Novel Options in Managing MDR

infections: Present & Future

Dr Vasanthakumar MD DNB IDCCM
ISCCM CHAIRMAN THANJAVUR
Cefepime/ Enmetazobactam

The world’s first novel BLBLI

developed by an Indian company
and approved by
USFDA, EMA, UKMHRA and CDSCO
Cefepime Enmetazobactam
Composition: Each vial contains:

• Cefepime Hydrochloride IP Monohydrate equivalent to

Cefepime………………………2 gm
• Enmetazobactam………….500 mg

Approved by CDSCO/EMA
Cefepime - 4th generation cephalosporin
• cUTI including AP
• It exerts bactericidal activity by inhibiting peptidoglycan cell wall • HAP/VAP
synthesis and inhibiting PBPs. • Associated bacteremia
• Commonly used in the treatment of Gram-positive and Gram-
negative bacterial infections
• Cefepime is generally stable to hydrolysis by class C- AmpC and Approved by USFDA
class D- OXA-48 enzymes.
• cUTI including AP

Enmetazobactam- A novel β-lactamase inhibitor

Approved by UKMHRA
Approved by UKMHRA for the following indications
• A methyl group - stronger interactions with ESBLs and AmpC
• Advantages over tazobactam • cUTI (bladder and kidneys)
• Zwitterion property enhances penetration into periplasmic • Certain types of pneumonia occur during a hospital stay
space • Bacteraemia due to, or possibly due to, any of the infections listed above
• Extended half-life relative to tazobactam
Cefepime Enmetazobactam

Dosage Recommended dosage based on renal function

• For cUTI, including AP- the Recommended Dosage for

Absolute eGFR (mL/min) Dosing Interval
Cefepime/Enmetazobactam
recommended dose for patients with
normal renal function is 2.5gm Mild (60 - <90) cefepime 2 g and enmetazobactam 0.5 g Every 8 hours
cefepime/ Enmetazobactam every 8 Moderate (30- <60) cefepime 1 g and enmetazobactam 0.25 g Every 8 hours
hours administered as an IV infusion Severe (15- <30) cefepime 1 g and enmetazobactam 0.25 g Every 12 hours
over 2 hours. End stage renal disease cefepime 1 g and enmetazobactam 0.25 g Every 24 hours
(<15)
• For HAP, including VAP – the
recommended dose for patients with Patients requiring cefepime 1 g and enmetazobactam 0.25 g Every 24 hours
normal renal function is 2.5gm cefepime/ hemodialysis loading dose on the first day of therapy and
Enmetazobactam every cefepime 0.5g and enmetazobactam 0.125 g
thereafter (every 24 hours but after the
8 hours administered as an IV infusion haemodialysis session on haemodialysis days).
over 4 hours.

• The usual duration of treatment is 7 to 10

Patients undergoing cefepime 2 g and enmetazobactam 0.5 g Every 48 hour
days. In patients with bacteraemia continuous ambulatory
treatment up to 14 days may be required. peritoneal dialysis (CAPD)
 Preparation of doses
• Cefepime/enmetazobactam must be reconstituted with
 0.9% NaCl solution for injection or
 5% glucose injection solution or
 2.5% glucose and 0.45% sodium chloride injection
• The reconstituted solution must be diluted further and used immediately within 6 hrs.
• Storage- refrigerated conditions at 2°C to 8 °C.

Reconstitution and dilution

Number of vials to Volume to withdraw from each Volume of infusion bag

Cefepime/enmetazobactam dose
reconstitute reconstituted vial for further dilution

