Ceftaroline- fosamil

Ceftaroline- fosamil belongs to the pharmacological class of Fifth-generation cephalosporin antibiotics.

Ceftaroline- fosamil has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection,Pneumonia, Skin and soft tissue infection, Cystic fibrosis pulmonary exacerbation, MRSA.

After intravenous administration of ceftaroline fosamil, the drug exhibits linear pharmacokinetics over a dose range of 50 to 600 mg. The bioavailability of ceftaroline fosamil is 100% after intravenous administration. The plasma protein binding of ceftaroline is approximately 20%. Ceftaroline is eliminated primarily by the kidneys with a mean elimination half-life of approximately 2.5 hours in healthy adults.

The common side effects involved in using Ceftaroline- fosamil are Diarrhea, Nausea, Vomiting, Abdominal pain, Headache, Dizziness, Rash, Itching, Elevated liver enzymes

Ceftaroline- fosamil is available in the form of Ceftaroline- fosamil is available in the form of Injectable, powder for reconstitution.

Ceftaroline- fosamil is approved in Germany, Japan, Malaysia, India, U.K.,U.S, and China.

Ceftaroline- fosamil belongs to the pharmacological class of Fifth-generation cephalosporin antibiotics.

Ceftaroline fosamil is a broad-spectrum cephalosporin antibiotic that works by inhibiting bacterial cell wall synthesis. Specifically, it binds to and inhibits the activity of penicillin-binding proteins (PBPs), which are enzymes involved in the final stages of peptidoglycan synthesis in bacterial cell walls. This results in bacterial cell death and eradication of the infection. Ceftaroline fosamil is active against both gram-positive and gram-negative bacteria, including MRSA (methicillin-resistant Staphylococcus aureus) and Streptococcus pneumoniae.

Ceftaroline- fosamil has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection,Pneumonia, Skin and soft tissue infection, Cystic fibrosis pulmonary exacerbation, MRSA.

The maximum concentration (Cmax) of ceftaroline fosamil is achieved immediately following the end of a 1-hour infusion. The time to reach maximum concentration (Tmax) is approximately 2 hours post-infusion. The onset of action for ceftaroline fosamil is rapid, with significant reductions in bacterial load observed as early as 6 hours post-infusion. The duration of action is approximately 12 hours, allowing for twice daily dosing in most indications.

Ceftaroline- fosamil is found to be available in the form of Injectable, powder for reconstitution.

Ceftaroline- fosamil can be used in the following treatment:

• Bloodstream infection
• Pneumonia
• Skin and soft tissue infection
• Cystic fibrosis pulmonary exacerbation, MRSA

Ceftaroline- fosamil can help to relieve symptoms and also for the treatment and maintenance of Bloodstream infection,Pneumonia, Skin and soft tissue infection, Cystic fibrosis pulmonary exacerbation, MRSA.

Ceftaroline- fosamil is approved for use in the following clinical indications:

• Bloodstream infection
• Pneumonia
• Skin and soft tissue infection
• Cystic fibrosis pulmonary exacerbation, MRSA

Bloodstream Infection

Ceftaroline fosamil is an alternative agent for the pathogen-directed therapy of methicillin-resistant S. aureus bloodstream infection. The recommended intravenous dosage is 600 mg every 8 hours. In persistent or refractory cases or isolates with reduced susceptibility, it should be used as part of an appropriate combination regimen. For the treatment of uncomplicated S. aureus bacteremia, ceftaroline fosamil should be continued for at least 14 days from the day of the first negative blood culture. Longer courses are warranted for endocarditis or metastatic sites of infection.

Pneumonia

Ceftaroline fosamil is an alternative agent for the treatment of community-acquired pneumonia in inpatients without risk factors for Pseudomonas aeruginosa. The recommended intravenous dosage is 600 mg every 12 hours as part of an appropriate combination regimen. The total duration of therapy, including oral step-down therapy, is a minimum of 7 days for methicillin-resistant S. aureus (MRSA) infection. Patients should be clinically stable with normal vital signs before therapy is discontinued. In hospital-acquired or ventilator-associated pneumonia, ceftaroline fosamil is used as a component of empiric therapy or pathogen-directed therapy for MRSA. The recommended intravenous dosage is 600 mg every 12 hours. The duration of therapy varies based on disease severity and response to therapy, and treatment is typically given for 7 days.

