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Abstract

Background:

Complicated urinary tract infections (cUTIs) cause significant morbidity and mortality. Multidrug-resistant (MDR) organisms complicate cUTI management, highlighting the need for effective antimicrobials.

Objective:

This scoping review was conducted to assess the role of plazomicin in managing cUTIs.

Eligibility criteria:

This review included observational studies, clinical trials, qualitative studies, and in vitro studies published between 01 January 2018 and 15 July 2025.

Source of evidence:

Searches were conducted on PubMed, MEDLINE, EMBASE, and Google Scholar.

Method:

The screening process involved reviewing titles and abstracts, followed by full-text evaluation.

Results:

Thirty studies were included in this review. Compared with meropenem, plazomicin demonstrated superior microbiological eradication at the test of cure (TOC; 89.5%), composite cure rate at the TOC (81.7%), and comparable clinical cure rates both at the TOC (89%) and end of intravenous therapy (96.3%). Adverse events, observed in 19.5% of patients, primarily included diarrhea, nausea, and renal dysfunction, indicating a favorable safety profile. In vitro data showed susceptibility rates for plazomicin ranging from 87% to 99.8% against Enterobacteriaceae, with superior activity over gentamicin, amikacin, and tobramycin. Plazomicin demonstrated synergistic effects with colistin, meropenem, and fosfomycin against extensively drug-resistant isolates and carbapenem-resistant Enterobacteriaceae.

Conclusion:

This review underscores plazomicin as a promising treatment for MDR cUTIs. However, limited data from low- and middle-income countries like India highlight the need for real-world studies on its efficacy, safety, and cost-effectiveness in such countries.

Plain language summary

Plazomicin in MDR cUTI in India

Plazomicin is a promising treatment for MDR cUTIs because of its superior microbiological eradication and comparable clinical cure rates compared with those of meropenem. Plazomicin has a favorable safety profile and high susceptibility against Enterobacteriaceae. Its synergistic effects with colistin, meropenem, and fosfomycin enhance its effectiveness against MDR and CRE isolates.

Keywords

acute pyelonephritis antimicrobial resistance MDR plazomicin urinary tract infections

Introduction

Urinary tract infections (UTIs) are among the most prevalent bacterial infections globally. In 2019, they accounted for more than 404 million clinical cases, which resulted in 236,790 deaths and 520,200 disability-adjusted life years.¹ In India, the prevalence of UTI reported in 2022 was 10.1 %, with more women (72.5 %) affected than men (27.5 %).² A complicated UTI (cUTI) refers to a UTI that occurs when there are structural or functional abnormalities in the genitourinary tract or when risk factors such as pregnancy; urinary tract carcinoma; a neurogenic bladder; renal, ureteral, or bladder calculi; catheterization; spinal cord injury; or renal failure/transplantation are present.^3,4 Individuals with cUTI may experience a relapse.⁵ cUTIs may progress to urosepsis, particularly in the presence of structural abnormalities in the genitourinary tract, where impaired urinary drainage facilitates bacterial overgrowth and hematogenous spread of pathogens.^6,7 These infections can result in significant complications, such as septic shock, renal failure, or even death.³

In India, the prevalence of Gram-negative bacteria causing UTIs is 59.3%.⁸ Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) are the two most common causative organisms.⁹ Other microorganisms causing UTIs are Enterococcus spp. (18.8%), Escherichia spp. (19.6%), Klebsiella spp. (16.3%), Pseudomonas spp. (11.1%), Proteus spp. (1.7%), and Enterobacter spp. (0.7%).^2,4,8,10 Gram-positive bacteria account for 19.3% and Candida spp. account for 23.2% of UTI cases.^7,11 In cUTIs, the most commonly isolated pathogen is uropathogenic E. coli (65%), followed by Enterococcus spp. (11%), K. pneumoniae (8%), Candida spp. (7%), Staphylococcus aureus (S. aureus) (3%), Proteus mirabilis (2%), Pseudomonas aeruginosa (2%), and group B Streptococcus (2%).¹²

Patients with cUTI symptoms are typically initiated on broad-spectrum empiric antibiotics and transitioned to targeted antibiotics after urine culture reports.¹³ The Indian Council of Medical Research (ICMR) recommends ertapenem, imipenem, meropenem, amikacin, nitrofurantoin, fosfomycin, co-trimoxazole, ceftriaxone, trimethoprim–sulfamethoxazole, ofloxacin, and levofloxacin for treating cUTIs due to the emergence of multidrug-resistant (MDR) organisms.¹⁴ According to the antimicrobial resistance surveillance network (AMRSN)-ICMR report 2023, K. pneumoniae showed varied susceptibility to various antimicrobial drugs such as colistin (92.3%), gentamicin (22.9%), meropenem (19.7%), amikacin (23.1%), and levofloxacin (8.2%).⁷ E. coli had higher susceptibility to colistin (93.5%), gentamicin (51.9%), meropenem (44.5%), and amikacin (56.9%) but lower susceptibility to levofloxacin (5.6%).⁷ In India, carbapenem-resistant Enterobacteriaceae (CRE) infection resistance rates are between 18% and 31%.^15,16 UTIs are caused by CRE limit treatment options, raising the risk of treatment failure and complications. Apart from carbapenemases, the spread of newly identified E. coli lineages containing penicillin-binding protein 3 (PBP3), which diminishes susceptibility to PBP3-targeted β-lactams such as ceftazidime–avibactam, also presents a concern regarding antimicrobial resistance (AMR).¹⁷ Furthermore, in India, the prevalence of AMR in UTIs is compounded by the emergence of the New Delhi metallo beta lactamase-1 (NDM) strain.¹⁸

