Cepim, 1 g

Pharmacotherapeutic group

Cephalosporin antibiotic

ATX code: J01DE01

Pharmacodynamics:

An antibacterial agent of generation IV cephalosporins. It acts bactericidally by disrupting synthesis of the cell wall of microorganisms. It has a wide range of action against Gram-positive and Gram-negative bacteria of strains resistant to aminoglycosides and/or III generation cephalosporin antibiotics. Highly resistant to hydrolysis of most beta-lactamases and quickly penetrates into Gram-negative bacterial cells. Penicillin-binding proteins are the molecular target inside the bacterial cell.

Active in vivo and in vitro against Gram positive aerobes: Staphylococcus aureus (methicillus and insensitive strains only) Streptococcus pneumoniae Streptococcus pyogenes (group A) Streptococcus viridans; Gram negative aerobes: Enterobacter spp. Escherichia coli. Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa. In vitro active against Gram-positive aerobes: Staphylococcus epidermidis (only methicillin-sensitive strains) Staphylococcus saprophytics Streptococcus agalactiae (group B); Gram-negative aerobes: Acinetobacter Kvoffii Citrobacter diversus Citrobacter freundii Enterobacter agglomerans Haemophilus influenzae (including beta-lactamase producing strains) Hafnia alvei Klebsiella oxytoca Moraxella catarrhal is (including beta-lactamase producing strains) Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia marccscens. Most strains of Enterococcus including Enterococcus faecalis methicillin-resistant Staphylococcus aureus Stenotrophomonas maltophilia (formerly known as Xanthomonas maltophilia) Clostridium difficile are not sensitive to cefepim.

Pharmacokinetics:

Bioavailability 100%. Time of reaching maximum concentration (TCmax) after intravenous (w/v) and intramuscular (i/m) administration at a dose of 0.5 g – by the end of infusion and 1 -2 h, respectively. Maximum concentration (Stal) when administered intramuscularly in doses of 0.5. 1 and 2 g – 14 30 and 57 mcg/ml, respectively; when administered v/v in doses of 0.25 0.5 1 and 2 g – 18 39 82 and 164 mcg/ml, respectively; time to reach mean therapeutic plasma concentration – 12 h; mean therapeutic concentration with v/v administration -0.2 µg/ml. when administered intravenously – 0.7 µg/ml.

High concentrations are detected in urine bile peritoneal fluid exudate blister mucous secretion of bronchi sputum prostate appendix and gallbladder. Volume of distribution – 0.25 l/kg in children from 2 months to 16 years – 0.33 l/kg. Binding with plasma proteins – 20%.
Metabolized in the liver and kidneys by 15%. Elimination half-life (T1/2) – 2 hours total clearance – 120 ml/min renal clearance – 110 ml/min. It is excreted by the kidneys (by glomerular filtration in unchanged form – 85%) with breast milk. T1/2 in hemodialysis is 13 h in continuous peritoneal dialysis is 19 h.

Indications

Pneumonia (moderate to severe) caused by sensitive strains of Streptococcus pneumoniae, including cases associated with simultaneous bacteremia of Pseudomonas aeruginosa, Klebsiella pneumoniae or Enterobacter species.

Febrile neutropenia (empirical monotherapy in patients at high risk for severe infection, including patients with a history of recent bone marrow transplantation, arterial hypotension at initial examination, hematologic malignancy, or severe or prolonged neutropenia. There is insufficient data to support the efficacy of cefepime monotherapy in these patients).

Uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by sensitive isolates of Escherichia coli or Klebsiella pneumoniae when the infection is severe, or Escherichia coli, Klebsiella pneumoniae or Proteus mirabilis when the severity of infection is mild to moderate, including cases associated with concurrent bacteremia caused by these bacteria.

Uncomplicated skin infections caused by Staphylococcus aureus (only methicillin-sensitive isolates) or Streptococcus pyogenes.

Complicated intra-abdominal infections (in combination with metronidazole) in adults caused by sensitive isolates of Escherichia coli, Streptococcus viridans, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species or Bacteroides fragilis.

In order to reduce the development of treatment-resistant bacteria and to maintain the effectiveness of cefepime, it should only be used to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. Information on culture and sensitivity should be considered when selecting or modifying antibiotic therapy. In the absence of such data, local epidemiologic data and susceptibility patterns may contribute to the empirical choice of therapy.

Active ingredient

Composition

How to take, the dosage

V/v, v/m. When administered intravenously, the duration of administration should be approximately 30 minutes. The maximum dose for pediatric patients should not exceed the recommended dose for adults.

The dose should be adjusted in patients with a creatinine Cl ≤60 mL/min to compensate for the slower renal excretion rate. In these patients, the recommended starting dose of cefepime should be the same as in patients with creatinine Cl >60 mL/min, except in patients on hemodialysis.