Skin and Soft Tissue Infection

For the treatment of skin and soft tissue infection, the recommended intravenous dosage of ceftaroline fosamil is 600 mg every 12 hours. The total duration of therapy is at least 5 days, including oral step-down therapy, and may extend up to 14 days depending on severity and clinical response.

• Injectable, powder for reconstitution: 400mg/vial, 600mg/vial

Injectable, powder for reconstitution.

• Dosage Adjustments in Kidney Patients:

The recommended dosages of Ceftaroline fosamil according to creatinine clearance (CrCl) levels are as follows: for CrCl 30-50 mL/min, 400 mg IV every 12 hours; for CrCl 15 to ≤30 mL/min, 300 mg IV every 12 hours; for end-stage renal disease (ESRD) patients including those undergoing hemodialysis, 200 mg IV every 12 hours.

• Dosage Adjustments in Pediatric Patients:

Cystic fibrosis (CF) pulmonary exacerbation, MRSA:

Children ≥6 years and Adolescents: IV: 15 mg/kg/dose every 8 hours; maximum dose: 600 mg/dose.

Pneumonia, community acquired:

Infants ≥2 months and Children <2 years: IV: 8 mg/kg/dose every 8 hours for 5 to 14 days.

Children ≥2 years and Adolescents <18 years:

≤33 kg: IV: 12 mg/kg/dose every 8 hours for 5 to 14 days.

>33 kg: IV: 400 mg every 8 hours or 600 mg every 12 hours for 5 to 14 days.

Adolescents ≥18 years: 600 mg every 12 hours for 5 to 7 days.

Skin and skin structure infection:

Infants <2 months: IV: 6 mg/kg/dose every 8 hours.

Infants ≥2 months and Children <2 years: IV: 8 mg/kg/dose every 8 hours.

Children ≥2 years and Adolescents <18 years:

≤33 kg: IV: 12 mg/kg/dose every 8 hours.

>33 kg: IV: 400 mg every 8 hours or 600 mg every 12 hours.

Adolescents ≥18 years: IV: 600 mg every 12 hours.

There are no specific dietary restrictions related to the use of ceftaroline fosamil according to the US FDA. However, it is recommended to follow a healthy and balanced diet while undergoing treatment with ceftaroline fosamil or any other medication.

Ceftaroline- fosamil may be contraindicated under the following conditions:

• In patients with known hypersensitivity to Ceftaroline- fosamil, cephalosporin, penicillin, or any component of the formulation.

The physician should closely monitor the patients and keep pharmacovigilance as follows:

Hypersensitivity Reactions

Beta-lactam antibacterial drugs have been associated with serious and sometimes fatal hypersensitivity (anaphylactic) reactions and serious skin reactions. Patients should be carefully screened for previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems before starting therapy with ceftaroline fosamil. Cross-sensitivity among beta-lactam antibacterial agents has been established, so caution is necessary when prescribing to patients with a history of beta-lactam allergy. If a patient experiences an allergic reaction, ceftaroline fosamil should be discontinued, and appropriate treatment and supportive measures should be initiated.

Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported in patients receiving nearly all systemic antibacterial agents, including ceftaroline fosamil. CDAD can range from mild diarrhea to fatal colitis, and it may occur more than two months after the administration of antibacterial agents. All patients who present with diarrhea following antibiotic use should be evaluated for CDAD. Antibacterial agents not directed against C. difficile should be discontinued, if possible. Management of CDAD may require fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation, depending on the severity of the disease.

Direct Coombs’ Test Seroconversion

Seroconversion from a negative to a positive direct Coombs' test result occurred in a small percentage of patients receiving ceftaroline fosamil in clinical trials. While no adverse reactions representing hemolytic anemia were reported in any treatment group, drug-induced hemolytic anemia should be considered if anemia develops during or after treatment with ceftaroline fosamil.

Development of Drug-Resistant Bacteria

Prescribing ceftaroline fosamil without a proven or strongly suspected bacterial infection is unlikely to benefit the patient and may increase the risk of developing drug-resistant bacteria.

According to the US FDA, there is no specific warning against the consumption of alcohol while taking Ceftaroline- fosamil.

It is not known whether ceftaroline is excreted in human milk. As many drugs are excreted in human milk, caution should be exercised when ceftaroline fosamil is administered to a nursing woman.