According to the AMRSN-ICMR 2023 report, a 14-day fatal outcome was reported in 20.7% of UTI cases, often influenced by primary illness or other underlying comorbidities.⁸ The increase in AMR and prevalence of specific resistance genes in E. coli affects the clinical management of cUTIs. Epidemiological data highlight the widespread challenge of AMR in cUTIs in India.¹⁸ The availability of appropriate antibiotics is limited due to widespread resistance. Aminoglycosides have shown activity against MDR pathogens; however, in 2023, the Clinical and Laboratory Standards Institute (CLSI) changed the susceptibility/resistance breakpoints for amikacin in Enterobacterales from ⩽16/⩾64 mg/L to ⩽4/⩾16 mg/L and for gentamicin and tobramycin from ⩽4/⩾16 mg/L to ⩽2/⩾8 mg/L, auguring decreased susceptibility rates of aminoglycosides.¹⁹ These long-established breakpoints may underestimate the required antibiotic dosages, potentially leading to insufficient treatment of bacterial infections and increasing AMR.²⁰ Colistin, a last-resort antibiotic, has limited utility due to rising resistance, neurotoxicity, and nephrotoxicity, highlighting the urgent need for newer antibiotics effective against MDR, CRE, and colistin-resistant cUTI pathogens.^21–24

Plazomicin, a next-generation semisynthetic aminoglycoside, offers a promising solution to the challenging landscape of increasing AMR. Its structure was established by appending hydroxylaminobutyric acid to DB12604 at position 1 and a 2-hydroxyethyl group at position 6′. This design overcomes all important aminoglycoside-modifying enzymes (AMEs), which play a critical role in providing resistance to aminoglycoside therapy.²⁵ Following phases II and III trials, plazomicin was approved by the United States (US) Food and Drug Administration in 2018 for treating cUTIs and acute pyelonephritis (AP) in patients aged 18 years and older.^26,27 India, via the Central Drugs Standard Control Organization (CDSCO), is the second country to approve plazomicin.²⁸ The usual administration involves a dosage of 15 mg/kg once daily for a duration of 4–7 days, with potential adjustments based on renal function changes.²⁶ Plazomicin exhibits in vitro activity against MDR organisms, including CRE and extensively drug-resistant (XDR) isolates.^27,29 It is also effective against Enterobacterales that are resistant to classical aminoglycosides as well as colistin-resistant, extended-spectrum beta-lactamase (ESBL)-producing, and NDM-producing strains.^26,30,31 The CLSI 2023 established a susceptibility breakpoint of ⩽2 mg/L, an intermediate breakpoint of 4 mg/L, and a resistant breakpoint of ⩾8 mg/L for plazomicin.¹⁹ Plazomicin was classified in the reserve category in the AWaRe classification by the World Health Organization.³²

Objective of the scoping review

The objective of this scoping review was to provide a comprehensive overview on the role of plazomicin in the treatment of drug-resistant cUTIs, including pyelonephritis.

Methods

This scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) and JBI Manual for Evidence Synthesis.^33,34 The quality assessment of the included studies was conducted using the JBI quality assessment checklist for randomized controlled trials and Checklist for Reporting In-vitro Studies guidelines for in vitro studies.^35,36

Eligibility criteria

Inclusion criteria

All observational studies (cross-sectional and retrospective studies), clinical trials, qualitative studies, in vitro studies, and conference abstracts that reported outcomes of plazomicin in adult patients with UTIs and cUTIs published in English language between January 01, 2018 and July 15, 2025 were included.

Exclusion criteria

Letters to editors, commentaries, case reports, case series, and review articles were excluded.

Search strategy

A pilot search was initially conducted on PubMed, using relevant keywords. This refined strategy adhered to the Canadian Agency for Drugs and Technologies Press peer-reviewed guidelines. The search was executed across multiple databases, including PubMed, MEDLINE (Ovid), EMBASE, and Google Scholar. Additionally, a citation search was performed. The detailed search strategy is provided in Table S1.

Screening of articles

The studies retrieved from various databases were imported into the Nested Knowledge^® AutoLit living review platform (Nested Knowledge (NK software), St. Paul, MN, USA) for the screening process.³⁷ Title and abstract screening, followed by full-text review, was conducted by author R.M. Articles marked as “uncertain” were reviewed by author V.G., who also examined a random 10% sample of the excluded records to ensure the accuracy of the screening process.

Data extraction/charting

The data from the included articles were exported into an MS Excel sheet in the NK software. Two independent reviewers performed data extraction (Tables 1 and 2).

Table 1.

Summary of characteristics and quality appraisal of the clinical trial studies.

Study ID	Country	Study year	No. patients with UTI/cUTI	Age in years (mean)/sex distribution	No. patients who received PLZ	Dosage and administration of PLZ	Name of the comparator, dosage, and administration	No. patients who received the comparator	Key findings	Overall appraisal
Cloutier 2017³⁹	USA	2016	226	66.0	107	IV PLZ (15 mg/kg 24 h); 4–7 days	IV MRP (1 g/h) for 4–7 days	119	PLZ demonstrated comparable superior activity and safety profile in comparison with MRP in the treatment of cUTI and AP.	High quality
Connolly 2018⁴²	USA, India, Colombia, and Chile	2010–2012	145	39.5 Female: 77 Male: 15	98	IV PLZ (10 or 15 mg/kg of body weight); 5 days	IV LV (750 mg) once daily for 5 days	29	PLZ is an effective treatment for cUTI/AP with high eradication rates.	High quality
Keepers 2018 (EPIC study)⁴⁰	USA	2016	407	NR	202	IV PLZ (15 mg/kg q24h); 4–7 days	MRP IV (1 g/kg q8h)	205	PLZ showed high efficacy against Enterobacteriaceae, including in cases with concurrent bacteremia.	High quality
McKinnell 2019 (CARE trial)⁴¹	Multicenter (North America and Europe)	2014–2016	37	66.7	17	IV PLZ (15 mg/kg q24h); 7–14 days	COL IV (5 mg/kg once daily); 7–14 days	20	PLZ outperformed COL in efficacy and safety, with a lower incidence of SAEs.	High quality
Wagenlehner 2019³⁸	USA	2016	609	59.4 Female: 205 Male: 183	191	IV PLZ at a dosage of 15 mg/kg once daily; 4–7 days	MRP IV at 1 g every 8 h; 4–7 days of LV IV at 500 mg once daily	197	PLZ showed greater efficacy against ESBL-producing strains and a favorable safety profile.	High quality
Daikos 2016⁴³	Greece	NR	10	74	10	Doses chosen as per weight, with adjustment by renal function or use of continuous renal replacement therapy for 4–14 days	NA	NA	Initial results indicate that therapeutic drug monitoring helps address pharmacokinetic variability in critically ill individuals. In this group of patients with CRE, plazomicin use under TDM guidance did not result in notable kidney injury.

