Cefepime-enmetazobactam for complicated urinary tract infections: Redefining ESBL therapy

Definition and scope of complicated UTI

Complicated UTI occur with structural/functional abnormalities (obstruction, stones, neurogenic bladder, reflux), indwelling devices, male sex, pregnancy, renal insufficiency/transplant, immunocompromised state, or upper-tract involvement (pyelonephritis, systemic illness/bacteraemia). Catheter-associated UTI is a complicated UTI. Uncomplicated cystitis is limited to the lower tract in healthy, non-pregnant women. This matters because drugs for uncomplicated cystitis (nitrofurantoin, fosfomycin) have inadequate renal tissue penetration and are unsuitable for pyelonephritis or complicated UTIs.^7,8

This review summarises the mechanism and resistance profile of CPM-EMT, evidence from the Phase 3 ALLIUM trial (randomised, double-blind, multicentre; NCT03687255), comparisons with other β-lactam/β-lactamase inhibitor (BL/BLI) combinations, pharmacokinetics/pharmacodynamics considerations, stewardship implications, and Indian regulatory and access issues, and concludes with priority evidence gaps.

Nitrofurantoin remains widely used for uncomplicated lower UTIs due to high urinary levels and low resistance, though prolonged use may cause pulmonary toxicity.⁹ Fosfomycin (3 g oral) retains broad activity, including against some ESBL producers, but resistance is emerging. TMP–SMX, once first line, is less suitable empirically owing to rising AMR and OTC misuse.¹⁰ Susceptibility varies: a multicentre Indian study showed ∼49% E. coli susceptibility to TMP–SMX vs. 94% for fosfomycin and 85% for nitrofurantoin,¹¹ though higher rates (∼82%) were reported from Hyderabad.¹² Consistent with the Infectious Diseases Society of America and the European Society of Clinical Microbiology and Infectious Diseases (IDSA/ESCMID) guidance, empiric TMP–SMX is recommended only where E. coli resistance is ≤20% or when culture-confirmed; it is discouraged for pyelonephritis and most complicated UTIs in India.¹³ Adverse effects include hypersensitivity and haematological toxicity. Fluoroquinolones are now restricted owing to high resistance and serious adverse effects.⁹ β-lactams (e.g., amoxicillin–clavulanate, cefixime) use is frequently compromised by ESBL-producing organisms.¹⁴ Pivmecillinam has re-emerged in Europe for uncomplicated UTIs owing to its efficacy and low resistance.¹⁵

CPM-EMT, a next-generation BL/BLI, shows strong activity against ESBL-producing Enterobacterales in the US and UK. Enmetazobactam, a penicillanic acid sulphone, inhibits class A ESBLs, restoring cefepime efficacy and helping where ESBL/AmpC co-production occurs. Limited anaerobic activity necessitates added therapy for polymicrobial infections.¹⁶ In vitro studies consistently show high susceptibility of ESBL-producing Enterobacterales to CPM–EMT, with only modest incremental activity against Pseudomonas aeruginosa (Supplementary Table I). As a carbapenem-sparing agent, CPM–EMT supports stewardship by conserving broader-spectrum agents while maintaining efficacy against serious Gram-negative infections.¹⁷ Figures 1 and 2 summarise its mechanism and clinical applications.

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Fig. 1.

Mechanism of action of cefepime-enmetazobactam (CPM-EMT) in Gram-negative infections (GNIs). PBP, penicillin-binding proteins; SHV, sulfhydryl variable; OXA-1, oxacillinase-1; TEM, temoneira; CTX-M-14 & CTX-M-15, cefotaximase Munich; KPC, Klebsiella pneumoniae carbapenemase; ESBLs, extended-spectrum β-lactamases; Ser70, serine residue at position 70; Lys73, lysine at position 73.

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Fig. 2.

