Cefepime, enmetazobactam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammad Waqas Danish, MBBS
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Overview
Cefepime, enmetazobactam is an fourth generation cephalosporin with an extended spectrum Beta-Lactamase Inhibitor that is FDA approved for the treatment of complicated urinary tract infections, including p.yelonephritis. Common adverse reactions include increase in transaminases, increased bilirubin, headache, and phlebitis/infusion site reactions..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Complicated Urinary Tract Infections, including Pyelonephritis
Cefepime,Enmetazobactam is indicated for the treatment of with complicated urinary tract infections (cUTI) including pyelonephritis in patients aged 18 and above, caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex . It should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria
Dosage
The recommended dosage is 2.5 grams (2 grams cefepime and 0.5 grams enmetazobactam) administered every 8 hours by intravenous (IV) infusion over 2 hours in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) between 60 and 129 mL/min. The duration of treatment is 7 days and up to 14 days for patients with concurrent bacteremia.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefepime, enmetazobactam in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefepime, enmetazobactam in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefepime, enmetazobactam in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefepime, enmetazobactam in pediatric patients.
Contraindications
The drug is contraindicated in patients with a history of serious hypersensitivity reactions to the components (cefepime and enmetazobactam) or other beta-lactam antibacterial drugs.
Warnings
Hypersensitivity Reactions
Hypersensitivity reactions have been reported in patients treated with this drug. 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 this drug is instituted, carefully inquire about previous hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactams because cross-hypersensitivity among beta-lactam antibacterial drugs have been reported. If an allergic reaction occurs, discontinue the drug and institute appropriate supportive measures.
Neurotoxicity
Neurotoxicity has been reported during treatment with cefepime, a component of this drug, 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 this drug therapy occurs, discontinue 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 this drug, 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 this drug. 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 EXBLIFEP, 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 this drug 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 the drug, may result in a false-positive reaction for glucose in the urine when using some methods.(e.g., ClinitestTM tablets)
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Cefepime, enmetazobactam Clinical Trials Experience in the drug label.
Postmarketing Experience
The following adverse reactions and altered laboratory tests have been identified during post-approval use of cefepime or other cephalosporin-class antibacterial drugs. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia, hemolytic anemia, pancytopenia Nervous system disorders: Encephalopathy (including disturbance of consciousness, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus Immune system disorders: Anaphylaxis including anaphylactic shock, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis Hepatobiliary disorders: Hepatic dysfunction including cholestasis Renal and urinary disorders: Renal dysfunction, toxic nephropathy Vascular disorders: Hemorrhage
Drug Interactions
Aminoglycoside
Monitor renal function if aminoglycosides are to be administered with this drug because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs.
Diuretics
Monitor renal function when this drug is concomitantly administered with potent diuretics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide.
Drug/Laboratory Test Interactions
It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used in patients using this drug. Administration may result in a false-positive reaction for glucose in the urine with certain methods
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There are no available data with the use of this drug, or 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefepime, enmetazobactam in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Cefepime, enmetazobactam during labor and delivery.
Nursing Mothers
Cefepime
Cefepime is present in human breast milk at low concentrations (approximately 0.5 mcg/mL) following a single intravenous 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 (see Data).
Enmetazobactam
Enmetazobactam was present in the milk of lactating rats (see Data). 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 this drug and any potential adverse effects on the breastfed child from this drug or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatic Use
Of the 516 patients treated with EXBLIFEP 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 this drug including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures. No dosage adjustment based on age is required. This drug 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. This drug.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.
Gender
There is no FDA guidance on the use of Cefepime and Enmetazobactam with respect to specific gender populations.
Race
There is no FDA guidance on the use of Cefepime and Enmetazobactam with respect to specific racial populations.
Renal Impairment
Cefepime and enmetazobactam, the components of this drug, are primarily renally excreted. Plasma exposures of both cefepime and enmetazobactam 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/min.
In patients with eGFR greater than or equal to 130 mL/min, 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, this drug should be administered after intermittent hemodialysis on hemodialysis days.
Hepatic Impairment
There is no FDA guidance on the use of Cefepime, enmetazobactam in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefepime and Enmetazobactam in women of reproductive potentials and males
Immunocompromised Patients
There is no FDA guidance on the use of Cefepime and Enmetazobactam in immunocompromised patients.
Administration and Monitoring
Administration
There is limited information regarding Cefepime, enmetazobactam Administration in the drug label.
Monitoring
There is limited information regarding Cefepime, enmetazobactam Monitoring in the drug label.