Pregnancy Category B

Ceftaroline fosamil was studied for developmental toxicity in rats and rabbits. In rats, intravenous doses up to 300 mg/kg showed no maternal toxicity or adverse effects on fetal development. However, a toxicokinetic study showed that rats were exposed to approximately 8 times the human exposure level (based on AUC) at this dose level.

In rabbits, intravenous doses of 25, 50, and 100 mg/kg did not result in drug-induced malformations in offspring. Maternal toxicity was observed, with changes in fecal output in all groups and dose-related reductions in body weight gain and food consumption at > 50 mg/kg. The highest dose was associated with maternal morbidity and mortality, as well as an increase in spontaneous abortion at 50 and 100 mg/kg. Additionally, an increased incidence of angulated hyoid alae, a common rabbit skeletal variation, was observed at the maternally toxic doses of 50 and 100 mg/kg. A separate toxicokinetic study showed that rabbits were exposed to approximately 0.8-1.5 times the human exposure level (based on AUC) at these doses.

There are no specific food warnings related to the use of Ceftaroline- fosamil. However, the medication should be administered by a healthcare professional and should not be self-administered at home. It should also be taken as directed by the healthcare provider, which may include taking it with food or on an empty stomach depending on the specific instructions.

The adverse reactions related to Ceftaroline- fosamil can be categorized as follows:

Common:

• Diarrhea
• Nausea
• Rash
• Increased liver enzymes
• Injection site reactions
• Vomiting

Less Common:

• Allergic reactions, including anaphylaxis
• Headache
• Dizziness
• Abdominal pain
• Constipation
• Itching

Rare:

• Clostridium difficile-associated diarrhea
• Seizures
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

The clinically relevant drug interactions of Ceftaroline- fosamil is briefly summarized here:

Ceftaroline fosamil and Drug-Drug Interactions: An Overview Ceftaroline fosamil is a medication that is used to treat bacterial infections such as acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). While it is an effective treatment option for these conditions, it is important to consider the potential for drug-drug interactions when prescribing ceftaroline fosamil alongside other medications.

Absence of Clinical Drug-Drug Interaction Studies

No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil. However, this does not mean that ceftaroline fosamil cannot interact with other drugs in a clinically relevant manner.

Minimal Potential for Drug Interactions

Studies suggest that there is minimal potential for drug-drug interactions between ceftaroline fosamil and certain types of drugs. These include drugs that are CYP450 substrates, inhibitors, or inducers, drugs that are known to undergo active renal secretion, and drugs that may alter renal blood flow.

In Vitro Studies

In vitro studies in human liver microsomes indicate that ceftaroline, the active ingredient in ceftaroline fosamil, does not inhibit the major cytochrome P450 isoenzymes. This means that ceftaroline is unlikely to interfere with the metabolism of drugs that are metabolized by these enzymes.

In vitro studies in human hepatocytes also demonstrate that ceftaroline and its inactive open-ring metabolite are not inducers of certain cytochrome P450 enzymes. This suggests that ceftaroline fosamil is not expected to interfere with the clearance of drugs that are metabolized by these enzymes.

The following are the side effects involving Ceftaroline-fosamil:

• Diarrhea
• Nausea
• Rash
• Headache
• Vomiting
• Constipation
• Increased liver enzymes
• Insomnia
• Dizziness
• Pain at the injection site.

Pregnancy:

Pregnancy Category B

Ceftaroline fosamil was studied for developmental toxicity in rats and rabbits. In rats, intravenous doses up to 300 mg/kg showed no maternal toxicity or adverse effects on fetal development. However, a toxicokinetic study showed that rats were exposed to approximately 8 times the human exposure level (based on AUC) at this dose level.

In rabbits, intravenous doses of 25, 50, and 100 mg/kg did not result in drug-induced malformations in offspring. Maternal toxicity was observed, with changes in fecal output in all groups as well as dose-related reductions in body weight gain and also food consumption at > 50 mg/kg. The highest dose was associated with maternal morbidity and mortality, as well as an increase in spontaneous abortion at 50 and 100 mg/kg. Additionally, an increased incidence of angulated hyoid alae, a common rabbit skeletal variation, was observed at the maternally toxic doses of 50 and also 100 mg/kg. A separate toxicokinetic study showed that rabbits were exposed to approximately 0.8-1.5 times the human exposure level (based on AUC) at these doses.