Clinical decision flowchart for the use of Cefepime-enmetazobactam (CPM-EMT) in complicated urinary tract infections. AmpC, ampC β-lactamase; MBL, metallo-β-lactamase; IV, intravenous; CPM–EMT, cefepime–enmetazobactam; q8h, every 8 h; CPM–EMT (2.5g, IV) offers a potent carbapenem-sparing option for ESBL and AmpC-producing Enterobacterales when susceptibility is confirmed. Fosfomycin=2-3g PO q2-3 days for 3 doses. Nitrofurantoin=100mg PO twice daily for 5-7 days. Ceftazidime-avibactam=2.5g IV every q8h, infused over 3h + Aztreonam: 2g IV q8h, infused over 3h. Cefiderocol=2g IV q8h, infused over 3h.

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Regulatory approvals and global use

CPM-EMT represents a milestone in Indian pharmaceutical innovation. Though EMT originated in India, licensing to Allecra Therapeutics enabled global development and regulatory success, showcasing a strong Indo-European antimicrobial partnership.¹⁸ CPM–EMT is now approved in the US, European Union, and India; in the US, it also carries Qualified Infectious Disease Product (QIDP) status under the Generating Antibiotic Incentives Now (GAIN) Act, which provides priority review and an additional five years of market exclusivity.¹⁹

Mechanism of action and resistance coverage

Designed to counter β-lactamase-mediated resistance in Gram-negative infections, especially complicated UTIs, EMT inhibits Ambler class A enzymes (TEM, SHV, CTX-M) by forming a stable acyl-enzyme complex, protecting CPM and restoring activity. These ESBLs dominate in E. coli and K. pneumoniae. The combination also has partial activity against class C (AmpC) β-lactamases in Enterobacter cloacae and Citrobacter freundii. Though EMT is less potent than avibactam against AmpC, CPM’s intrinsic stability supports efficacy in selected cases.^16,17

A major limitation is the lack of activity against Ambler class B metallo-β-lactamases (MBLs), including NDM, VIM and IMP. In such infections, cefiderocol or aztreonam-avibactam are preferred, whereas aztreonam plus CPM-EMT remains investigational. MBL-producing organisms remain a significant therapeutic challenge.^16,20-22 According to EMA risk management plan data, resistance was not detected in susceptible baseline isolates during Phase 3 trials of CPM-EMT.²³ Resistance may arise through β-lactamase mutations, porin loss, efflux upregulation, or altered penicillin-binding proteins,²⁰ underscoring the need for ongoing post-marketing surveillance and robust antimicrobial stewardship programme (AMSP).¹⁷

Clinical efficacy and spectrum of activity

Having outlined its mechanism and resistance profile, we summarise CPM-EMT’s clinical efficacy for complicated UTIs. CPM–EMT is active against ESBL-producing Enterobacterales, including E. coli, K. pneumoniae, Proteus mirabilis, and the E. cloacae complex. It maintains CPM-class activity against P. aeruginosa; EMT offers little additional benefit as it does not inhibit the predominant resistance mechanisms (AmpC hyperproduction, efflux, porin loss). Susceptibility is largely attributable to CPM, and CPM-EMT should not be considered a targeted option for multidrug-resistant (MDR) P. aeruginosa.¹⁷ (Supplementary Table I for MIC and susceptibility data).

CPM-EMT remains ineffective against MRSA, Enterococcus spp., Acinetobacter spp., and anaerobes; additional agents may be required for polymicrobial infections. Given rising carbapenem use for ESBL-producing Enterobacterales, CPM–EMT provides a carbapenem-sparing alternative by restoring activity against ESBLs and selected carbapenemases.²⁴

Because approval in the US and EU occurred only in 2024, longitudinal real-world data are still limited (Supplementary Table I).^21,25