IV Compatibility
This drug is compatible with 0.9% Sodium Chloride Injection, 5% Dextrose injection, and 2.5% Dextrose and 0.45% Sodium Chloride. Compatibility for administration with other drugs has not been established.
Overdosage
Patients who receive an overdose should be carefully observed and given supportive treatment. Cefepime and enmetazobactam can be removed by hemodialysis. No clinical information is available on the use of hemodialysis to treat overdosage. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, neuromuscular excitability and nonconvulsive status epilepticus
Pharmacology
There is limited information regarding Cefepime, enmetazobactam Pharmacology in the drug label.
Mechanism of Action
The cefepime component of this drug 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 of this drug is a beta-lactamase inhibitor that protects cefepime from degradation by certain serine beta-lactamases such as ESBL.
Structure
This drug (cefepime and enmetazobactam) for injection is a combination product that contains cefepime, a cephalosporin antibacterial drug, and enmetazobactam, a beta-lactamase inhibitor, for intravenous administration
Cefepime
Cefepime, present as cefepime hydrochloride monohydrate, is a white to pale yellow powder. The chemical name for cefepime is (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2 (methoxyimino)acetamido)-3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate. The empirical formula of cefepime hydrochloride monohydrate is C19H24N6O5S2·2HCl·H2O, the molecular weight is 571.50
Enmetazobactam
Enmetazobactam is a white to off-white powder, with a molecular weight of 314.38. The chemical name for enmetazobactam is (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide. Its empirical formula is C11H14N4O5S.
Pharmacodynamics
Similar to other beta-lactam antibacterial drugs, the percentage of time that unbound plasma concentrations of cefepime exceed the cefepime-enmetazobactam minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. The percentage of time that enmetazobactam concentrations exceed a threshold concentration is the index that best predicts efficacy of enmetazobactam in combination with cefepime in animal and in vitro models of infection.
Cardiac Electrophysiology
At approximately 12 times the peak enmetazobactam concentrations of the maximum recommended dosing regimen of this drug, clinically significant QTc interval prolongation was not observed.
Pharmacokinetics
Pharmacokinetic (PK) Parameters The pharmacokinetic properties of cefepime and enmetazobactam are summarized in Table 5 as mean (SD) in patients with cUTI and eGFR greater than or equal to 60 mL/min.
Specific Population
No clinically significant differences in the pharmacokinetics of cefepime or enmetazobactam were observed based on age (18 – 94 years), gender, or weight (45 – 135 kg). There was insufficient information to evaluate the effect of race on the pharmacokinetics of cefepime or enmetazobactam.
Patients with Hepatic Impairment
Cefepime and enmetazobactam are primarily cleared renally; therefore, hepatic impairment is not likely to have a significant effect on cefepime or enmetazobactam exposures.
Patients with Renal Impairment
In a single-dose trial evaluating the effect of renal impairment on the pharmacokinetics of cefepime and enmetazobactam, dose-normalized systemic exposures of cefepime and enmetazobactam were higher at all levels of renal impairment compared to healthy subjects with CLcr greater than or equal to 90 mL/min . In subjects with creatinine clearance (CLcr) < 15 mL/min on hemodialysis, the fraction of the dose removed by hemodialysis was 0.30 and 0.35 for cefepime and enmetazobactam, respectively
Patients with eGFR 130 mL/min or Greater
Increased cefepime and enmetazobactam clearance have been observed in patients with eGFR of 130 mL/min or greater. A drug (2 g cefepime and 0.5 g enmetazobactam) dose every 8 h infused over 4 hours provided cefepime and enmetazobactam exposures comparable to those in patients with eGFR 90 to 129 mL/min who received EXBLIFEP (2 g cefepime and 0.5 g enmetazobactam) dose every 8 h over 2 hours.
Nonclinical Toxicology
Carcinogenesis
Long-term carcinogenicity studies have not been performed with cefepime or enmetazobactam.
Mutagenesis
Cefepime
In chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (2 chromosomal aberration and 2 micronucleus studies) were negative for clastogenicity.
Enmetazobactam
Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.
Impairment of Fertility
Cefepime
No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m2 basis).
Enmetazobactam
In male and female fertility studies in rats, enmetazobactam was administered intravenously in doses of 125, 250, and 500 mg/kg/day in males for 28 days before mating and for 14 days before the start of the mating period, throughout the mating period, and until Gestation Day (GD) 7 in females. Enmetazobactam had no adverse effect on fertility in either sex and no effect on early embryonic development in female rats at doses up to 500 mg/kg/day, (approximately 7 times in males and 8 times in females the maximum recommended human dose (1.5 g/day) based on plasma AUC comparison).