2.5 gm (2 gm / 0.5 gm) 1 Entire content (approximately 23 mL) 250 mL

1.25 gm (1 gm / 0.25 gm) 1 11.5 mL (discard unused portion) 250 mL

0.625 gm (0.5 gm / 0.125 gm) 1 5.8 mL (discard unused portion) 250 mL
 Pharmacokinetic Parameters of Cefepime and Enmetazobactam
Pharmacokinetic Parameters Cefepime (Mean [SD]) Enmetazobactam (Mean [SD])
Lung penetration
Cmax (µg/mL)1 99.8 (26.4) 19.8 (6.3)
AUClast (μg•h/mL)1 379.5 (123.3) 75.3 (30.8) An epithelial lining fluid (ELF) study
% Bound to human plasma protein 20% Negligible in healthy volunteers showed
Vss (L) 20.02 (6.44) 25.26 (9.97) similar lung penetration
CL (L/h) 5.8 (1.9) 7.6 (2.9) • Cefepime up to 73%
T1/2 (h) 2.7 (1.1) 2.6 (1.1) • Enmetazobactam up to 62% at
8 hours post-start of infusion
Metabolism2 Minimally metabolized
Route of elimination Renal
% Excreted unchanged in urine 85% 90% A biodistribution coefficient
Proportionality Exposure approximately proportional to dose following IV fAUC (ELF/plasma) over the
administration entire 8h dosing interval of 47%
Accumulation Similar pharmacokinetics following single and multiple dosing for Cefepime and 46% for
Enmetazobactam.
Values represent mean (SD) in patients with cUTI and eGFR greater than or equal to 60 mL/min.
1
Pharmacokinetic parameters are presented at steady state (Day 7) in patients with cUTI and eGFR ≥ 60 mL/min at a dosage of 2 g cefepime and 0.5 g enmetazobactam/ 8 hrs
2
Approximately 7% of the cefepime dose is metabolized to N-methylpyrrolidine
AUC0-last = area under the plasma concentration time curve from time of dosing to the last measurable concentration; CL = clearance; Cmax = maximum concentration; SD =
standard deviation, T1/2 = terminal half-life; Vss = volume of distribution at steady state

https://www.ema.europa.eu/en/documents/product-information/exblifep-epar-product-information_en.pdf
Cefepime/ Enmetazobactam
In-vitro activity
 Spectrum of Activity Breakpoints
Cefepime Enmetazobactam used to treat USFDA provided Minimum Inhibitory
infections that are caused by following breakpoints of Concentrations (mcg/mL)
Cefepime/
susceptible bacteria: Enmetazobactam
against
Escherichia Klebsiella
Pathogen S SDD I R
coli pneumoniae
Enterobacterales <8/8 - - >16/8

Pseudomonas <8/8 - - >16/8

aeruginosa
Pseudomonas Proteus
aeruginosa mirabilis

EUCAST breakpoints for Enterobacterales are

Enterobacter S≤4, R>4 mg/L
cloacae complex

USFDA breakpoints: https://www.fda.gov/drugs/development-resources/cefepime-and-enmetazobactam-injection

EUCAST breakpoints: https://www.eucast.org/eucast_news/news_singleview?tx_ttnews%5Btt_news%5D=585&cHash=b88acafdf84e6e15d8f8df308ef2a514
Aim
To determine in vitro activity of cefepime-
Enmetazobactam for 1,993 clinical isolates of
In vitro study - 1
Enterobacteriaceae and Pseudomonas aeruginosa

Material and methods

MIC (g/ml) % Susceptible
Bacteria were isolated from hospitalized
Species (n), drug, and region MIC50 MIC90 Range CLSI EUCAST
patients with cUTI or AP, pneumonia, and
intraabdominal infections
Enterobacteriaceae

All (1,696)
Cefepime Enmetazobactam MICs were
Cefepime 0.06 32 0.015 to >64 83.7 82.5
determined using Enmetazobactam at a fixed
concentration of 8 ug/ml Cefepime-enmetazobactam 0.06 0.25 0.015 to >64 NAc NA
Piperacillin-tazobactam 2 64 0.12 to >128 85.7 820

The species distribution was Meropenem 0.03 0.06 0.008 to > 8 96.2 96.4
• 40% K. pneumoniae Ceftolozane-tazobactam 0.25 2 0.06 to > 32 90.7 88.5
• 35% E. coli Ceftazidime Applying 0.25 breakpoints
64 0.03
cefepime ofto1>-864ug/ml
81.2
to 77.7
• 15% P. aeruginosa
Cefepime Enmetazobactam
Ceftazidime-avibactam 0.12 0.5 resulted
≤0.015 in
to >cumulative
64 99.7 99.7
• 10% Enterobacter spp. (5% E. aerogenes and
Gentamicin inhibitions of0.596.2% 16
to 98.1%,
0.12respectively
to >32 89.0 88.3
E. cloacae) &
Ciprofloxacin 0.03 > 16 0.004 to >16 71.7 71.7
Morrissey, I., et al., 2019. Antimicrobial Agents and Chemotherapy, 63(7), 10-1128.
 Activities of Cefepime Enmetazobactam against clinical Gram-negative isolates