Indian context: Local resistance data

ICMR-AMRSN 2023–24 data show rising resistance among major uropathogens, particularly E. coli and K. pneumoniae, the leading causes of UTIs in India. E. coli demonstrated <20% susceptibility to cefotaxime, ceftazidime, ciprofloxacin, and levofloxacin across ICU and outpatient settings. K. pneumoniae susceptibility to piperacillin–tazobactam declined from 56.8% in 2017 to 42.4% in 2023, with parallel increases in carbapenem resistance. P. aeruginosa also showed reduced susceptibility to carbapenems and aminoglycosides.²⁶

Tertiary centres (PGIMER-Chandigarh, AIIMS-New Delhi, CMC-Vellore) have reported high ESBL prevalence in community- and hospital-acquired UTIs, with rising AmpC and carbapenemase detection, especially in ICUs.²⁷ This burden highlights the need for carbapenem-sparing agents; newer BL/BLI combinations like CPM–EMT show promising activity.

Although the Phase 3 ALLIUM trial did not enrol in India, its relevance is supported by Drugs Controller General of India (DCGI) approval and EMT’s Indian origin.²⁸ Early real-world evidence and expert consensus suggest improved outcomes in ESBL-positive complicated UTIs, reduced carbapenem use, favourable tolerability, and potential cost-effectiveness in public healthcare settings.^29,30 Continued ICMR surveillance will be essential for guiding optimal use.

In severe Indian settings, K. pneumoniae often carries NDM or OXA-48 carbapenemases, making empirical CPM–EMT unsuitable in unstable patients or high-prevalence areas. It should be reserved for culture-confirmed ESBL/AmpC Enterobacterales with documented susceptibility or after rapid tests exclude carbapenemases (see AMSP section). If carbapenemases are suspected or confirmed, ceftazidime–avibactam (± aztreonam) or cefiderocol are preferred.^8,31,32

Comparative efficacy and safety

Across randomised controlled trials (RCT), CPM–EMT achieved superior overall treatment success compared with piperacillin-tazobactam in adults with complicated UTIs/acute pyelonephritis, including ESBL-producing Enterobacterales (Table I). This superiority was primarily driven by higher microbiological eradication, as clinical cure rates were otherwise similar.³³ In India, emerging multicentric in vitro studies report high susceptibility among ESBL-dominant isolates; however, no head-to-head real-world comparative data are yet available. Agent selection should be guided by mechanism (ESBL/AmpC vs KPC/OXA-48 vs. MBL), severity, and local antibiograms, with CPM–EMT distinguished by RCT-demonstrated superiority over piperacillin-tazobactam.^8,5,24,26

CPM–EMT offers strong in vitro activity against ESBL-producing Enterobacterales and stability against AmpC, but activity against carbapenemase producers remains limited: it is inactive against class B MBLs (e.g., NDM, VIM, IMP), and evidence in KPC/OXA-48 CRE is limited.¹⁶ Animal data suggest CPM may outperform meropenem against OXA-48K. pneumoniae in pneumonia models, but clinical corroboration is currently lacking.³³

Nitrofurantoin and fosfomycin retain good activity against ESBL-producing E. coli but are unsuitable for complicated UTIs and pyelonephritis due to inadequate renal parenchymal penetration.³⁴ Fluoroquinolones face rising resistance and significant collateral effects, including Clostridioides difficile infection.³⁵ Third-generation cephalosporins (e.g., ceftriaxone, ceftazidime) are widely used yet frequently compromised by ESBL-mediated resistance.³⁶

CPM–EMT is useful for resistant Gram-negative infections, notably ESBL Enterobacterales and P. aeruginosa. Its superiority over piperacillin–tazobactam in complicated UTIs supports a carbapenem-sparing role, though activity against carbapenemase producers is limited and cefepime-related neurotoxicity is a concern. In vitro, cefepime-zidebactam may show lower MICs than CPM–EMT against resistant GNIs, including some carbapenemase producers, but clinical data remain scarce.³⁷

From a stewardship view, CPM-EMT is a preferred non-carbapenem for ESBL-positive complicated UTIs when MBL risk is low, reducing carbapenem use and preserving newer BL/BLI and siderophore agents for confirmed CRE/MBL infections.^16,24,33