AK, Amikacin; AME, Aminoglycoside-modifying enzyme; AMX, Amoxicillin; AP, Acute pyelonephritis; AST, Antimicrobial susceptibility testing; AZT, Aztreonam; CARE, Combating Antibiotic-resistant Enterobacterales; CAUTI, Community-acquired urinary tract infection; CIP, Ciprofloxacin; CLSI, Clinical Laboratory Standards Institute; COL, Colistin; CPE, Carbapenemase-producing Enterobacteriaceae; CRE, Carbapenem-resistant Enterobacteriaceae; CTRX, Ceftriaxone; CTZ, Ceftazidime; cUTI, Complicated urinary tract infection; DOR, Doripenem; ENT, Enterobacteriaceae; EPIC, Evaluating Plazomicin in cUTI; ESBL, Extended-spectrum beta-lactamase; EUCAST, The European Committee on Antimicrobial Susceptibility Testing; FM, Fosfomycin; GN, Gentamicin; IMP, Imipenem; IV, Intravenous; KN, Kanamycin; KPC, Klebsiella pneumoniae carbapenemase; KPN, KPC-producing Klebsiella pneumoniae; LV, Levofloxacin; MCR, Mobilized colistin resistance; MDR, Multidrug-resistant; MIC, Minimal inhibitory concentration; MRP, Meropenem; MRSA, Methicillin-resistant Staphylococcus aureus; NA, Not available; NDM, New Delhi metallo-β-lactamase; NR, Not reported; PLZ, Plazomicin; PTZ, Piperacillin–tazobactam; q8h, every 8 h; q24, every 24 h; SAE, Serious adverse events; SMX/TMP, Sulfamethoxazole–trimethoprim; TG, Tigecycline; TOB, Tobramycin; USA, United States of America; USCAST, United States Committee on Antimicrobial Susceptibility Testing; USFDA, United States Food and Drug Administration; UTI, Urinary tract infection; VIM-MBL, Verona integron-encoded metallo-β-lactamase; XDR, Extensively drug-resistant.

Table 2.

Summary of characteristics and quality appraisal of the included in vitro studies.