MIC (g/ml) % Susceptible

Species (n), drug, and region MIC50 MIC90 Range CLSI EUCAST
E. coli (697)
Cefepime 0.06 16 0.015 to >64 85.8 84.4
Cefepime-enmetazobactam 0.06 0.12 0.015 to >32 NAc NA
Piperacillin-tazobactam 2 8 ≤0.12 to >128 85.7 820
Meropenem 0.015 0.03 0.008 to > 8 99.6 99.7
Ceftolozane-tazobactam 0.25 0.5 0.06 to > 32 98.1 96.8
Applying a breakpoint of 1 ug/ml
Ceftazidime 0.25 16 0.06 to > 64 86.7 82.2
Ceftazidime-avibactam 0.12 0.25 ≤0.015 to > 64 86.7 82.2 to Cefepime Enmetazobactam
Gentamicin 0.5 32 0.12 to >32 86.2 85.5
Ciprofloxacin 0.015 > 16 0.004 to >16 64.1 64.1 inhibited 99.7% of all E. coli
E.. coli ESBL genotypeα (109)
Cefepime 16 >64 0.12 to >64 13.8 6.4 isolates
Cefepime-enmetazobactam 0.06 0.12 0.016 to 32 NA NA
Piperacillin-tazobactam 4 64 0.5 to >128 82.6 75.2
Meropenem 0.03 0.03 0.008 to 8 99.1 99.1
Ceftolozane-tazobactam 0.5 2 0.12 to > 32 93.6 88.1
Ceftazidime 16 64 1 to >64 26.6 3.7
Ceftazidime-avibactam 0.12 0.25 ≤0.015 to 2 100 100
Gentamicin 1 >32 0.12 to > 32 59.6 58.7
Ciprofloxacin >16 >16 0.008 to >16 9.2 9.2
Morrissey, I., et al., 2019. Antimicrobial Agents and Chemotherapy, 63(7), 10-1128.
 Activities of Cefepime Enmetazobactam against clinical Gram-negative isolates
MIC (g/ml) % Susceptible
Species (n), drug, and region MIC50 MIC90 Range CLSI EUCAST
K. Pneumoniae ESBL genotypeα (102)
Cefepime 64 >64 1 to >64 3.9 2.0
Cefepime- enmetazobactam 0.12 1 0.03 to 8 NAc NA
Piperacillin-tazobactam 32 >128 1 to >128 44.1 28.4
Meropenem 0.03 1 0.016 to > 8 92.2 91.2
Ceftolozane-tazobactam 2 32 0.12 to > 32 52.9 47.1 Applying breakpoints of 1 to 8 ug/ml
Ceftazidime 64 >64 0.25 to > 64 4.9 2.0
Ceftazidime-avibactam 0.25 1 ≤0.015 to > 2 100 100 to Cefepime- Enmetazobactam
Gentamicin 32 >32 0.25 to >32 41.2 38.2
Ciprofloxacin
Cefepime Enmetazobactam outperformed
>16
piperacillin-tazobactam resulted
> 16
and wasin as
cumulative
0.008 to >16
potent inhibitions
as
7.8 of in
7.8
meropenem
K. Pneumoniae KPC genotype (45) α

Cefepime >64 >64 8 to >64 0.0 0.0

Enterobacteriaceae specifically ESBL-producing E. coli and K. pneumoniae 93.2% to 96.4%, respectively, for all K.
Cefepime- enmetazobactam 16 >64 0.5 to 64 NA NA
Piperacillin-tazobactam
Meropenem
>128
>32
>128
>8
1 to >128
4 to 8
2.2
0.0
2.2
0.0
pneumoniae isolates
Ceftolozane-tazobactam >64 >32 16 to > 32 0.0 0.0
Ceftazidime 1 >64 32 to >64 0.0 0.0
Ceftazidime-avibactam 1 4 0.03 to 16 97.8 97.8
Gentamicin 2 >32 0.12 to > 32 71.1 66.7
Ciprofloxacin >16 >16 0.5 to >16 0.0 0.0

