38(1):141-148. doi: 10.1177/08971900241273212

16. Hudson CS, Smith JE, Vuong LT, et al. Drug development studies supporting zileuton as a parenteral adjuvant to attenuate antibiotic-associated nephrotoxicity. Antimicrob Agents Chemother. Published online July 8, 2025. doi:10.1128/aac.00287-25

17. Wu Q-Q, Deng W, Xiao Y, et al.The 5-lipoxygenase inhibitor zileuton protects pressure overload-induced cardiac remodeling via activating PPARα. Oxid Med Cell Longevity 2019; 2019: 7536803. https://doi.org/10. 1155/2019/3832648

18. Hudson CS, Smith JE, Eales BM, et al. Zileuton ameliorates aminoglycoside and polymyxin-associated acute kidney injury in an animal model. J Antimicrob Chemother. 2023;78(10):2435-2441. doi:10.1093/jac/dkad246

19. Matt T, Ng CL, Lang K, et al. Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin. Proc Natl Acad Sci U S A. 2012;109(27):10984-10989. doi:10.1073/pnas.1204073109

20. Ishikawa M, García-Mateo N, Čusak A, et al. Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use. Sci Rep. 2019;9(1):2410. Published 2019 Feb 20. doi:10.1038/s41598-019-38634-3

21. A phase I, open-label study to assess lung pharmacokinetics and safety of a single dose of apramycin administered intravenously in healthy adult subjects.ClinicalTrials.gov identifier: NCT05590728. Updated March 6, 2025. Accessed July 25, 2025. https://www.clinicaltrials.gov/study/NCT05590728?intr=apramycin&rank=1

22. A phase I, randomized, double-blind, placebo-controlled, single ascending dose study to assess the safety, tolerability, and pharmacokinetics of apramycin administered intravenously in healthy adults. ClinicalTrials.gov identifier: NCT04105205. Updated February 23, 2021. Accessed July 25, 2025. https://www.clinicaltrials.gov/study/NCT04105205?intr=apramycin&rank=2