Study ID	Country	Study year	Total sample size/isolates	Outcomes of interest	Comparator	AST method	Breakpoints	Resistance	Key findings	Overall appraisal
Castanheira 2020⁵⁰	USA	2016	8783	Activity and susceptibility of PLZ and the comparator	AK, GN, and TOB	Broth microdilution method	USCAST:PLZ: ⩽4 µg/mLAK: ⩽4 µg/mLGN: ⩽2 µg/mLTOB: ⩽2 µg/mLUSFDA:PLZ: ⩽2 µg/mLAK: ⩽16 µg/mLGN: ⩽4 µg/mLTOB: ⩽4 µg/mL	Of the 264 isolates resistant to plazomicin, 227 had MIC values of 4 mg/L and were classified as intermediate. Among these intermediate isolates, 184 were identified as Proteus mirabilis (MIC₅₀/₉₀, 2/4 mg/L), while 25 additional isolates comprised Proteus (MIC₅₀/₉₀, 1/4 mg/L), Providencia (MIC₅₀/₉₀, 2/8 mg/L), and Morganella (MIC₅₀/₉₀, 1/4 mg/L) species.	PLZ has significantly greater activity than GN and TOB against CRE, MDR, and XDR isolates, which have limited effective therapeutic options.	Medium quality
Tenover 2011⁴⁷	USA	2009–2010	493	Activity of PLZ against gram-negative organisms and S. aureus including MRSA	AK, GN, TOB, linezolid, TG, vancomycin, daptomycin, ceftobiprole, CIP, clindamycin, erythromycin, LV, moxifloxacin, mupirocin, nitrofurantoin, oxacillin, tetracycline, SMX/TMP	Broth microdilution method	NA	PLZ: 0%AK: 4.1%CIP: 82.8%clindamycin (not induced): 45.2% clindamycin (after induction): 60%, daptomycin: 0.6%, erythromycin: 88.8% GN: 3.4%LV: 79.5%, moxifloxacin: 64.5% mupirocin: 4.1% nitrofurantoin: 0.2% oxacillin: 100% tetracycline: 4.5% TOB: 48.3%SMX/TMP: 5.7%	PLZ was more active than TOB and AK and showed similar activity to GN in this recent collection of nasal and blood isolates of MRSA from USA hospitals. PLZ has the potential to be useful for treating staphylococcal infections, particularly in countries or regions where the aph(2'')-Ia/aac(6')-Ie resistance determinant is widely disseminated among S. aureus isolates.	Medium quality
Castanheira 2017⁵¹	USA	2016	2295	Activity of PLZ and aminoglycoside against ENT collected in USA hospitals during 2016	GN, AK, and TOB	Broth microdilution method	NR	NA	PLZ displayed activity against isolates carrying AME genes that represent 12% of selected species. AK, GN, and TOB, highlighting the importance of PLZ to treat infections caused by these organisms.	NA
Castanheira 2018⁵⁵	USA	2014–2017	8510	Activity of PLZ against ENT isolates	AK, GN, and TOB	Broth microdilution method	CLSI breakpoints	NR	The activity of PLZ and AK was similar against ENT isolates from USA hospitals and did not vary by infection type; however, AK activity against CRE isolates varied by infection source, while PLZ remained active against CRE isolates regardless of the infection source.	NA
Landman 2010⁵²	USA	2009	4205	Activity of PLZ against contemporaryclinical isolates of E. coli and K. pneumoniae	AK, GN, and TOB	Agar dilution method and broth microdilution method	NA	E. coli:GN: 12.9%,TOB: 6.9%,AK: 0.5%K. pneumoniae:AK: 4.5%GN: 25.7%TOB: 46.0%	Based on our in vitro results, PLZ is a potentially useful therapeuticagent against MDR E. coli and K. pneumoniae, including KPC-producing strains.	Medium quality
Landman 2011⁴⁶	USA	2009	1086	Activityof ACHN-490 against A. baumannii and P. aeruginosa from a contemporary collection of clinical isolates	AK, GN, and TOB	Broth or agar dilution method	NA	A. baumannii (407):GN: 66%TOB: 56%AK: 37%P. aeruginosa (679):GN: 17%TOB: 14%AK: 3%	For A. baumannii, the MICs of PLZ were lower than those of traditional aminoglycosides. For P. aeruginosa, the activity of PLZ was similar to that of AK.	Medium quality
Martins 2017⁴⁵	Brazil	2013–2015	4000	To evaluate the activity of PLZ against CPE from different Brazilian hospitals	TG, COL, GN, AK, and MRP	CLSI broth microdilution method	USFDA, CLSI, and EUCAST	Based on EUCAST MRP: 97%COL: 33%TG: 24%GN: 81%AK: 51%	PLZ is a promising drug in antimicrobial therapy for MDR CPE, including NDM-1 producers.	Medium quality
Pragasam 2020³¹	India	2016–2020	383	To predict the efficacy of PLZ in India based on the antimicrobial resistance profile derived from whole-genome sequencing	NR	Kirby–Bauer disk diffusion method	NR	NR	NR	Medium quality
Sader 2020⁴⁴	USA, Europe, Asia-Pacific, Latin America	2018–2019	9303	To assess the susceptibility rates of PLZ, AK, GN, and TOB	AK, GN, and TOB	Broth microdilution method	CLSI, EUCAST, USCAST, and USFDA	NR	PLZ retained potent activity against ENT, including resistant subsets.	NA
Sader 2021⁴⁸	USA	2016–2020	10,008	Susceptibility rate	AK, GN, and TOB	Broth microdilution method	CLSI, EUCAST, USCAST, and USFDA	NR	PLZ demonstrated potent activity against a large collection of temporary ENT isolates from USA hospitals, with 4-fold lower MIC values than those of AK.	NA
Sader 2023¹⁹	USA	2017–2021	9809	Susceptibility rate	AK, GN, and TOB	Broth microdilution method	CLSI 2022 and 2023 and USFDA 2022	NR	PLZ outperformed traditional aminoglycosides (AK, GN, and TOB) against challenging isolates. According to the 2023 CLSI and 2022 USFDA breakpoints, PLZ showed superior activity:CREs: 94.0%ESBL producers: 98.9%AME producers: 97.3%MDR isolates: 94.8%XDR isolates: 94.0%	Medium quality
Castanheira 2022⁵⁸	Multinational (Italy, Brazil, and USA)	2016–2019	339	Susceptibility rate	AK, GN, TOB, beta-lactam agents, LV, and TG	Broth microdilution method	USFDA	NR	PLZ showed greater activity against KPC-producing K. pneumoniae, suggesting that it is a suitable treatment for MDR KPN infections.	NA
Abd-Elmonsef 2021⁵⁹	Egypt	2019–2020	127	Susceptibility rate	AK, GN, MRP, IMP, PTZ, SMX/TMP, and AMX	Disc diffusion method and MIC test strip	PLZ:Susceptible: ⩽2 g/mLIntermediate: 4 g/mLResistant: ⩾8 g/mL	NR	PLZ may be promising for CAUTI caused by quinolone-resistant pathogens, showing equivalent activity against AME-carrying and non-AME–carrying isolates.	Medium quality
Castanheira 2019³⁰	USA	2014–2015	3675	Susceptibility rate	AK, GN, MRP, IMP, PTZ, SMX/TMP, and AMX	Broth microdilution method	PLZ:Susceptible: ⩽2 g/mLIntermediate: 4 g/mLResistant: ⩾8 g/mLCLSI 2018b, EUCAST, and USFDA	NR	PLZ was more effective than other aminoglycosides against AME gene-carrying isolates.	NA
Thwaites 2018⁵⁶	USA	NR	30	Susceptibility rate	PTZ, CTZ, MRP, LV, TG, and COL	Broth microdilution method	NA	NR	PLZ showed potent activity against aminoglycoside-resistant organisms in synergy with β-lactam agents.	Medium quality
Walkty 2018⁶²	Canada	2013–2017	12,193	Evaluate the in vitro activities of PLZ and comparator antimicrobial agents	AK, GN, and TOB	Broth microdilution method	NA	E. coli:PLZ: 0.1%AK: 0.1%GN: 8.8%TOB: 5.5%,K. pneumoniae:PLZ: 0.1%AK: 0.1%GN: 4.2%TOB: 2.9%E. cloacae:PLZ: 0%AK: 0%GN: 2.1%TOB: 2.3%K. oxytoca:PLZ: 0%AK: 0%GN: 1.1%TOB: 0.4%	PLZ demonstrated excellent in vitro activity against Enterobacteriaceae, including MDR isolates.	Medium quality
Zhang 2017⁵⁴	USA	2010–2013	110	Evaluate the in vitro activities of PLZ and comparator antimicrobial agents	AK, GN, TOB, MRN, IMP, and KN	Microbroth dilution	Susceptible breakpoints according to CLSI	NR	CRE isolates generally responded to PLZ with lower MICs than that of other antibiotics.	Medium quality
Galani 2019⁶¹	Greece	2014–2016	300	In vitro activities of PLZ and comparator aminoglycosides	AK, GN, and TOB	CLSI broth microdilution method	PLZ:USFDA breakpoints (Susceptible; ⩽2 mg/L, Resistance; ⩾8 mg/L)	TOB: 89% (EUCAST) and 83.3% (CLSI)Netilmicin: 87.3% (EUCAST), 84.3% (CLSI)80 (26.7%) isolates resistant to AK, TOB, GN, netilmicin (EUCAST)43 (14.3%) isolates resistant to AK, TOB, GN, and netilmicin (CLSI)	PLZ was more potent than comparators against CRE K. pneumoniae isolates from Greece.	High quality
Rodríguez-Avial 2015⁶⁴	Spain	2010–2012	164	Activity against CPE strains	COL, AK, GN, TOB, TG, and FM	Agar dilution method	EUCAST susceptibility breakpoints	AK: 4.3%GN: 45.7%TOB: 64%FM: 29.3%TG: 22.6%COL: 25.6%	PLZ demonstrated potent in vitro activity against CPE strains.	High quality
Tendon 2017⁵⁷	Multinational (Angola, Colombia, France, Portugal, South Africa, Spain, Switzerland, and Turkey)	NR	95	Activity of PLZ and comparators against COL-resistant clinical Enterobacterial isolates with resistance conferred by a wide variety of genetic mechanisms	COL, AK, GN, TOB, IMP, DOR, MRP, TG, LV, CTZ, CTRX, AZT, PTZ, and SMX	Broth microdilution method	NR	Intrinsic resistance:PLZ: 0 mg/LCOL: 8 mg/LAK: 0 mg/LGN: 1 mg/LTOB: 1 mg/LIMP: 6 mg/LDOR: 0 mg/LMRP: 0 mg/L	PLZ remained effective against COL-resistant Enterobacteriaceae, with no impact from MCR-1/MCR-2 resistance traits.	High quality
Jacobs 2020⁵³	USA	2012–2016	697	In vitro activities of PLZ and comparators evaluated against a CRACKLE collection of KPC clinical isolates	GN, TOB, AK, CTRX, CTZ, AZT, IMP, MRP, DOR, PTZ, LV, SMX, COL, and TG	Broth microdilution method	USFDA and CLSI breakpoints	NR	PLZ showed in vitro activity against KPC isolates, with a good susceptibility rate for 97.6% of isolates.	Medium quality
Galani 2012⁶⁰	Greece	2008–2010	300	In vitro activity of PLZ against a collection of 300 MDR clinical isolates of K. pneumoniae, E. coli, and Enterobacter spp.	COL, AK, GN, TOB, IMP, DOR, MRP, TG, LV, CTZ, CTRX, AZT, PTZ, and SMX	NA	AK (⩽8 µg/mL, >16 µg/mL)GN (⩽2 µg/mL, >4 µg/mL)TOB (⩽2 µg/mL, >4 µg/mL)IMP (⩽2 µg/mL, >8 µg/mL)MRP (⩽2 µg/mL, >8 µg/mL)PTZ (⩽8 µg/mL, >16 µg/mL)COL (⩽2 µg/mL, >2 µg/mL)FM /G6P (⩽32 µg/mL, >32 µg/mL) CIP (⩽0.5 µg/mL, >1 µg/mL)TG (⩽1 µg/mL, >2 µg/mL)	NR	PLZ retained activity against MDR isolates, including those with ESBL, KPC, and VIM-MBL resistance mechanisms.	High quality
Walkty 2014⁶³	Canada	2011–2012	5015	In vitro activities of PLZ and comparator antimicrobials against commonly encountered gram-negative bacilli	AK, GN, TOB, and TG	Broth microdilution method CLSI	AK, GN, and TOB: CLSI breakpointsTG: USFDA breakpoint	E. coli:AK: 0.0%GN: 10.5%TOB: 4.8%K. pneumoniae:AK: 0.3%GN: 1.8%TOB: 1.0%,E. cloacae:AK: 0.0%GN: 4.6%TOB: 1.7%,K. oxytoca:AK: 0.0%GN: 0.0%TOB: 0.0%,P. aeruginosa:AK: 2.5%GN: 6.4%TOB: 4.6%	PLZ showed potent activity against Enterobacteriaceae and similar activity to AK against MDR P. aeruginosa.	Medium quality
Castanheira 2017⁴⁹	USA	2014–2015	4362	In vitro activities of PLZ and comparator aminoglycosides	AK, GN, and TOB	Broth microdilution method	CLSI and EUCAST criteria	NR	PLZ was active against ENT isolates from USA hospitals regardless of infection type. It displayed activity against isolates carrying AME genes that represented 12.0% of the selected species. AME-carrying isolates were considerably more resistant to AK, GN, and TOB, highlighting the potential value of PLZ in treating infections caused by these organisms.	NA