Morrissey, I., et al., 2019. Antimicrobial Agents and Chemotherapy, 63(7), 10-1128.
Cefepime/ Enmetazobactam
Clinical Evidences
 Phase 1 Phase 2 Phase 3

Pharmacokinetics, Safety and Study of Cefepime/ Efficacy and safety of

Tolerability studies of Enmetazobactam in Cefepime/ Enmetazobactam
cefepime/Enmetazobactam in hospitalized adults with cUTI, compared to
subjects with varying degrees including acute pyelonephritis Piperacillin/Tazobactam in
of renal function the treatment of cUTI,
including acute
The dose of 2g cefepime pyelonephritis.
Enmetazobactam had showed a combined with 500 mg of
favorable pharmacokinetic (PK) Enmetazobactam showed a Cefepime/Enmetazobactam
profile with linear PK good safety profile. met the criteria for
noninferiority as well as
superiority for the primary
outcome of clinical cure and
microbiological eradication as
compared with
piperacillin/tazobactam.
Phase 3
Objective
To evaluate whether cefepime/enmetazobactam
was noninferior to piperacillin/tazobactam for the
primary outcome of treatment efficacy in patients
with cUTIs or acute pyelonephritis (AP).

Design ALLIUM - A Phase 3, Randomized, Double-Blind, Multi-Center Study to Evaluate the Efficacy, Safety, and Tolerability of
Cefepime-AAI101 Compared to Piperacillin/Tazobactam in the Treatment of Complicated Urinary Tract Infections,
Including Acute Pyelonephritis, in Adults

Participants • Male or female patients ≥18 years old with complicated UTI or AP
• Patients who will require hospitalization and treatment with IV antibiotics for at least 7 days

Total 1041 participants

Randomization

Cefepime, 2 g/enmetazobactam, Piperacillin, 4 g/tazobactam, 0.5 g

0.5 g (n = 520), or (n = 521),

2-hour infusion every 8 hours for 7- 14 days

Kaye KS., et al., 2022, JAMA. 2022; 328(13): 1304–1314.
Results

Patient Disposition
• Presence of gram-negative bacterium that was
A total of 1034 received at least not resistant to either treatment
1 dose of the study drug  48.5% had a complicated UTI and 51.5%
had acute pyelonephritis
 Infections with Enterobacterales occurred
The median treatment duration in 95.6% of patients.
was 8.0 days.

The primary analysis set included • The most common pathogen at baseline
678 patients who received at least 1 was Escherichia coli (76.4%), followed by Klebsiella
dose of treatment pneumoniae (9.7%), Proteus
mirabilis (5.6%), Pseudomonas aeruginosa (3.5%),
and Enterobacter cloacae (1.5%).

Kaye KS., et al., 2022, JAMA. 2022; 328(13): 1304–1314.

 Response at visit No. (%) Piperacillin/tazobactam Treatment difference,
Primary Outcome Cefepime/ (n = 518) % (95% CI)a
Enmetazobactam (n=345)
• The primary outcome of a composite of complete Day 14
resolution of the clinical cure and
Overall success 273 (79.1) 196 (58.9) 21.2 (14.3 to 27.9)
microbiological eradication at day 14 was
79.1% in the cefepime/ Enmetazobactam Clinical cure 319 (92.5) 296 (88.9) 3.5 (-1.0 to 8.0)
group and 58.9% in the Microbiological 286 (82.9) 216 (64.9) 19.0 (12.3 to 25.4)
eradication
piperacillin/tazobactam group (difference,
21.2% [95% CI, 14.3%-27.9%]; Day 3 of treatment
• Cefepime/enmetazobactam was noninferior to Overall success 318 (92.2) 293 (88.0) 4.1 (-0.6 to 8.9)
piperacillin/tazobactam. Clinical cure 18 (5.2) 16 (4.8) 0.5 (-3.1 to 4.0)
• Cefepime/enmetazobactam also met the
Improvement 317 (91.9) 302 (90.7) Not determined
criterion for superiority compared with
Secondary Outcome
piperacillin/tazobactam Microbiological 323 (93.6) 299 (89.8) 3.8 (-0.6 to 8.3)

