Why the newly licensed antibiotic cefepime should be introduced to UK formularies

Patients with infections caused by multidrug-resistant (MDR) Enterobacteriales — for which carbapenem antimicrobials are often the medicines of choice — can be difficult to manage. The number of carbapenem-resistant organisms is rising^[1]
and we need alternative options.

Cefepime, a fourth-generation broad-spectrum cephalosporin, has been used extensively in the United States, Europe and parts of Asia, but it was not until December 2017 that it was licensed for use in UK healthcare, where it may be particularly useful.

In recent years, there has been a UK-wide drive to move towards ambulatory care^[2]
— a streamlined ‘outpatient’ approach to managing patients who present in the hospital, without admitting them. Although submitting service data is not a mandatory requirement, data obtained from the National Outcome Registry System suggest that uptake of cefepime has been slow since it was licensed: only two UK trusts appear to have prescribed cefepime for patients using outpatient services^[3]
. However, with its stability and spectrum of activity, cefepime is a welcome alternative antimicrobial agent for use in this setting.

Outpatient services

Cefepime is licensed for twice-daily dosing for non life-threatening infections, so it is a good option for outpatient parenteral antimicrobial therapy (OPAT) services. These services allow medically stable patients to receive their intravenous antibiotics in the outpatient clinic by visiting the hospital once or twice per day, or to have the antibiotic administered in their own homes if they are unable to visit for daily administration. OPAT services reduce the demand for hospital beds and prevent patients from being exposed to potential infections in an outpatient setting.

In cases where 2g three times daily dosage is required, such as for pseudomonal infections, treatment can be facilitated by continuous infusion via elastomeric pumps.

Sparing the use of carbapenem

Among MDR Enterobacteriales, the most common resistance mechanisms are the production of either AmpC enzymes or extended-spectrum beta-lactamases (ESBL). Several studies have demonstrated that using cefepime in the treatment of ESBL-producing pathogens leads to increased mortality, and therefore it is not recommended. However, cefepime may be useful to treat AmpC-producing Enterobacteriales while sparing the use of carbapenem^{[4]
,[5]
,[6]
,[7]
,[8]}
.

A study by Tamma et al. found no difference in outcome (30-day mortality and length of stay) for hospitalised patients who received meropenem or cefepime for the treatment of blood, bronchoalveolar lavage or intra-abdominal fluid cultures growing AmpC-producing Enterobacter spp., Serratia spp., or Citrobacter spp.^[9]
. Similarly, a small study by Blanchette et al. found no difference in clinical success between patients treated with ertapenem or cefepime for infections caused by AmpC-producing Enterobacteriales^[10]
.

However, there is some evidence to suggest against using cefepime as a carbapenem-sparing agent. One study of 305 adults with monomicrobial AmpC-producing Enterobacter cloacae bacteremia found higher mortality among the cefepime-susceptible dose-dependent (defined as cefepime minimum inhibitory concentration [MIC] 4–8 mg/L) isolates than those treated with carbapenem^[11]
. The authors concluded that cefepime is one of the therapeutic alternatives for cefepime-susceptible (that is, MIC <4mg/L) E. cloacae bacteremia, but where there is laboratory evidence of a raised MIC, cefepime is inferior to carbapenem therapy for E. cloacae bacteremia^[11]
.

Doses and stability

Cefepime can be administered intravenously or intramuscularly. The dose can vary depending on the severity of the infection and the patient’s renal function — it can range from 500mg every 12 hours to 2g every 8 hours^[12]
. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the US Food and Drug administration (FDA) recommend 2g every eight hours for Pseudomonas aeruginosa
^[13]
.

Cefepime has a Gram-positive activity similar to that of ceftriaxone; it is also active against Pseudomonas aeruginosa, which makes its Gram-negative activity similar to that of ceftazidime

The stability of cefepime in elastomeric pumps has not yet been investigated by the British Society for Antimicrobial Chemotherapy. These pumps are used by many OPAT services to provide a continuous infusion of antimicrobial agents and the stability of the antimicrobial agent is the main limiting factor for administration in this way. Although no formal evaluation by a UK institution has taken place, studies conducted outside of the UK have demonstrated the stability of cefepime in continuous infusions and elastomeric pumps^{[14]
,[15]
,[16]}
.