Data summarization

In clinical trials, the efficacy of drug therapy was assessed using parameters such as microbiological (microbiological eradication) and clinical outcomes (composite cure and clinical cure) at the test of cure (TOC) and at the end of intravenous (EOIV) therapy, susceptibility rate, survival rate, relapse rate, and microbiological recurrence. The clinical cure rate was defined as a reduction in the severity of symptoms (assessed on the fifth day or at EOIV therapy) or complete resolution of all symptoms at the end of TOC without any new symptoms or return to the patient’s baseline status prior to the onset of the UTI, without using nontrial antibiotics for the current cUTI. The safety profile was assessed based on adverse events (AEs), an increase in serum creatinine concentration, and serious adverse events (SAEs).

Results

Literature search

The PRISMA flow diagram (Figure 1) details the screening and selection process of the articles. Of the 159 articles screened, 44 were retrieved for full-text screening based on the inclusion criteria. The reasons for exclusion of articles are provided in Table S2. A total of 30 studies (27% published after 2019) met the eligibility criteria.^{19,30,31,38–64}

Figure 1.

PRISMA flow diagram depicting the screening and selection of studies.

Summary characteristics

The baseline characteristics and quality assessment of the included studies conducted in the United States (n = 17), India (n = 1), Greece (n = 3), Brazil (n = 1), Egypt (n = 1), Canada (n = 2), Spain (n = 1), and multiple countries (n = 4) are presented in Tables 1 and 2.^{19,30,31,38–64}

The total sample size across the clinical trials was 1424, ranging from 37 to 609 patients. The mean age ranged from 39.5 to 66.7 years. Three studies mentioned gender distribution (58.7% (53%–84%) female and 41.3% (16%–47%) male).^38,39,42 Four studies reported results from two phase III trials (evaluating plazomicin in cUTI (EPIC) (388 patients) and combating antibiotic-resistant Enterobacteriaceae (CARE) (39 patients)) and one reported results from a phase II trial (145 cUTI and AP patients).^38–42 The EPIC trial compared plazomicin with meropenem, and the results were reported by Cloutier et al.³⁸ (efficacy, safety, and diagnosis-specific baseline characteristics), Keeper et al.³⁹ (microbiological outcomes), and Wagenlehner et al. (efficacy and safety outcomes).⁴⁰ McKinnell et al.⁴¹ reported the outcomes of the CARE trial, and Connolly et al.⁴² reported the outcomes of the phase II trial. The EPIC and phase II trials were randomized and double-blinded.^38–40,42 The CARE trial was a multicenter, randomized, and open-label trial.⁴¹ The dosage and administration routes of plazomicin were consistent across all trials (10–15 mg/kg, intravenous (IV), once daily for 4–7 days). The comparators of plazomicin used were meropenem (1 g, three times a day) (n = 3 studies), levofloxacin (750 mg, once a day) (n = 1 study), and colistin (5 mg colistin base per kg per day) (n = 1 study).^38–42