In patients on continuous ambulatory peritoneal dialysis, cefepime may be administered in the recommended doses at dosing intervals of every 48 hours. In patients on hemodialysis, approximately 68% of the total amount of cefepime present at the start of dialysis will be removed during the 3-hour dialysis period.

Interaction

Impact on laboratory tests

The administration of cefepime may lead to false positives for glucose in the urine in certain methods. The use of glucose tests based on enzymatic glucose oxidase reactions is recommended.

Positive direct Coombs tests have been reported during treatment with cefepim. If hemolytic anemia develops, the use of cefepime should be discontinued and appropriate therapy should be prescribed. Positive Coombs test may be observed in neonates whose mothers received cephalosporin drugs before delivery.

The use of many cephalosporins, including cefepime, has been associated with decreased prothrombin activity. Patients at risk include those with renal or hepatic insufficiency or poor nutrition, as well as those receiving a long-term course of antimicrobial therapy. In patients at risk, PV should be monitored and exogenous vitamin K should be administered as indicated.

Drug interactions

The aminoglycosides. Renal function should be monitored if aminoglycosides are to be administered concomitantly with cefepime because of the increased potential for nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs.

Diuretics. Nephrotoxicity has been reported after concomitant use of other cephalosporins with potent diuretics, such as furosemide. Renal function should be monitored when concomitant use of cefepime with potent diuretics.

Special Instructions

Contraindications

Side effects

Clinical trial experience

Because clinical trials are conducted in different settings, the rate of adverse reactions observed in one clinical trial cannot be directly compared to data from another clinical trial and may not reflect the rates observed in practice.

In clinical trials using multiple doses of cefepime, 4137 patients received the recommended doses (500 mg to 2 g IV every 12 hours). No cases of death or permanent disability presumably related to the adverse effects of cefepime were identified. Because of adverse reactions, 64 (1.5%) patients discontinued use, 33 (51%) of whom did so because of a rash. The proportion of patients receiving cefepime who discontinued due to adverse reactions was similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8; 1.1 and 2%, respectively). However, the rate of cefepime discontinuation due to rash increased with increasing recommended doses.

The adverse reactions of cefepime when administered in multiple doses (North American clinical trial data, n=3125) reported with a frequency of ≥1% included local adverse reactions (3%), including phlebitis (1.3%), pain and/or inflammation (0.6%), and rash (1.1%).

A frequency of less than 1% but greater than 0.1% included colitis (including pseudomembranous), diarrhea, erythema, fever, headache, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting, and anemia.

The higher dose (2 g every 8 hours) had a higher incidence of adverse reactions in the 795 patients who received this dose of cefepime. The adverse reactions were rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), itching (1%), fever (1%), and headache (1%).

The abnormal laboratory findings reported with a frequency of ≥1% included a positive Coombs test (without hemolysis) (16.2%), decreased phosphorus levels (2.8%), increased ALT (2.8%), AST (2.4%), eosinophilia (1.7%), abnormal ACTV (1.6%) and PV (1.4%).

A frequency of less than 1% but greater than 0.1% were elevated levels of ALP, blood urea, calcium, creatinine, phosphorus, potassium, total bilirubin; decreased calcium levels (hypocalcemia was more often seen in older patients, no clinically significant effects of calcium or phosphorus levels were reported), hematocrit, neutrophil count, platelets, and leukocytes.

Post-registration observational experience

The following adverse reactions have been identified during clinical use of cefepime after registration, but because these reactions are voluntarily reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In addition to adverse reactions reported in clinical trials, the following adverse reactions have been reported during post-registration use. Encephalopathy (impaired consciousness, including confusion, hallucinations, stupor and coma), aphasia, myoclonus, seizures and epilepsy without seizures have been reported. Cases of anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia have been reported.

Adverse reactions characteristic of cephalosporin class drugs

In addition to the above adverse reactions observed in patients receiving cefepime, the following adverse reactions and changes in laboratory parameters have been reported when using cephalosporin class antibacterial drugs Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, liver dysfunction, including cholestasis, and pancytopenia.

Overdose

Symptoms: encephalopathy (impaired consciousness, including confusion, hallucinations, stupor and coma), myoclonus, seizures, neuromuscular excitability and epileptic nonconvulsive status.

Treatment: patients with cefepime overdose should be closely monitored and receive supportive treatment. If renal impairment is present, hemodialysis or peritoneal dialysis is recommended to help eliminate cefepime from the body.

Pregnancy use

The FDA fetal category is B.

There are no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always able to predict human response, cefepime should be used during pregnancy only if clearly necessary.

Cefepime had no teratogenic or embryocidal effects when administered during organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the MRHD per body surface area) or to mice at doses up to 1200 mg/kg (approximately equal to the MRHD per body surface area), or to rabbits at 100 mg/kg (0.3 MRHD per body surface area).

Cefepim has not been studied for use during labor. Treatment should be administered only when strictly indicated.

Cefepim is excreted with the female breast milk. Caution should be exercised when prescribing cefepime to a nursing woman.

Similarities