Comparative positioning versus recent BL/BLI agents and cefiderocol

The therapeutic niche of CPM–EMT is best defined in relation to other contemporary BL/BLI combinations and cefiderocol. CPM-EMT combines a fourth-generation cephalosporin with a penicillanic sulfone, restoring activity mainly against class A ESBLs (CTX-M, TEM, SHV) and some AmpC producers. It shows limited efficacy against MBLs and is not directed at KPC or OXA-48 carbapenemases. In the Phase 3 ALLIUM trial, CPM-EMT outperformed piperacillin–tazobactam, supporting its role as a carbapenem-sparing option for ESBL-producing Enterobacterales when local susceptibility patterns are favourable.^8,24,33

In contrast, newer BL/BLI combinations, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and ceftolozane-tazobactam, and the siderophore cephalosporin cefiderocol provide broader activity, including coverage of CRE and/or difficult-to-treat P. aeruginosa. Stewardship guidance recommends reserving these broader agents for infections caused by carbapenemase producers (e.g., KPC, OXA-48) or highly resistant non-fermenters to preserve their effectiveness.⁸

Choice among CPM-EMT, newer BL/BLIs, and cefiderocol should be tailored to resistance mechanisms, infection site and severity, local susceptibility, and stewardship goals. Supplementary Table III outlines their key advantages, limitations, and preferred uses.

Pharmacokinetics and pharmacodynamics profile

CPM–EMT demonstrates time-dependent killing, with efficacy best predicted by %f T> MIC. Both components are renally eliminated, necessitating dose adjustment in renal impairment. Prolonged or extended infusion improves probability of target attainment (PTA) at MIC values ≤8 mg/L^16,38,39 (Table II).

Dosing should be tailored to renal function: reduce or extend intervals in impairment, use prolonged infusion in augmented clearance, and follow modality-specific guidance for haemodialysis or peritoneal dialysis. Evidence is lacking for continuous renal replacement therapy. No adjustment is needed for hepatic impairment or age. Table III summarises dosing by eGFR and dialysis modalities.⁴⁰

Drug-drug interactions with cefepime–enmetazobactam (CPM–EMT)

Data on pharmacokinetics and pharmacodynamics interactions remain limited due to the recent introduction of CPM–EMT, but extrapolation from the individual components and early clinical and in vitro findings is informative. Both CPM and EMT are renally excreted with minimal metabolism and are not significant substrates, inducers, or inhibitors of cytochrome P450 (CYP450) enzymes;⁴¹ thus, clinically relevant CYP-mediated interactions are unlikely. Potential interactions mainly relate to nephrotoxicity: concomitant use with aminoglycosides, vancomycin, or high-dose furosemide may increase renal risk, as with other β-lactams. CPM may also cause false-positive urine glucose tests, so glucose oxidase-based assays are recommended.⁴² Probenecid can reduce renal tubular secretion of several β-lactams and may prolong CPM or EMT half-life.⁴³ As with other broad-spectrum antibacterials, CPM–EMT may reduce the effectiveness of live attenuated bacterial vaccines (e.g., oral typhoid).³⁹ No antagonism or synergism has been reported, but additive nephrotoxicity and microbiological effects warrant consideration.

Use in special populations

There are no clinical data on CPM–EMT in pregnancy. Preclinical studies show EMT-related reproductive toxicity (delayed cranial ossification in animals) but no teratogenicity. Use in pregnancy should be reserved for cases where maternal benefit outweighs potential fetal risk.⁴⁰

As of mid-2025, CPM–EMT is unapproved for paediatric use, with data limited to adults. The EMA has endorsed a paediatric investigation plan (neonates to adolescents), and a Phase I/II trial (NCT05826990) is assessing pharmacokinetics, safety, and dosing in children with complicated UTIs, anticipated to complete in 2026; no interim results are available.⁴⁴ The EMA risk management plan confirms the absence of paediatric safety data and requires post-approval monitoring.⁴⁰ In India, off-label paediatric use is undocumented, with anecdotal interest in older adolescents with MDR infections. Until dosing and safety are validated, use should be limited to adults. CPM alone remains an effective, well-tolerated option for paediatric community-acquired pneumonia.⁴⁵