Spectrum of activity

Cefepime has a Gram-positive activity similar to that of ceftriaxone; it is also active against Pseudomonas aeruginosa, which makes its Gram-negative activity similar to that of ceftazidime. Importantly, cefepime is stable against some of the common plasmid- and chromosome-mediated beta-lactamases and is a poor inducer of AmpC beta-lactamases. As a result, it retains activity against some Enterobacteriales that are resistant to third-generation cephalosporins.

This antibiotic also has a linear pharmacokinetic profile. It is excreted unchanged via the kidneys and has a half-life of two hours^[17]
. Cefepime achieves adequate concentration in the gall bladder, pancreas, peritoneum, lung, prostate and bone, but has variable concentration levels in the cerebral spinal fluid^[17]
.

The MICs of cefepime needed to determine whether a pathogen is susceptible or resistant vary by organism; these breakpoints are set by EUCAST^[11]
. For complex patients or deep-seated infections, clinicians should obtain an actual MIC rather than rely on disc susceptibility testing^[13]
.

Adverse events and safety concerns

While cefepime may be useful in some circumstances, healthcare professionals should be aware of safety concerns for its use in some patients. In May 2007, the FDA published a safety alert in response to a meta-analysis of the efficacy and safety of cefepime^[12]
. The article described higher all-cause mortality in patients treated with cefepime compared with other beta-lactam antibiotics for neutropenic fever, pneumonia, urinary tract and gynaecological infection, and a mix of other infections^[12]
.

However, in 2009, the FDA issued an update following a further review of the data and an analysis submitted by Bristol Meyers Squibb. The analysis determined that the data do not indicate a higher rate of death in patients treated with cefepime; the drug was therefore able to maintain all listed indications^[12]
. Data for the use of cefepime as empiric monotherapy in patients low in neutrophils were not conclusive. As a result, the FDA does not recommend cefepime monotherapy in high-risk neutropenic patients (for example, those who have recently had stem-cell transplant)^[10]
.

In 2017, a study by Andreatos et al. aimed to address the controversy around empiric use of cefepime in febrile neutropenia, as cefepime remains the first-line treatment in guidelines issued by the Infectious Diseases Society of America, the European Society for Medical Oncology, and the Japan Febrile Neutropenia Study Group. This review found increased mortality and toxicity-related treatment discontinuation in the cefepime arm of patients with febrile neutropenia, compared with patients treated with a carbapenem. The authors also demonstrated that the lower-dose regimen for cefepime resulted in a lower toxicity rate, but overall mortality rates were higher^[18]
.

Cefepime is likely to feature more prominently in UK healthcare in the near future, particularly when cefepime with a novel beta-lactamase inhibitor has been successfully trialled

The neurotoxic effects of cefepime are well established, and drug accumulation due to renal insufficiency is a known risk factor. In 2012, the FDA issued a safety announcement to this effect, which highlighted the need for cefepime dosage adjustment in patients with renal impairment^[17]
. The document was published as a result of reported cases of patients developing non-convulsive status epilepticus (seizure without tonic–clonic activity); most cases were identified in those with renal impairment whose doses had not been appropriately adjusted.

In the majority of cases, the seizures were reversible and resolved after discontinuing cefepime and/or after haemodialysis^[19]
. A recent study in Switzerland (a major user of cefepime in Europe) reported an overall neurotoxicity incidence rate of 23%, and some hospitals now conduct therapeutic dose monitoring. Boschung-Pasquier et al. reported that a trough cefepime level of <7.7mg/L is associated with no neurotoxicity, while levels >38.1mg/L always led to neurological side effects^[20]
.

A valuable option

Cefepime is likely to feature more prominently in UK healthcare in the near future, particularly as the combination of cefepime with a novel beta-lactamase inhibitor (such as AAI101) — which aims to restore the activity of cefepime against ESBL-producing Enterobacteriales (for example, CTX-M-15) — has been successfully trialled^[21]
,[22]
. Other studies have investigated the in vitro activity of cefepime–zidebactam (FEP–ZID) against MDR pathogens, with positive outcomes, although randomised clinical trials are required to evaluate the effect of these combinations and their safety and efficacy in patients^[23]
,[24]
.

Based on the current evidence in the literature, cefepime is a welcome addition to the list of antimicrobial agents licensed in the UK — particularly since novel antimicrobial development pipelines are sparse. Healthcare organisations should consider adding the antibiotic to their formularies for OPAT services in which treatment with the antibiotic carbapenem is becoming challenging.

However, treatment with cefepime requires a risk-versus-benefit assessment on a case-by-case basis, and sites looking to introduce cefepime as an option to their formulary should ensure appropriate monitoring and safety checks are in place.