Role of Cefepime/Enmetazobactam in Ventilator-associated Pneumonia (VAP)

Key Takeaways:

• Ventilator-associated pneumonia (VAP) is the most common ICU infection, affecting up to 20% of critically ill patients with a mortality rate of approximately 13%, significantly increasing the healthcare burden.
• Gram-negative bacilli, especially multidrug-resistant pathogens like Pseudomonas spp., Acinetobacter spp., and ESBL-producing Enterobacteriaceae, as well as Staphylococcus aureus, are the main causative agents of VAP.
• Cefepime-Enmetazobactam, a novel β-lactam–β-lactamase inhibitor combination, shows strong activity against ESBL and Amp C-producing Gram-negative pathogens, with effective lung penetration and a favorable safety profile.
• The Central Drugs Standard Control Organization(CDSCO, India) (1), the European Medicines Agency (EMA), and the United Kingdom Medicines and Healthcare Products Regulatory Agency (UKMHRA) (2) approved the combination of cefepime/enmetazobactam in 2024 for the treatment ventilator-associated pneumonia (VAP) in patients who are 18 years of age or older. 

Ventilator-associated pneumonia (VAP) is the most prevalent healthcare-associated infection in intensive care units, impacting up to 20% of critically ill patients worldwide. This condition not only increases the use of antibiotics but also contributes significantly to antibiotic resistance, posing a serious public health challenge.(3)

Ventilator-associated Pneumonia (VAP) -Healthcare Burden in India: In India, VAP carries a mortality rate of approximately 13%. The majority of infections (about 58%) are attributed to Gram-negative bacilli, with Staphylococcus aureus responsible for approximately 20% of cases. Notably, common multidrug-resistant (MDR) pathogens include Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBL), AmpC, or metallo-β-lactamases (MBL). (4)

VAP is associated with significantly longer hospital stays, averaging about 21 days compared to just 8.2 days for non-VAP patients. This extended hospitalization places considerable strain on healthcare resources, with treatment costs reaching approximately INR 544,467 for VAP patients, contrasted with INR 207,416 for those without the infection. (5)Given these challenges, effective prevention and management strategies for VAP are essential for improving patient outcomes and reducing healthcare costs. In this context, exploring the role of cefepime/enmetazobactam as a treatment option for VAP is particularly relevant.

Cefepime-Enmetazobactam for Ventilator-Associated Pneumonia:

A demographic study among 20 participants assesses the pharmacokinetics, safety, and clinical efficacy of cefepime-enmetazobactam, a β-lactam–β-lactamase inhibitor combination, for the treatment of nosocomial pneumonia, especially VAP. This combination exhibits strong activity against Enterobacteriaceae, including ESBLs and AmpC, providing a promising carbapenem-sparing alternative. Key findings include:

• Pharmacokinetics: Cefepime-enmetazobactam showed similar behavior in plasma and epithelial lining fluid(ELF), with mean drug partitioning of 60.59% for cefepime and 53.03% for enmetazobactam, indicating effective lung penetration.
• Monte Carlo Simulations: Cefepime-enmetazobactam demonstrates near 100% joint probability of target attainment (PTA) in ELF for ESBL-producing Klebsiella pneumoniae isolates with a MIC of ≤4 mg/L, and 94.4% and 78.1% for MICs of 8 mg/L and 16 mg/L, respectively. This efficacy supports its potential as a reliable treatment option, particularly in overcoming resistant infections. (Figure 1)
• Safety Profile: Well tolerated with no serious adverse events leading to discontinuation.(6)

Figure 1: The probability of target attainment in epithelial lining fluid (ELF), shown as solid circles, is plotted alongside the distribution of minimum inhibitory concentration (MIC) values for cefepime-enmetazobactam against 102 ESBL-producing Klebsiella pneumoniae isolates, represented by solid squares.

Given its broad-spectrum efficacy, safety, and favorable pharmacokinetic properties, cefepime-enmetazobactam presents a strong candidate for use in treating VAP, potentially allowing for carbapenem-sparing strategies.(6)

Cefepime/enmetazobactam offers a promising option for managing VAP, effectively targeting ESBL and AmpC-producing Gram-negative pathogens and reducing reliance on carbapenems.

References:

1. DCGI Approval for antibiotic drug combination of cefepime and enmetazobactam. Retrieved oon 15th July 2024 from https://www.expresspharma.in/orchid-pharma-receives-dcgi-approval-for-its-antibiotic-drug-combination-of-cefepime-and-enmetazobactam-nce/

2. Keam SJ. Cefepime/Enmetazobactam: First Approval. Drugs. 2024 Jun;84(6):737-744. doi: 10.1007/s40265-024-02035-2. Epub 2024 May 18. PMID: 38761353.

3. Howroyd, F., Chacko, C., MacDuff, A. et al. Ventilator-associated pneumonia: pathobiological heterogeneity and diagnostic challenges. Nat Commun 15, 6447 (2024). https://doi.org/10.1038/s41467-024-50805-z

4. Thakur HK, Tarai B, Bhargava A, et al. Pathogenesis, Diagnosis and Therapeutic Strategies for Ventilator-associated Pneumonia. J Pure Appl Microbiol. 2024;18(2):772-796. doi: 10.22207/JPAM.18.2.10

5. Thimmaiah, Guruprasad1; Pandey, Navin1; Prinja, Shankar2; Jain, Kajal3; Biswal, Manisha4; Agarwal, Ritesh5; Koushal, Vipin1; Sethi, Saru1. Ventilator-associated pneumonia – What price does the public health system pay?. Lung India 41(4):p 278-283, Jul–Aug 2024. | DOI: 10.4103/lungindia.lungindia_597_23