Breastfeeding:

It is not known whether ceftaroline is excreted in human milk. As many drugs are excreted in human milk, caution should be exercised when ceftaroline fosamil is administered to a nursing woman.

Pediatric use:

Safety as well as effectiveness in pediatric patients have not been established.

Geriatric use:

Of the 1300 patients treated with ceftaroline fosamil in Phase 3 trials for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, 30.5% were ≥ 65 years of age. The clinical cure rates in patients ≥ 65 years of age were similar to those < 65 years of age.

The adverse reaction profiles for ceftaroline fosamil in patients aged ≥ 65 years and < 65 years were similar, but a slightly higher percentage of adverse reactions were observed in patients aged ≥ 65 years. Since ceftaroline is primarily excreted by the kidneys, patients with impaired renal function may be at greater risk of adverse reactions. As elderly patients are more likely to have decreased renal function, dose selection and renal function monitoring should be done with caution.

Pharmacokinetics:

Elderly subjects have a greater exposure to ceftaroline compared to non-elderly subjects when administered the same single dose of ceftaroline fosamil, but the higher exposure is mainly attributed to age-related changes in renal function. Therefore, dosage adjustment for elderly patients should be based on renal function.

Physicians should be knowledgeable and vigilant about the treatment and identification of over dosage of Ceftaroline-fosamil.

If a patient experiences an overdose of ceftaroline- fosamil, the medication should be stopped immediately, and general supportive care should be provided. Hemodialysis can be used to eliminate ceftaroline from the body. For individuals with end-stage renal disease (ESRD) who received a 400 mg dose of ceftaroline- fosamil, the average total recovery of ceftaroline in the dialysate was found to be 76.5 mg (21.6% of the dose) following a 4-hour hemodialysis session that started 4 hours after the dose was administered. It is worth noting, however, that there is currently no information available regarding the use of hemodialysis to manage cases of ceftaroline fosamil overdosage.

Pharmacodynamics

Like other beta-lactam antibiotics, research has demonstrated that the effectiveness of ceftaroline in treating infections caused by S. aureus and S. pneumoniae is strongly linked to the length of time that the concentration of the medication in the blood is higher than the minimum inhibitory concentration (MIC) of the infectious organism. This finding was discovered through testing on mice with neutropenic thigh infections.

Exposure-response analysis of Phase 2/3 trials examining the treatment of acute bacterial skin and skin structure infections (ABSSSI) provides further support for the recommended dosing regimen of ceftaroline fosamil, which calls for an intravenous infusion of 600 mg every 12 hours over a period of one hour. In contrast, when examining the treatment of community-acquired bacterial pneumonia (CABP) in Phase 3 trials, no exposure-response relationship was established due to the limited range of ceftaroline exposure experienced by most patients.

Pharmacokinetics

Pharmacokinetic Parameters:

• Absorption:

The pharmacokinetic parameters of ceftaroline were measured in healthy adults with normal renal function after single and multiple intravenous (IV) infusions of 600 mg ceftaroline fosamil administered every 12 hours. The study found similar pharmacokinetic parameters for both single and multiple dose administration. The parameters measured were Cmax, Tmax, AUC, T1/2, and CL.

• Distribution:

The average binding of ceftaroline to human plasma proteins is found to be approximately 20%. The median steady-state volume of distribution of ceftaroline in healthy adult males is 20.3 L, which is similar to extracellular fluid volume.

• Metabolism:

Ceftaroline fosamil is converted into a bioactive ceftaroline in plasma by a phosphatase enzyme. Hydrolysis of the beta-lactam ring of the drug ceftaroline occurs to form the open-ring metabolite ceftaroline M-1. The study found that ceftaroline is not a substrate for hepatic CYP450 enzymes.

• Excretion:

The primary route of elimination of ceftaroline and its metabolites is through the kidneys. After a single 600 mg IV dose of radiolabeled ceftaroline fosamil was administered to healthy male adults, approximately 88% of radioactivity was recovered in urine and 6% in feces within 48 hours. The mean renal clearance of ceftaroline was 5.56 L/h, indicating that ceftaroline is predominantly eliminated by glomerular filtration.

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5. https://www.ceftaroline fosamil.com/
6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/200327s015lbl.pdf
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