Clinical efficacy demonstrated in seriously ill patients with HABP and VABP1,2

Studied in a multicenter, double-blind, randomized trial vs extended-infusion, high-dose meropenem in HABP/VABP1,2

Study design1,2

Clinical trial assessment timeline: Fetroja vs meropenem. Primary efficacy endpoint: All-cause mortality (ACM) rate at Day 14 in modified ITT population. Fetroja (n=148) 2 grams IV over 3 h q8h + linezolid for at least 5 days. Meropenem (n=150) 2 grams IV over 3 h q8h + linezolid for at least 5 days. Day 1 start therapy Day 3-4: Early assessment End of Treatment (EOT): up to day 21. Test of Cure: EOT +7 days (±2) Follow-up: EOT +14 days (±3) End of Study: EOT +28 day (±3)

  • Non-inferiority trial in patients with nosocomial pneumonia, randomized 1:11,2*
    • Patients with HABP, VABP, and HCABP† were included (N=298)
  • Key secondary endpoints included Day-28 ACM and clinical cure1,2
  • At time of randomization, patients with a carbapenem-resistant Gram-negative infection (if known) were excluded3
  • The top 5 baseline Gram-negative pathogens were Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Enterobacter cloacae3
  • ~30% of patients in both arms had ESBL-producing bacterial isolates at baseline1
  • The study evaluated a seriously ill nosocomial pneumonia population1,3
    • Patients had a mean APACHE II score of 16; 49% of patients had a score of ≥16
    • 60% of patients were ventilated, while 68% were in the ICU
    • ~33% had failed empiric treatment, a marker for drug resistance

APEKS-NP included a higher dose of meropenem as a comparator for patients at risk for MDR Gram-negative infections vs similar HABP/VABP studies (meropenem 2 grams IV over 3 h q8h vs 1 gram)1,3-5

*
All patients received Gram-positive treatment with linezolid for at least 5 days.1
†
Study was initiated before Infectious Diseases Society of America/American Thoracic Society guidance to remove HCABP from HABP/VABP category.6
ACM=all-cause mortality; EOT=end of treatment; ESBL=extended-spectrum β-lactamase; HCABP=healthcare-associated bacterial pneumonia; ITT=intent to treat; MDR=multidrug resistance; q8h=every 8 hours.

Primary endpoint: Day 14 all-cause mortality mITT1,2a

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a
mITT population included all randomized patients who received study medication with evidence of bacterial pneumonia, except those with only anaerobic or Gram-positive aerobic infections.1
b
The adjusted treatment difference (Fetroja minus meropenem) and associated 95% CI were based on the Cochran-Mantel-Haenszel method. Subjects with unknown survival status were considered deaths. For Day 14 all-cause mortality, 1 meropenem subject had unknown status; for Day 28 all-cause mortality, 1 meropenem subject and 2 Fetroja subjects had unknown status.1

Day 14 and Day 28 all-cause mortality were similar regardless of pathogen type, including A baumannii, K pneumoniae, and P aeruginosa1,2,7

All-cause mortality rate was similar for Fetroja vs extended-infusion, high-dose meropenem against ESBL-producing bacteria in the mITT population1

Fetroja demonstrated clinical efficacy against pathogens with several key carbapenem-resistant mechanisms, including metallo-carbapenemases (IMP, VIM, and NDM) and serine carbapenemases (OXA-48, OXA-23)3,8,9‡

‡
Post-randomization, carbapenem-resistant infections were detected.3
CI=confidence interval; mITT=modified intent to treat.

Adverse reactions

Fetroja adverse reactions vs extended-infusion, high-dose meropenem in HABP and VABP1

Serious adverse reactions and adverse reactions leading to discontinuation
ADVERSE REACTION
(SAFETY POPULATIONc)		 FETROJA (n=148) EXTENDED-INFUSION, HIGH-DOSE MEROPENEM (n=150)
Serious adverse reactions 36.5% 30.0%
Death 26.4% 23.3%
Discontinuation of treatment due to adverse reaction 8.1% 9.3%
Selected adverse reactions occurring in ≥4% of patients receiving Fetroja in the HABP/VABP trial
ADVERSE REACTION FETROJAd (n=148) EXTENDED-INFUSION, HIGH-DOSE MEROPENEMd (n=150)
Elevations in liver testse 16% 16%
Hypokalemiaf 11% 15%
Diarrhea 9% 9%
Hypomagnesemia 5% <1%
Atrial fibrillation 5% 3%
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c
Safety population: all randomized subjects who received at least 1 dose of the study treatment (Fetroja, n=148, and extended infusion, high-dose meropenem, n=150).1,3
d
2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function).1
e
Elevations in liver tests include the following terms: aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyl transferase increased, liver function test increased, liver function test abnormal, hepatic enzyme increased, transaminases increased, hypertransaminasemia.1
f
Hypokalemia includes blood potassium decreased.1