Cefepime Hydrochloride and Enmetazobactam (Monograph)

Brand name: Exblifep
Drug class: Fourth Generation Cephalosporins

Introduction

Cefepime hydrochloride and enmetazobactam is a fixed combination of cefepime (a fourth generation cephalosporin antibiotic) and enmetazobactam (a -lactamase inhibitor).

Uses for Cefepime Hydrochloride and Enmetazobactam

Cefepime hydrochloride and enmetazobactam has the following uses:

Cefepime hydrochloride and enmetazobactam (cefepime/enmetazobactam) is indicated for the treatment of patients 18 years and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by designated susceptible microorganisms.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefepime/enmetazobactam and other antibacterial drugs, the fixed combination preparation should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

Cefepime Hydrochloride and Enmetazobactam Dosage and Administration

General

Cefepime/enmetazobactam is available in the following dosage form(s) and strength(s):

Single-dose vials containing sterile powder for reconstitution labeled as containing 2.5 g of cefepime and enmetazobactam (2 g of cefepime and 0.5 g of enmetazobactam).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Dosage of the fixed combination of cefepime/enmetazobactam is expressed in terms of the total of the cefepime and enmetazobactam content.

• Administer by IV infusion; must be reconstituted and further diluted prior to administration. See Full Prescribing Information for instructions for reconstituting supplied dry powder and subsequent required dilution.

• The recommended dosage of cefepime/enmetazobactam is 2.5 g (2 g cefepime and 0.5 g enmetazobactam) administered every 8 hours by IV infusion over 2 hours in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) between 60 to 129 mL/minute. The duration of treatment is 7 days and up to 14 days for patients with concurrent bacteremia.

• Dosage adjustment is recommended in patients with renal impairment who have an eGFR < 60 mL/minute or ≥ 130 mL/minute (see Table 1). eGFR should be calculated using the Modification of Diet in Renal Disease (MDRD) formula.

See Full Prescribing Information for drug compatibilities.

Cautions for Cefepime Hydrochloride and Enmetazobactam

Contraindications

Cefepime/enmetazobactam is contraindicated in patients with a history of serious hypersensitivity reactions to the components of the fixed-combination preparation, or other beta-lactam antibacterial drugs.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions have been reported in patients treated with cefepime/enmetazobactam. Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with cefepime/enmetazobactam is instituted, carefully inquire about previous hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactams because cross-hypersensitivity among beta-lactam antibacterial drugs has been reported. If an allergic reaction to cefepime/enmetazobactam occurs, discontinue the drug and institute appropriate supportive measures.

Neurotoxicity

Neurotoxicity has been reported during treatment with cefepime, a component of cefepime/enmetazobactam, including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with cefepime/enmetazobactam therapy occurs, discontinue the fixed-combination preparation and institute appropriate supportive measures.

Clostridioides Difficile-associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime/enmetazobactam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Positive Direct Coombs' Tests

Positive direct Coombs' tests with or without hemolysis have been reported during treatment with cefepime, a component of cefepime/enmetazobactam. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy. Positive Coombs' test may be observed in newborns whose mothers have received cephalosporin antibacterial drugs before parturition.

Prolonged Prothrombin Time

Many cephalosporins, including cefepime, a component of cefepime/enmetazobactam, have been associated with a decrease in prothrombin activity. Those at risk of developing a prolonged prothrombin time include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

Development of Drug-resistant Bacteria

Prescribing cefepime/enmetazobactam in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Interactions with Urine Glucose Testing

The administration of cefepime, a component of cefepime/enmetazobactam, may result in a false-positive reaction for glucose in the urine when using some methods (e.g., Clinitest^TM tablets).

Specific Populations

Pregnancy

There are no available data with the use of cefepime/enmetazobactam during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from published observational studies and case reports over several decades with cephalosporin use, including cefepime, in pregnant women have not established drug-associated risks of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Cefepime was not associated with adverse developmental outcomes in rats, mice, or rabbits when administered parenterally during organogenesis. The doses used in these studies were 1.6 (rats), approximately equal to (mice), and 0.3 times (rabbits) the maximum recommended human dose (MRHD).

IV administration of enmetazobactam to pregnant rats and rabbits during organogenesis was associated with maternal toxicity and reduced fetal weights, but not fetal malformations at approximately 7 times and 11 times, respectively, the MRHD (1.5 g/day).

IV administration of enmetazobactam to pregnant rats during organogenesis through lactation resulted in reduction of maternal body weights and reduced fetal body weights and delayed pinna detachment in first-generation offspring in the absence of any other adverse effects on the survival, growth, and development of first- and second-generation offspring at exposures 7-times the MRHD.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

While available studies cannot definitively establish the absence of risk, published data from case-control studies and case reports over several decades have not identified an association with cephalosporin use, including cefepime, during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.

Lactation

Cefepime is present in human breast milk at low concentrations (approximately 0.5 mcg/mL) following a single IV dose of 1000 mg. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day.

Enmetazobactam was present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. There is no information regarding the effects of cefepime, enmetazobactam or their combination on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for cefepime/enmetazobactam and any potential adverse effects on the breastfed child from the drugs or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of cefepime/enmetazobactam in pediatric patients (younger than 18 years of age) have not been established.