The total number of isolates were 82,594, ranging from 10 to 12,193.^43,62 The isolates were Gram-negative and Gram-positive organisms such as E. coli (16%), K. pneumoniae (10.8%), Acinetobacter spp. (0.5%), Pseudomonas spp. (6%), Citrobacter spp. (0.4%), Enterobacter spp. (7.5%), Klebsiella spp. (0.5%), Serratia spp. (0.97%), Morganella spp. (0.1%), Proteus spp. (1.9%), Enterobacteriaceae (23.15%), methicillin-resistant S. aureus (11.7%), CRE isolates (1.25%), AME isolates (0.06%), Streptococcus spp. (1.08%), Salmonella spp. (0.003%), and Providencia spp. (0.05%). The antibiotic susceptibility testing (AST) methods used in the studies included the broth microdilution method (n = 18), agar dilution method with or without broth dilution (n = 2), and Kirby–Bauer disk diffusion method (n = 2).^{19,30,31,43–47,49,50,52–64} Three studies did not mention the AST method used.^43,48,51 In 23 studies, the comparators against plazomicin were traditional aminoglycosides (84.6%) such as amikacin (91.6%), gentamicin (91.6%), and tobramycin (83.3%); kanamycin (8.3%); levofloxacin (42%); tigecycline (50%); meropenem (42%) and imipenem (33%); piperacillin/tazobactam (33%); sulfamethoxazole (8.3%) and trimethoprim (8.3%); trimethoprim/sulfamethoxazole (8.3%); amoxicillin (8.3%); ceftazidime (33%) and ceftriaxone (25%); colistin (42%); and ciprofloxacin (8.3%).^{19,30,44–64} Two studies did not mention the details of the comparators used.^31,43 The quality assessment of the included studies showed that nine of the studies were of high quality and 13 studies were of moderate quality (Table S3a and S3b).

Evidence from included studies

Efficacy of plazomicin against MDR pathogens

Microbiological eradication

In the phase II trial, the microbiological eradication rate of plazomicin at TOC (day 5–12 after the last dose) was 50% (10 mg/kg) to 60.8% (15 mg/kg) in the modified intention-to-treat (MITT) population and 85.7% (10 mg/kg) to 88.6% (15 mg/kg) in the microbiologically evaluable (ME) population. The microbiological eradication rate of levofloxacin (750 mg) was 58.6% in the MITT group and 81% in the ME group.⁴² Figure 2 presents the microbiological eradication, survival rate, clinical relapse, and microbiological recurrence reported in the EPIC, CARE, and phase II trials.

Figure 2.

Microbiological eradication and recurrence, survival rate, and clinical relapse in the EPIC, CARE, and phase II trials.^38,39,41,42

Clinical cure rate

In the phase II trial, the clinical cure rate for plazomicin was 66.7% (10 mg) and 70.6% (15 mg) in the MITT population.⁴² In the ME population, the clinical cure rate for plazomicin was 57.1% (10 mg) and 80% (15 mg). For levofloxacin (750 mg), it was 65.5% in the MITT and 76.2% in the ME groups.⁴² The clinical and composite cure rates in the EPIC trial are depicted in Figure 3.

Figure 3.

Clinical and composite cure rates in the phase III EPIC trial.³⁹

Safety of plazomicin

Adverse events

The most frequent AEs with plazomicin use in the EPIC trial were diarrhea (2.3%), hypertension (2.3%), headache (1.3%), nausea (1.3%), vomiting (1.3%), hypotension (1%), renal dysfunction (3.6%), and vestibular dysfunction (0.3%).³⁸ In the meropenem group, the AEs were diarrhea (1.7%), hypertension (2.3%), headache (3%), nausea (1.3%), vomiting (1%), hypotension (0.7%), renal dysfunction (1.3%), and vestibular dysfunction (0.3%).³⁸ In the phase II trial, plazomicin at either 10 or 15 mg/kg once daily over 5 days proved to be well tolerated among the patients. AEs were reported in 31.8%, 35.1%, and 47.7% of patients receiving plazomicin 10 mg, 15 mg, and levofloxacin, respectively.⁴²

Serum creatinine

In the CARE trial, serum creatinine increased (⩾0.5 mg/dL) in 16.7% of plazomicin-treated patients compared with 50% in colistin-treated patients.⁴¹ In the EPIC trial, serum creatinine increased in 7% of plazomicin-treated patients, with 90% having baseline renal impairment, compared with 4% in the meropenem group.³⁸ Serum creatinine remained stable (<0.5 mg/dL) in most cases, and nephrotoxicity rates were lower in plazomicin-treated patients with normal renal function (creatinine clearance (CL_CR) >90 mL/min) than in meropenem-treated patients.³⁸

Serious adverse events

In the EPIC trial, SAEs such as acute kidney injury, AP, metastatic neoplasm, UTI, and urinary calculus were reported in the plazomicin and meropenem groups. However, none of the SAEs were related to the drug therapy provided to both groups of patients. Among both groups, 1.7% of patients treated with either plazomicin or meropenem experienced SAEs.³⁸ In the CARE trial, SAEs were reported by 50% and 81% of patients receiving plazomicin and colistin, respectively.⁴¹ In the phase II trial, AEs were reported by 1.4% and 4.5% of patients treated with plazomicin 15 mg and levofloxacin, respectively.⁴²

MIC, susceptibility rates, growth inhibition, and breakpoints of antimicrobial agents

Minimum inhibitory concentration

Plazomicin demonstrated high susceptibility against Enterobacteriaceae isolates (87%–99.5%) at MIC_50/90 0.12/32 mg/L. The details of the MIC_50/90 and susceptibility rates reported in these studies are presented in Tables 3 and 4, respectively.^{19,30,31,43–64}

Table 3.

List of MIC_50/90 values of antimicrobial agents against Enterobacteriaceae as reported in the included studies.

