What are the considerations for antibiotic de-escalation from Merrem (Meropenem) to Cefepime?

From the Guidelines

Antibiotic de-escalation from meropenem (Merrem) to cefepime is appropriate when culture and sensitivity results show that the infecting organism is susceptible to cefepime, as recommended by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines 1. This transition should occur as soon as microbiology results are available, typically within 48-72 hours of starting empiric therapy. The standard adult dose of cefepime is 1-2g IV every 8-12 hours, adjusted based on infection severity, site of infection, and renal function. When de-escalating, maintain the same treatment duration originally planned for the infection. Before making this change, ensure the patient has shown clinical improvement on meropenem and that all identified pathogens are sensitive to cefepime. Some key points to consider when de-escalating include:

• De-escalation helps reduce the risk of developing antimicrobial resistance, decreases potential adverse effects, and lowers healthcare costs.
• Meropenem is a broader-spectrum carbapenem antibiotic that covers gram-positive, gram-negative, and anaerobic bacteria, while cefepime is a fourth-generation cephalosporin with good gram-negative coverage but more limited against certain resistant organisms and anaerobes.
• The Surviving Sepsis Campaign guidelines also recommend daily assessment for de-escalation of antimicrobial therapy in patients with sepsis and septic shock 1.
• The ESCMID guidelines suggest that stepdown targeted therapy following carbapenems once patients are stabilized, using old beta-lactam/beta-lactamase inhibitors (BLBLI), quinolones, cotrimoxazole or other antibiotics based on the susceptibility pattern of the isolate, is good clinical practice 1. However, they also suggest that cephamycins (e.g. cefoxitin, cefmetazole, flomoxef) and cefepime not be used for third-generation cephalosporin-resistant Enterobacterales (3GCephRE) infections, due to limited evidence 1. In this case, since cefepime is being considered for de-escalation, it is essential to ensure that the infecting organism is susceptible to cefepime. It is also crucial to monitor the patient's clinical response and adjust the treatment plan accordingly. By following these guidelines and considering the specific characteristics of the infecting organism, antibiotic de-escalation from meropenem to cefepime can be a safe and effective way to manage infections while promoting antimicrobial stewardship.

From the Research

Antibiotic De-escalation from Merrem to Cefepime

• De-escalation of antimicrobial therapy is often advocated to reduce the use of broad-spectrum antibiotics in critically ill patients 2.
• A study found that empirical prescription of meropenem was de-escalated in 42% of the patients, with patients in whom antibiotics were de-escalated having a trend toward a lower mortality rate (7% vs 21%, P = .12) 2.
• Cefepime is a broad-spectrum fourth-generation cephalosporin with activity against Gram-positive and Gram-negative pathogens, and is generally safe and efficacious 3.
• The pharmacokinetics of cefepime is altered under certain pathophysiological conditions, resulting in high inter-individual variability in cefepime volume of distribution and clearance 3.
• A prospective drug utilization evaluation found that the vast majority of courses with cefepime, piperacillin-tazobactam, and meropenem are empirically selected and continued, underlying the importance of an optimal initial choice 4.
• Appropriate meropenem de-escalation in patients with febrile neutropenia is safe and can result in improved clinical outcomes, including lower 30-day all-cause mortality and median hospital length of stay 5.
• The protein binding of meropenem, cefepime, and piperacillin was found to be highly variable, with average unbound fraction values lower than those reported in the literature 6.

De-escalation Criteria

• De-escalation was defined as the administration of an antibiotic with a narrower spectrum within 3 days of the start of meropenem 2.
• Reasons for not de-escalating included the absence of conclusive microbiology and colonization with multiresistant gram-negative organisms (MRGN) 2.
• Logistic regression model demonstrated that positive culture, including positive blood culture, and graft-versus-host disease (GVHD) were associated with high rates of appropriate de-escalation, while immunosuppression was associated with lower rates of appropriate de-escalation 5.

Clinical Implications

• Antibiotic stewardship is a critical aspect of managing cancer patients with febrile neutropenia to limit the development of drug-resistant organisms and minimize adverse drug effects 5.
• Therapeutic drug monitoring of cefepime may be beneficial in certain patients, including those who are critically ill, have life-threatening infections, or are infected with more resistant pathogens 3.
• The high inter-individual variability in cefepime volume of distribution and clearance poses challenges for population dosing approaches, and direct measurements of free drug concentrations should be considered when managing patients administered with these drugs 3, 6.