•
Cefepime/Enmetazobactam, compared with piperacillin/tazobactam, met the criteria for
The cefepime/enmetazobactam group had a significantly higher
eradication
End of treatment
noninferiority as well as superiorityOverall
for success
the primary318
rate of ME compared with piperacillin/tazobactam (82.9% vs outcome
(92.2) of clinical
311 (93.4) cure and
-1.3 (5.3 to 2.9)
64.9%] at day 14.
• microbiological
Clinical cure eradication.
The cefepime/enmetazobactam group had significantly better 323 (93.6) 315 (94.6) -1.1 (-4.8 to 2.7)
improvement in the composite outcome at day 21 Microbiological 332 (96.2) 322 (96.7) -0.7 (-3.7 to 2.5)
eradication
Day 21
Exploratory Outcomes Overall success 236 (68.4) 196 (58.9) 10.7 (3.4 to 17.8)
• Microbiological recurrence was lower in patients receiving Clinical cure 299 (86.7) 279 (83.8) 2.8 (-2.7 to 8.3)
cefepime/enmetazobactam (11.3%) compared with Microbiological 258 (74.8) 221 (66.4) 9.5 (2.6 to 16.3)
piperacillin/tazobactam (29.4%) at day 14. eradication

• The most common treatment-emergent adverse events were elevations of liver

Post Hoc Analyses function parameters:
•  Alanine aminotransferase (11.4% vs 11.6%),
A significantly better clinical cure in the Cefepime
 Aspartate aminotransferase (9.1% vs 8.9%), and
Enmetazobactam than piperacillin/tazobactam 80.9% vs
 Blood bilirubin (5.8% vs 3.9%).
60.7%. Kaye KS., et al., 2022, JAMA. 2022; 328(13): 1304–1314.
In vitro Analysis of in vitro data from Phase 3 ALLIUM trial
study- 2

Objective
• To investigate the in vitro susceptibility profile and β-lactamase genotypes of Enterobacterales baseline qualifying urinary pathogens
obtained from ALLIUM patients
• Enterobacterales urinary baseline pathogens were analyzed from both mMITT and mMITT+R population

Secondary population mMITT+R

Primary efficacy population
(n=704 of 787 total BP)
mMITT (n=663 of 690 total BP)
mMITT+R included pathogens in
mMITT included pathogens with
mMITT as well as those resistant to
Cefepime/Enmetazobactam (FPE)
either agent (FPE MIC ≥16 µg/ml; PTZ
MIC≤8 µg/ml or PTZ MIC≤64 µg/ml
MIC≥128 µg/ml) or with a missing MIC
determination

E. coli and K. pneumoniae are predominant Enterobacterales baseline pathogens in ALLIUM trial
• Clinical isolates of Enterobacterales with MIC ≥1 µg/ml to ceftazidime, ceftriaxone, cefepime, meropenem, or FPE were genotyped
by multiplex PCR for β-lactamases
Belley A et al., Poster presented at 31st ECCMID conference 2021
Summary of MIC and susceptibility results of the Enterobacterales baseline pathogens
mMITT population
MIC (g/ml) CLSI EUCAST

Organism group/antibacterial agent MIC50 MIC90 Range %S %I %R %S %R

All Enterobacterales (n=663)
Cefepime 0.06 64 ≤0.008->64 79.5 4.7 15.8 77.7 18.4
Meropenem ≤0.0115 0.03 ≤0.015-0.5 100 0.0 0.0 100.0 0.0
Piperacillin-tazobactam 1 8 ≤0.25-64 96.1 3.9 0.0 92.5 7.5
Cefepime-enmetazobactam 0.03 0.12 ≤0.008-4 99.7 0.3 0.0 99.2 0.0
Enterobacterales, ESBL positive
(n=142)