S. No.	Antimicrobial agent	MIC₅₀	MIC₉₀
1	Plazomicin	0.12–0.5	<1–32
2	Gentamicin	0.5–4	16 to >256
3	Amikacin	2–64	16–128
4	Tobramycin	<0.5–32	32–256
5	Imipenem	8	32
6	Meropenem	>16	⩾16
7	Colistin	1	512
8	Piperacillin–tazobactam	4	64
9	Tigecycline	1	4

Source: References 19, 30, 31, and 43–64.

MIC, Minimal inhibitory concentration.

Table 4.

Susceptibility rates reported in the included studies.

S. no.	Antimicrobial agent	Enterobacteriaceae	E. coli	K. pneumoniae	A. baumannii	P. aeruginosa	CRE	MDR isolates	XDR isolates	MRSA
1	Plazomicin	87%–99.8%	99.7%	87%–99.8%	5%–44%	6%–30%	84%–100%	89.8%	89.2%	100%
2	Gentamicin	37.3%–90.3%	86.5%–90%	52.5%–98%	27%	78%–89.2%	22%–56.7%	33.8%–43.9%	30.4%–40.5%	96.6%
3	Amikacin	31.3%–98.9%	99%	61.1%–99%	38%	92%–94.6%	38.5%–78.6%	71%–94.3%	65.5%–72.5%	95.9%
4	Tobramycin	3.6%–90.3%	86.9%–91%	14.3%–98.2%	34%	84%–94.4%	13.4%–23%	15.2%–32.1%	0%–7.8%	6.7%
5	Meropenem	97.6%	NR	NR	NR	NR	NR	NR	NR	NR
6	Colistin	74.4%	NR	85.3%	NR	NR	NR	NR	NR	NR
7	Levofloxacin	82.9%	NR	NR	NR	NR	NR	NR	NR	20.5%

Source: References 19, 30, 31 and 43–64.

A. baumannii, Acinetobacter baumannii; CRE, Carbapenem-resistant Enterobacteriaceae; E.coli, Escherichia coli; K. pneumoniae, Klebsiella pneumoniae; MDR, Multidrug-resistant; MRSA, Methicillin-resistant Staphylococcus aureus; NR, Not reported; P. aeruginosa, Pseudomonas aeruginosa; XDR, Extensively drug-resistant.

Plazomicin showed high efficacy against ESBL-encoding isolates (MIC_50/90, 0.5–1 mg/L) with 98.9% susceptibility, against NDM isolates (MIC_50/90, 0.125–2 mg/L), and CRE isolates (MIC_50/90, 0.25–1 mg/L) with 100% susceptibility. Additionally, plazomicin had an MIC₉₀ of <1–1 mg/L for both methicillin-sensitive S. aureus and methicillin-resistant S. aureus isolates.^{19,30,44,48,50,61–63}

Inhibition of growth

The inhibition rate for plazomicin, amikacin, and gentamicin was 90%, 59.7%, and 49.4%, respectively.²⁹

Change in breakpoints

The recent change in breakpoints has drastically reduced the susceptibility of amikacin, gentamicin, and tobramycin.¹⁹ Plazomicin showed superior susceptibility versus amikacin against CRE (94% vs 59%), ESBL producers (98.9% vs 79.7%), AME producers (97.3% vs 68.4%), MDR organisms (94.8% vs 71%), and XDR pathogens (94% vs 41.7%).^{19,52–59,61,62}

Synergistic bactericidal activity against MDR Enterobacteriaceae

Synergy within an antimicrobial combination is defined as a reduction of ⩾2 log₁₀ CFU/mL by the combination compared with its most potent individual component.⁶⁴ Checkerboard analysis conducted with plazomicin in combination with all antimicrobials revealed synergy in 26.5%, partial synergy in 41.2%, and indifference in 32.4% of isolates, and no antagonism was observed with any of the combinations.⁶⁴ Furthermore, a synergistic effect with colistin was observed in 60% of the isolates, whereas synergy between plazomicin with meropenem and fosfomycin was detected in 20% and 25% of the isolates, respectively.⁶⁴ Checkerboard studies and time-kill assays validated the synergy between plazomicin and piperacillin/tazobactam or ceftazidime.⁵⁶

Efficacy and safety of plazomicin in the Indian context

No clinical trials specifically focused on plazomicin in Indian populations; however, the multinational phase II study did enroll Indian patients. This trial did not conduct a subgroup analysis for Indian participants, who constituted 25% of the cohort.⁴² The study reported that a dosage of 15 mg/kg of plazomicin once daily for 5 days was effective and well tolerated by the whole cohort, including Indian participants.⁴² Furthermore, a retrospective study conducted in India utilized whole-genome sequencing-derived AMR profiles to predict the efficacy of plazomicin.³¹ This study focused on assessing the susceptibility of plazomicin against Indian MDR pathogens, such as E. coli, K. pneumoniae, and Acinetobacter baumannii. The findings suggested that plazomicin has the potential to be used as a carbapenem-sparing agent for ESBL producers and a colistin-sparing agent for carbapenemase producers, offering effective therapeutic options against Indian MDR pathogens (Table 1).

Pharmacokinetics of plazomicin

Plazomicin has a half-life of 4 h and a lower protein-binding capacity (16% ± 5) than gentamicin (half-life: 1.25 h, protein-binding capacity: 34%), tobramycin (half-life: 3 h), and amikacin (half-life: 4.8 h, protein-binding capacity: <20%).^27,65–69 The recommended dosage of plazomicin is 15 mg/kg once a day via a 30-min IV infusion, with treatment lasting 4–7 days based on infection severity. Patients with mild renal impairment (CL_CR 60–90 mL/min) do not require dose adjustments.⁷⁰ For moderate (CL_CR 30–59 mL/min) and severe impairments (CL_CR 15–29 mL/min), the recommended dosages are 10 mg/kg daily and 10 mg/kg every alternate day, respectively.⁷⁰ The slow clearance of plazomicin enables a predictable linear pharmacokinetic profile, with 97.5% excreted unchanged in the urine.²⁷ The dosing regimen, as observed in clinical trials (e.g., 15 mg/kg once daily), allows once-daily administration, which improves convenience and reduces the risk of toxicity.²⁷ In the CARE trial, plazomicin’s efficacy and safety were reported in once-daily dosing regimens for up to 14 days.⁴¹ The pharmacokinetic parameters of plazomicin are presented in Table 5.²⁶

Table 5.

Pharmacokinetic parameters of plazomicin.