Clinical Studies
Complicated Urinary Tract Infections, including Pyelonephritis
A total of 1041 adults with cUTI, including pyelonephritis, were randomized in a 1:1 ratio into in a multinational, double blind, noninferiority trial (Trial 1, NCT03687255), comparing EXBLIFEP (2 grams cefepime and 0.5 grams enmetazobactam) to piperacillin/tazobactam (4 grams piperacillin and 0.5 grams tazobactam) both administered intravenously every 8 hours (infused over 2 hours) for 7 days, or up to 14 days for patients with concurrent bacteremia. No switch from IV to oral antibacterial therapy was permitted. The microbiological modified intent-to-treat population (mMITT) was the primary efficacy analysis population and included all randomized patients who received any study drug and had at least 1 baseline gram-negative pathogen ≥105 colony-forming-units (CFU)/mL in urine culture or the same pathogen in blood and urine cultures that is not resistant to cefepime/enmetazobactam or piperacillin/tazobactam (defined as MIC ≤ 8/8 mcg/mL or MIC ≤ 64/4 mcg/mL, respectively). A total of 345 and 333 patients were included in the mMITT population in EXBLIFEP and piperacillin/tazobactam treatment groups, respectively.
Patient demographic and baseline characteristics were balanced between treatment groups in the mMITT population. Approximately 95% of patients were Caucasian and 60% were female in both treatment groups. The mean age was 54 years with 38% and 31% of patients greater than 65 years of age in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. Mean body mass index was approximately 26.5 kg/m2 in both treatment groups. Concomitant bacteremia was identified in 38 (11%) and 28 (8%) patients at baseline in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. The proportion of patients with diabetes mellitus at baseline was 16% and 12% in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. The majority of patients (93%) were enrolled from Europe. Overall, in both treatment groups, 51% of patients had pyelonephritis and 49% had cUTI, with 27% and 22% of patients having a non-removable and removable source of infection, respectively. Mean duration of treatment in both treatment groups was 8 days. EXBLIFEP demonstrated efficacy with regard to composite response, defined as clinical cure and microbiological response, at the Test of Cure (TOC) visit (7 days after the end of treatment) in the mMITT population as shown in Table 7. Clinical cure was defined as the complete resolution (or return to premorbid state) of the baseline signs and symptoms of cUTI or pyelonephritis that were present at Screening (and no new urinary symptoms or worsening of symptoms). Microbiological response was defined as the baseline qualifying Gram-negative pathogen(s) reduced to <103 colony-forming units/mL in urine culture and a negative blood culture for a Gram-negative pathogen that was identified as a uropathogen (if repeated after positive baseline blood culture).
Composite response in patients with bacteremia at baseline was achieved in 27/38 (71%) patients in the EXBLIFEP group and 14/28 (50%) patients in the piperacillin/tazobactam group at the TOC visit in the mMITT population.
In a subset of the E. coli and K. pneumoniae isolates, genotypic testing identified certain ESBL groups (e.g., TEM, CTX-M, SHV and OXA) in both treatment groups of the cUTI Trial 1. The proportion of patients with composite response at TOC was 56/76 (74%) and 34/66 (52%) in the EXBLIFEP group, and the piperacillin/tazobactam group, respectively, in patients with ESBL- producing bacteria at baseline. A sensitivity analysis where patients with organisms resistant to piperacillin/tazobactam, according to the current FDA breakpoints (defined as MIC >16/4 mcg/mL for Enterobacterales and >64/4 mcg/mL for P. aeruginosa) and one patient with Stenotrophomonas maltophilia were excluded from the mMITT population, demonstrated similar efficacy results as in the mMITT population.
How Supplied
2.5 grams (cefepime and enmetazobactam) for injection is supplied as a white to off-white sterile powder for reconstitution in single-dose, clear glass vials sealed with a rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial is supplied in cartons of 10 vials (NDC 83289-101-02).Each vial contains 2 grams of cefepime and 0.5 grams of enmetazobactam.
Storage
Store this drug vials refrigerated at 2°C to 8°C (36°F to 46°F); excursions are permitted to 15°C to 25°C (59°F to 77°F) [see USP, Controlled Room Temperature (CRT)]. Keep the vials in the outer carton to protect from light.
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Patient Counseling Information
There is limited information regarding Cefepime, enmetazobactam Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Cefepime, enmetazobactam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
EXBLIFEP
Look-Alike Drug Names
There is limited information regarding Cefepime, enmetazobactam Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.