Cefepime 64 >64 0.03->64 12.7 16.2 71.1 5.6 81.7 Cefepime Enmetazobactam exhibited
0.03 0.06 ≤0.015-0.25 100.0 0.0 0.0 100.0 0.0
Meropenem
Piperacillin-tazobactam 4 16 ≤0.25-64 90.8 9.2 0.0 81.7 18.3
comparable in vitro antibacterial
Cefepime- enmetazobactam 0.06 0.12 ≤0.015-4 98.6 1.4 0.0 91.2 0.0 activity to meropenem and was
E. Coli (n=518)
Cefepime 0.03 64 ≤0.008->64 80.1 5.0 14.9 78.4 17.8
more potent than
Meropenem ≤0.015 0.03 ≤0.015-0.06 100.0 0.0 0.0 100.0 0.0 piperacillin/tazobactam against the
Piperacillin-tazobactam 1 8 ≤0.25-64 97.3 2.7 0.0 93.6 6.4
ESBL-producing Enterobacterales in
Cefepime- enmetazobactam 0.03 0.06 ≤0.008-4 99.6 0.4 0.0 99.0 0.0
K-pneumoniae (n=66)
mMITT
Cefepime 0.06 >64 0.03->64 69.7 3.0 27.3 69.7 28.8
Meropenem 0.03 0.06 ≤0.015-0.5 100.0 0.0 0.0 100.0 0.0
Piperacillin-tazobactam 2 32 ≤0.5-64 89.4 10.6 0.0 83.3 16.7
Cefepime- enmetazobactam 0.03 0.12 ≤0.015-1 100.0 0.0 0.0 100.0 0.0
Belley A et al., Poster presented at 31st ECCMID conference 2021
Summary of MIC and susceptibility results of the Enterobacterales baseline pathogens
mMITT+R population
MIC (g/ml) CLSI EUCAST
Organism group / antibacterial agent
MIC 50 MIC90 Range %S %I %R %S %R
All Enterobacterales (n=663)
Cefepime 0.06 >64 <0.008->64 75.9 4.7 19.5 74.0 21.9
Meropenem ≤0.015 0.06 ≤0.05->32 97.9 0.6 1.6 98.4 1.3
Piperacillin-tazobactam 1 16 ≤0.25->256 91.1 3.8 5.1 87.5 12.5
Cefepime-enmetazobactam 0.03 0.12 ≤0.008->64 98.2 0.4 1.4 97.3 1.4
Enterobacterales, ESBL positive (n=165)
3

Cefepime 64 >64 0.03->64 11.5 13.9 74.5 4.8 83.6

Meropenem 0.03 0.12 ≤0.05->32 95.8 2.4 Cefepime Enmetazobactam exhibited
1.8 98.2 1.2
Piperacillin-tazobactam 4 >256 ≤0.25->256 78.2 8.5 13.3 70.3 29.7
Cefepime- enmetazobactam 0.06 0.5 0.015-16 97.6 1.8 0.6 95.2 0.6
comparable in vitro antibacterial
E.Coli (n=526) activity to meropenem and was
Cefepime
Cefepime
Meropenem
0.06
Enmetazobactam
64
≤0.015 0.03 in
≤0.008->64
vitro
≤0.015-0.06
79.5 5.3
antibacterial
100.0 0.0
15.2
0.0
77.8 18.1
activity
100.0 0.0
more
was unaffected by potent than of ESBL
the presence
Piperacillin-tazobactam 1 8 ≤0.25->256 96.2 2.7 1.1 92.6 7.4 piperacillin/tazobactam against the
thereby
Cefepime- supporting its
enmetazobactam 0.03 development
0.06 ≤0.008-4 as99.6a novel
0.4 0.0carbapenem
98.9 0.0 sparing therapiesEnterobacterales in
ESBL-producing
K-pneumoniae (n=92)
Cefepime 0.25 >64 0.03>64 53.3 2.2 44.6 52.2 45.7 mMITT+R population
Meropenem 0.03 4 ≤0.015->32 83.7 4.3 12.0 88.0 9.8
Piperacillin-tazobactam 4 >256 0.5->256 64.1 8.7 27.2 59.8 40.2
Cefepime- enmetazobactam 0.06 4 0.015->64 89.1 1.1 9.8 89.1 9.8
E-dependent breakpoint of 8g/ml. Cefepime/ enmetazobactam MIC was determined using a fixed enmetazobactam
2

concentration producing isolates that co-express metallo=β-lactamases

Belley A et al., Poster presented at 31st ECCMID conference 2021
in vitro study 3- Indian data
Objective