Parameter	Healthy subjects^a Mean ± SDN = 54	cUTI patients^b Mean ± SDN = 87
AUC (mcg·h/mL)	257 ± 67.0	226 ± 113
C_max (mcg/mL)	73.7 ± 19.7	51.0 ± 26.7
C_min (mcg/mL)	0.3 ± 0.2	0.5 ± 1.2

Pharmacokinetic (PK) parameters following a single dose of 15 mg/kg. Based on noncompartmental analysis of PK data. AUC_0–inf is reported.

Day 1 PK parameters following administration of plazomicin 15 mg/kg. Derived based on the population PK model. AUC_0–24h is reported.

AUC, area under the curve; C_max, maximum plasma concentration of a drug; C_min, concentration at 24 h; cUTI, complicated urinary tract infection; SD, standard deviation.

Discussion

The present scoping review reported that the clinical and microbiological outcomes of plazomicin were noninferior to those of meropenem, colistin, and levofloxacin.^38–42 This efficacy of plazomicin could be due to its ability to bind to the bacterial 30S ribosomal subunit and inhibit protein synthesis in a concentration-dependent manner while resisting inactivation by AMEs.^3,71,72 The synergistic interaction between plazomicin and other antibiotics (meropenem, fosfomycin, piperacillin–tazobactam, and ceftazidime) reiterates its potential for delivering beneficial effects in both standalone therapy and combination treatment approaches.⁵⁶ This review highlighted plazomicin’s rapid bactericidal activity and effectiveness against MDR Enterobacterales, including strains with fluoroquinolone mutations, AMEs, ESBL, carbapenemases, and colistin resistance.^{30,31,49–51,55,58} Its consistent and stable activity across different infection types, such as cUTI including pyelonephritis, bloodstream infection, and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia, suggests its reliability and versatility in diverse clinical scenarios. These findings align with previously published literature, which reported susceptibility rates of 46.9% for amikacin, 32.1% for gentamicin, and 6.1% for tobramycin against metallo-β-lactamase (MBL)-producing CRE. In contrast, plazomicin demonstrated a higher susceptibility rate of 57.7% against MBL-producing CRE.⁷³ This underscores the superior efficacy of plazomicin against NDM, AME, and CRE strains, including those producing MBL.

The relapse and recurrence rates of cUTI among patients treated with plazomicin were lower than patients treated with other antibiotics (such as meropenem), underscoring plazomicin’s importance in the management of MDR cUTI.^38,42 These findings align with those of a meta-analysis, which reported that the plazomicin group had a lower clinical relapse rate (3.19%) than the levofloxacin and meropenem groups, and the overall pooled clinical remission rate of plazomicin was 85.7% in treating cUTIs, bloodstream infections, and HAP within the MITT population.²⁹ The AEs due to plazomicin (19.5%–50%) either had a similar or lower rate than that of other antibiotics.^38,41,42 Additionally, plazomicin has an extended elimination half-life of 4 h (longer half-life), which offers a therapeutic advantage over gentamicin, tobramycin, and amikacin. This attribute allows for once-daily dosing, a benefit derived from its unique chemical structure that resists enzymatic degradation.⁷⁰

Although plazomicin has demonstrated activity against NDM, AME, and CRE strains, including MBL isolates, it lacks activity against bacteria with 16S rRNA methyltransferase genes, mainly found in East Asia and potentially coexpressed with NDM.⁷⁴ Considering the substantial impact of rising MDR cUTIs, there is an urgent need for effective treatment measures. Though plazomicin represents a promising therapeutic option, its usage must be guided by comprehensive antimicrobial stewardship strategies, which are essential to manage and curb the spread of these resistant pathogens.^75–77 The implementation of rigorous infection control measures and judicious antibiotic prescribing practices are of utmost importance.^76,77 In the Indian healthcare scenario, the practical utility of plazomicin not only depends on its microbiological efficacy but also its accessibility, affordability, and alignment with national regulatory policies.⁷⁷ In order to maximize the effectiveness of plazomicin as a therapeutic agent while minimizing the development of antibiotic resistance, it is crucial to implement policies that promote its careful and judicious use.⁷⁸

This scoping review provides a comprehensive overview of the efficacy of plazomicin in the management of cUTI. While the findings underscore its potent activity against resistant infection, the review has a few limitations. The existing literature is largely derived from studies conducted in high-income countries, which may not fully reflect the clinical, microbiological, and healthcare infrastructure realities of low- and middle-income settings such as India. Furthermore, implementation research and economic evaluations to assess the feasibility, cost-effectiveness, and scalability of integrating plazomicin in treatment protocols are lacking. These gaps emphasize the need for further region-specific research to guide evidence-based decision-making.

Conclusion

The results of this scoping review advocate that plazomicin can be a useful therapeutic option for tackling AMR, especially as traditional antibiotics face diminishing efficacy. Plazomicin’s activity against CRE and colistin-resistant Enterobacteriaceae, rapid bactericidal activity, once-daily dosing, low relapse rates, favorable safety, and synergistic potential with other antibiotics underscore its utility in managing MDR cUTIs, including pyelonephritis. Given the high prevalence of ESBL-producing strains and CRE in India, plazomicin can be a potential option for the treatment of cUTI, including pyelonephritis. However, due to limited data in developing countries like India, future studies to generate real-world evidence on clinical efficacy, safety, economic impact, and barriers to implementation are recommended.

Supplemental Material

sj-docx-1-tai-10.1177_20499361251401104 – Supplemental material for Plazomicin in multidrug-resistant complicated urinary tract infections: a scoping review

Supplemental material, sj-docx-1-tai-10.1177_20499361251401104 for Plazomicin in multidrug-resistant complicated urinary tract infections: a scoping review by Subhash Todi, Rajeev Soman, Yatin Mehta, V. Ramasubramanian, Veeraraghavan Balaji, Sanjay Pandey, Senthur Nambi, Rohit Malabade, Vaishali Gupte, Senthilnathan Mohanasundaram and Jaideep Gogtay in Therapeutic Advances in Infectious Disease

Footnotes

Appendix

Acknowledgements

The authors of the manuscript thank BioQuest Solutions for editorial assistance.

Declarations

ORCID iD

Vaishali Gupte

Supplemental material

Supplemental material for this article is available online.

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