Evaluation of cefepime-enmetazobactam against ESBL and AmpC β-lactamase producing Gram-negative bacteria: In- vitro study

Anitha Jasmine

Consultant – Microbiologist, Kauvery Hospital, Cantonment, Trichy

Background

Drug resistance in GNB (Gram-negative bacteria) is a global concern.

ICMR AMR Antimicrobial Resistance surveillance report 2023,

coli isolates
- Piperacillin-tazobactam – 8% in 2017 to 42.4% in 2023
- Carbapenems (81.4% in 2017 to 62.7% in 2023 for imipenem and 2% in 2017 to 66.0% in 2023 for meropenem).

pneumoniae

Piperacillin tazobactam – 42.6% to 26.5%,
Carbapenems (imipenem from 5% to 35.6% and meropenem from 48% to 37.6%).

WHO Priority Pathogens List 2024

Cefepime Enmetazobactam

Developed by Orchid pharma, India and out-licensed to Allecra Therapeutics.

Why CPM?	Enmetazobactam
Better antibacterial spectrum compared to others β-lactams	Advantage of tazobactam
Enhanced porin penetration	Zwitterion property (Enhances penetration into periplasmic space)
Intrinsic resistance to hydrolysis by Amp C and Oxa 48 like enzymes.	Extended half-life related to tazobactam

Indications

Approved by FDA on Feb 2024 for complicated UTIs

Approved by European Medicines Agency for Complicated UTIs, Hospital acquired pneumonia incl VAP, Bacteremia secondary to UTI/ Hospital acquired pneumonia, caused by Enterobacterales and Pseudomonas aeruginosa

Materials and Methods

Population: 95 isolates

Study Period: Dec 2024 – Jan 2025

Inclusion criteria:

ESBL isolates of Enterobacterales
AmpC isolates of Enterobacterales

Exclusion criteria

MDR isolates of Enterobacterales

Non fermenters

Kirby – Bauer Disc diffusion testing
FDA breakpoints

Results

	MIC (µg/ml)				Disk Diffusion (mm)
Pathogen	S	SDD	I	R	S	SDD	I	R
Enterobacterales	≤8/8	-	-	≥16/8	≥ 21	-	-	≤20
Pseudomonas aeruginosa	≤8/8	-	-	≥16/8	≥ 18	-	-	≤17

Distribution of Isolates

Sample Distribution

Isolate vs Sample

Distribution of Strains

Efficacy of Enmetazobactam vs other bl-bli /Meropenem in e. coli

*bl-bli – Beta-Lactam/Beta-Lactamase Inhibitor

Efficacy of Enmetazobactam vs other bl-bli /meropenem in klebsiella pneumoniae and proteus mirabilis

Discussion

Sensitivity percentage of FEP-ETAZ – 100% vs PIT 70% and AMC 39%
Similar sensitivity percentage when compared to cefoperazone sulbactam (96%)

	ESBL producing E.coli			ESBL producing K.pneumoniae
	PIT	MRP	FEP/ETAZ	PIT	MRP	FEP/ETAZ
Kauvery, Trichy	76%	100%	100%	40%	100%	100%
CMC, Vellore	20%	100%	100%	46%	100%	100%

PK/PD: Piperacillin tazobactam vs Cefepime enmetazobactam

	Piperacillin tazobactam	Cefepime enmetazobactam
Dosing regimen	Dosing regimen	2/05g.q8H, 2 hr infusion
Protein binding	Piperacillin: 30% Tazobactam: 30%	Cefepime: 16-19% enmetazobactam: Negligible
Half life	1/1.8 hours	2.7/2.6 hours
fT/MIC	Piperacillin: 50% tazobactam: 77%	Cefepime: 60% Enmetazobactam: 20-45%
Urinary recovery of the given dose	Piperacillin: 68% tazobactam: 80%	Cefepime: 85% Enmetazobactam: 90%

Clinical Trial

ALLIUM RCT trial (Phase 3)

(Piperacillin tazobactam vs Cefepime enmetazobactam)

Group A

345 patients
2g cefepime + 500mg enmetazobactam q8H (2hr infusion) for 7 days
Overall success rate based on repeat culture after 7 days – 73/345(1%)
Clinical response: 5%
Microbiological recurrence: 39/345 (3%) at day 14

Group B

333 patients
5g piperacillim tazobactam cefepime q8H (2hr infusion) for 7 days
Overall success rate based on repeat culture after 7 days 196/333(9%)
Clinical response: 9%
Microbiological recurrence: 98/333 (4%) at day 14

Adverse Effects

Common side effects
- Elevation in AST/ALT and bilirubin levels (1 in 10)
- Phlebitis
- Diarrhoea
Serious side effects
- Colitis (1 in 1000)
Others
- Neurotoxicity due to cefepime

Limitations

Efficacy of other Enterobacterales needs to be analyzed
Numbers of AmpC producers were less compared to ESBL producers
In-vitro study

Conclusion

Novel Beta-Lactam/Beta-Lactamase Inhibitor

Meropenem sparing agent in place of Piperacillin tazobactam for cUTIs and Acute pyelonephritis

5g (2g cefepime and 0.5g enmetazobactam) every 8 hours IV over 2 hr for 7 -14 days in patients 18 years and older with estimated GFR between 60 – 129ml/min.
Dose adjustment is recommended in patients with renal impairment who have an eGFR <60ml/min or ≥130ml/min.

Further clinical studies on pneumonia and bacteremia needed.

References

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 Oct 4;328(13):1304-1314. doi: 10.1001/jama.2022.17034. PMID: 36194218; PMCID: PMC9533186.
Darlow, C. A., Hope, W., & Dubey, V. (2024). Cefepime/Enmetazobactam: a microbiological, pharmacokinetic, pharmacodynamic, and clinical evaluation. Expert Opinion on Drug Metabolism & Toxicology, 21(2), 115–123. https://org/10.1080/17425255.2024.2427310
Balaji V, Solaimalai D, Yamuna DB, Abirami S, et al. In-vitro microbiologic activity of cefepime enmetazobactam against ESBL and/or ampC producing E.coli and K. pneumonia from Indian clinical isolates. CMC, Vellore.
Annual report. Antimicrobial Resistance Research & Surveillance Network. ICMR 2024.

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Evaluation of cefepime-enmetazobactam against ESBL and AmpC β-lactamase producing Gram-negative bacteria: In- vitro study