No dose adjustment is required purely on the basis of age. As both components are renally excreted, dose modification is recommended in patients with creatinine clearance (CrCl)<60 mL/min.³⁹ Renal-based dosing recommendations are summarised in Table III.⁴⁰

Cost-effectiveness modelling: Lessons from the US and global implications

As of mid-2025, no formal cost-effectiveness studies or HTA reports (e.g., National Institute for Health and Care Excellence (NICE), Institute for Clinical and Economic Review (ICER) modelling) have evaluated CPM–EMT. NICE has not selected it for appraisal, and current National Health Service (NHS) antimicrobial evaluation is aligned with the subscription model rather than traditional economic metrics.⁴⁶ ID stewardship estimates a daily acquisition cost of USD 750–1,500/day, far higher than generic comparators such as meropenem or ertapenem (<USD 50/day).⁴⁷ Such pricing limits routine use in resource-constrained systems, despite stewardship advantages (e.g., carbapenem-sparing). By comparison, ceftolozane–tazobactam has robust pharmacoeconomic evidence: US and Japanese studies in ventilator-associated pneumonia demonstrated higher cure rates and lower mortality than meropenem, with ICERs ranging between USD 4,775–12,126/quality-adjusted life-year (US) and ∼USD 15,763 (Japan), below willingness-to-pay thresholds. CPM–EMT shows higher cure rates in complicated UTIs (79.1%) but lacks formal ICER modelling; nonetheless, it is considered cost-effective in India due to substantially lower pricing.^24,48,49

In the Phase 3 ALLIUM trial, CPM–EMT showed higher eradication and cure rates, implying possible savings from shorter stays and fewer recurrences,^24,28 though no economic modelling has quantified these downstream savings.

At the 13th Annual International Best of Brussels Symposium (India), CPM–EMT was highlighted as costing approximately one-tenth of the cost of comparable internationally developed antibiotics.⁵⁰ This affordability strengthens its role as a cost-effective carbapenem-sparing option, particularly in public sector hospitals where budget constraints restrict access to newer BL/BLI agents.^50,51 In the context of rising carbapenem resistance and constrained healthcare budgets, CPM–EMT offers a practical and economically advantageous therapeutic alternative.⁵¹

Bridging the evidence gap

Role of CPM–EMT in antimicrobial stewardship programme (AMSP): CPM–EMT supports three key AMSP goals in complicated UTIs

(i) carbapenem-sparing treatment for ESBL-producing Enterobacterales; (ii) earlier, microbiology-guided de-escalation; and (iii) reduced collateral damage from broader agents. In the Phase 3 ALLIUM trial, CPM–EMT achieved higher overall treatment success than piperacillin–tazobactam, primarily through improved microbiological eradication.²⁴ Observational data in ESBL UTIs similarly show that non-carbapenem β-lactams can equal or surpass carbapenems in clinical cure while avoiding unnecessary carbapenem use.³⁰ This aligns with IDSA AMR guidance, which recommends preserving broader agents (e.g., ceftazidime–avibactam, cefiderocol) for confirmed carbapenemase producers or difficult-to-treat non-fermenters.⁸

Documented AMSP impact in India: Facts and figures

A multi-centre ‘hub-and-spoke’ AMSP across four secondary hospitals in India reduced overall antibiotic duration of therapy (DOT) from 1,952.6 to 1,483.1/1,000 patient-days (P=0.001), increased de-escalation from 12.5 to 44.0%, and achieved 79.9% appropriateness, with 77.7% full acceptance of AMSP recommendations.⁵³ At a public tertiary hospital (AIIMS Bhopal), a year-long AMSP led to ∼50% reductions in ICMR priority antibiotics (e.g., meropenem, colistin), with progressive quarterly declines.⁵⁴ Nationally, stewardship capacity remains uneven: among 20 tertiary hospitals surveyed, only 25% routinely analysed antimicrobial use and 30% conducted prescription audit with feedback.⁵⁵