Geriatric Use

Of the 516 patients treated with cefepime/enmetazobactam in the cUTI trial (Trial 1), 204 (40%) patients were 65 years of age and older, while 78 (15%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

Serious neurologic adverse reactions have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, a component of cefepime/enmetazobactam including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures.

No dosage adjustment based on age is required. Cefepime/enmetazobactam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored as appropriate. Dosage adjustment for elderly patients should be based on renal function.

Renal Impairment

Cefepime and enmetazobactam, the components of cefepime/enmetazobactam, are primarily renally excreted. Plasma exposures of both drugs increase with decreasing renal function, therefore dosage adjustments are recommended to compensate for the slower rate of renal clearance in patients with eGFR less than 60 mL/minute.

In patients with eGFR greater than or equal to 130 mL/minute, plasma exposures of cefepime and enmetazobactam are decreased. Therefore, dosage adjustments are recommended to compensate for the higher rate of renal clearance in these patients.

Both cefepime and enmetazobactam are hemodialyzable; thus, cefepime/enmetazobactam should be administered after intermittent hemodialysis on hemodialysis days.

Monitor renal function regularly and adjust the dosage of cefepime/enmetazobactam accordingly as renal function may change during the course of therapy.

Common Adverse Effects

The most frequently reported adverse reactions occurring in ≥5% of patients treated with cefepime/enmetazobactam were increased transaminases, increased bilirubin, headache, and phlebitis/infusion site reactions.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions and Spectrum

Mechanism of Action

Cefepime/enmetazobactam is an antibacterial drug.

The cefepime component is a cephalosporin antibacterial drug. The bactericidal action of cefepime results from the inhibition of cell wall synthesis. Cefepime penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Cefepime is stable to hydrolysis by some beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of extended spectrum beta-lactamases (ESBL), some oxacillinases, and carbapenem hydrolyzing beta-lactamases.

The enmetazobactam component is a beta-lactamase inhibitor that protects cefepime from degradation by certain serine beta-lactamases such as ESBL.

Spectrum

Cefepime hydrochloride and enmetazobactam has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections.

Gram-negative Bacteria

• Escherichia coli

• Klebsiella pneumoniae

• Pseudomonas aeruginosa

• Proteus mirabilis

• Enterobacter cloacae complex

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefepime and enmetazobactam against isolates of similar genus or organism group. However, the efficacy of cefepime and enmetazobactam in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-negative Bacteria

• Citrobacter freundii

• Klebsiella aerogenes

• Klebsiella oxytoca

• Providencia stuartii

• Providencia rettgeri

• Serratia marcescens

In vitro synergy studies did not demonstrate antagonism between cefepime/enmetazobactam and azithromycin, aztreonam, ceftazidime-avibactam, clindamycin, daptomycin, doxycycline, levofloxacin, linezolid, meropenem, metronidazole, trimethoprim-sulfamethoxazole, or vancomycin.

Resistance

Mechanisms of resistance to cefepime/enmetazobactam may include the production of beta-lactamases that are not inhibited by enmetazobactam, modification of PBPs by target alteration, overexpression of efflux pumps, and outer membrane porin mutations.

Clinical isolates may produce multiple beta-lactamases, express varying levels of beta-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.

Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.

Cefepime/enmetazobactam demonstrated in vitro activity against Enterobacterales in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBL) of the following groups: CTX-M, SHV, TEM, and VEB. Cefepime/enmetazobactam is not active against bacteria that produce KPC, metallo-beta-lactamases or some oxacillinases (OXA). Cefepime is inherently stable to hydrolysis by some AmpC cephalosporinases and OXA-48.

In the Phase 3 cUTI trial with cefepime/enmetazobactam, some isolates of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae species complex, Citrobacter braakii, Citrobacter freundii, and Proteus mirabilis, that produced beta-lactamases had a minimum inhibitory concentration ≤4 μg/mL for cefepime/enmetazobactam. These isolates carried genes for one or more beta-lactamases of the following enzyme groups: CTX-M, TEM, SHV, VEB, CMY, and OXA-48.

In the Phase 3 cUTI trial with cefepime/enmetazobactam, some beta-lactamases were also produced by isolates of K. pneumoniae and an isolate of E. cloacae that had a minimum inhibitory concentration ≥16 mcg/mL for cefepime/enmetazobactam. The K. pneumoniae isolates contained genes for NDM-1, OXA-48, or KPC-3 along with CTX-M, CMY, TEM, and/or SHV. The E. cloacae isolate encoded CTX-M.

No cross-resistance with other non-beta-lactam classes of antimicrobials has been identified. Some isolates resistant to carbapenems and to cephalosporins may be susceptible to cefepime/enmetazobactam.

Advice to Patients

• Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Advise patients to discontinue cefepime/enmetazobactam and seek immediate medical attention if allergic reactions occur.

• Advise patients of neurological adverse reactions that could occur with cefepime/enmetazobactam. Instruct patients or their caregivers to inform their healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia (disturbance of speaking and understanding spoken and written language), myoclonus, seizures and nonconvulsive status epilepticus.

• Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterial drug is discontinued. Inform patient that they may develop watery and bloody stools (with or without stomach cramps and fever) during treatment and as late as two or more months after having taken the last dose of the antibacterial drug. Inform patients that they should contact their physician as soon as possible if this occurs.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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