 To assess the in vitro activity of FEP/ETAZ against recent genotyped Escherichia coli and Klebsiella
pneumoniae clinical isolates collected in India.

Methods

 Third-generation cephalosporin-susceptible (E. coli, n=51 and K. pneumoniae, n=52) and cephalosporin-
resistant (E. coli, n=195 and K. pneumoniae, n=158) isolates collected from blood culture samples.

 Presence of ESBL (TEM, SHV, CTX-M-1,2,8,9,25), OXA-1 and ampC (ACC, ACT, DHA, CIT, FOX, CMY)
genes were detected by multiplex PCR.

 The MICs were determined using the CLSI-recommended reference broth microdilution method.

 MICs of FEP/ETAZ were determined using a fixed 8 mg/L of Enmetazobactam and susceptibility was
interpreted using EUCAST breakpoints.
In-vitro activity of FEP/ETAZ and comparators against ESBL with OXA-1/ampC producing
E. coli (n=195) and K. pneumoniae (n=158) isolates
 Results

 At current CLSI breakpoints, 40% of ESBL-E. coli and 73.4% of ESBL-K. pneumoniae were
susceptible to TZP
Pathogens MIC90 mg/L
.
TZP Ceftriaxone/sulbactam Ceftriaxone/ FEP/ETAZ
sulbactam/EDTA
ESBL/ampC- E. coli >128 >128 32 ≤2
ESBL/ampC- K. 32 >128 64 ≤1
pneumoniae
 The addition of Enmetazobactam greatly enhanced the activity of cefepime against E. coli
and K. pneumoniae isolates co-harbouring ESBL with OXA-1/ampC genes.
 FEP/ETAZ showed a meropenem comparable activity against the collection of ESBL and/or
ampC harboring E. coli and K. pneumoniae isolates.
 The addition of Enmetazobactam restored the activity of cefepime against these isolates
and indicated the potential utility of FEP/ETAZ against ESBL-producing Enterobacterales as
a carbapenem-sparing option.
Use In Special Population and Important Warnings

• Pregnancy & lactation- no efficacy and safety data is

available
• Pediatric population- no efficacy and safety data is
Special available
population • Geriatric use- Serious neurologic adverse reactions
with unadjusted doses
• Hepatic impairment- No dose adjustment is necessary
• Renal impairment- Dose adjustment based on eGFR

Important • Hypersensitivity reaction

Warnings • Neurotoxicity- with unadjusted dose
Cefepime Enmetazobactam Positioning

In the treatment of cUTI/acute pyelonephritis, HAP including VAP and

bacteremia associated with the above-mentioned conditions

 As a first-line therapy where ESBL Enterobacterials are suspected

(instead of other BLBLIs such as Pip/taz)

 As carbapenem sparer
 Summary
Cefepime Enmetazobactam:
 A novel BLBLI with Enmetazobactam having more potent activity than Tazobactam
 Approved by CDSCO, EMA, USFDA and UKMHRA
 Approved indications- cUTI including AP, HAP/VAP and associated bacteremia
 In vito activity against ESBL-producing Enterobacterales
Cefepime
 Comparable Enmetazobactam is a useful addition in the treatment of cUTI
to Meropenem
 More potent than Piperacillin/tazobactam
including AP, HAP/VAP and associated bacteremia caused by ESBL
 Clinical evidence-
 Non-inferior and superior composite Enterobacteriaceae
outcomes (clinical cure + microbiological eradication) as
compared to Piperacillin/tazobactam in the treatment of cUTI
 Less relapse rate as compared to piperacillin/tazobactam in patients with cUTI
 Acceptable safety profile