Practical AMS use-criteria

Operationalising CPM–EMT within AMSP should include auditable endpoints such as:

• Empiric therapy: Unstable/ICU or high CRE prevalence (NDM/OXA-48/KPC): Avoid empiric CPM–EMT. Use mechanism-appropriate empiric therapy per local policy (e.g., meropenem ± aminoglycoside; ceftazidime–avibactam for suspected KPC/OXA-48; cefiderocol or aztreonam–avibactam when MBL is likely) while obtaining rapid carbapenemase testing.^{8,24,26,30,31} Stable ward patients with high ESBL risk and low MBL prevalence: Consider CPM–EMT empirically only when rapid carbapenemase PCR is negative or local epidemiology suggests low MBL prevalence; otherwise await culture/rapid results.^5,6,8

• Targeted therapy (Culture confirmed): ESBL (e.g., CTX-M) or ESBL ± AmpC, CPM–EMT susceptible: CPM–EMT preferred as a carbapenem-sparing option; use extended infusion (2–4 h) with renal adjustment.^8,24,39 KPC or OXA-48-like: Do not use CPM–EMT. Prefer ceftazidime–avibactam (± aztreonam when indicated) or meropenem–vaborbactam/imipenem–relebactam.⁸ NDM/VIM/IMP (MBL): CPM–EMT is inactive. Use cefiderocol or aztreonam plus avibactam; aztreonam + CPM–EMT remains investigational.^8,22 P. aeruginosa complicated UTI: CPM–EMT adds little where resistance is CPM-driven. For difficult-to-treat strains, consider ceftolozane–tazobactam or imipenem–relebactam.^8,17,36

• De-escalation and duration: De-escalate from empiric carbapenem to CPM–EMT once ESBL/AmpC susceptibility is confirmed and MBL excluded; step down to an appropriate oral agent when feasible. Follow standard complicated UTI/pyelonephritis durations, tailoring to clinical response and source control.^7,8,13,15 Safety and dosing: Monitor for CPM-associated neurotoxicity, especially in renal impairment; ensure appropriate renal dose adjustment (Supplementary Table III, Table II and III).

• Diagnostics and stewardship: Use rapid carbapenemase assays (e.g., PCR for blaNDM/blaOXA-48/blaKPC) to enable early mechanism-directed therapy and de-escalation; align with institutional AMSP metrics (carbapenem DOT reduction, reserve-agent use).^5,6,8,26

Effective integration into AMSP should follow local AMR patterns, rapid ESBL/carbapenemase detection, and strict escalation protocols.

CPM–EMT provides a mechanism-directed, carbapenem-sparing option for ESBL- and selected AmpC-mediated complicated UTIs, with RCT evidence of superior success over piperacillin–tazobactam. As it lacks activity against class B MBLs (NDM, VIM) and is unreliable against KPC/OXA-48, use should be limited to low-MBL risk settings confirmed by rapid testing and avoided empirically in unstable patients in high-CRE areas. Within AMSPs, CPM–EMT enables de-escalation from carbapenems for ESBL/AmpC infections and supports goals such as reduced carbapenem DOT and rational reserve-agent use, aligned with local antibiograms, extended-infusion dosing, and renal adjustment. Wider adoption in India requires surveillance, formulary pathways, and access planning. Evidence gaps remain in paediatric dosing, Indian real-world outcomes, carbapenemase-prevalent settings, Pseudomonas-specific applications, and cost-effectiveness. Overall, CPM–EMT is a timely addition to mechanism-guided complicated UTI pathways, helping preserve carbapenems without compromising outcomes.