Ceftaroline fosamil (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

) , brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant ''Staphylococcus aureus'' (MRSA) and other

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against

Gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wa ...

bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for

community-acquired pneumonia Community-acquired pneumonia (CAP) refers to pneumonia (any of several lung diseases) contracted by a person outside of the healthcare system. In contrast, hospital-acquired pneumonia (HAP) is seen in patients who have recently visited a hospital ...

and complicated skin and skin structure infection. Ceftaroline is being developed by

Forest Laboratories Forest Laboratories was a company in the pharmaceutical industry incorporated in Delaware, with its principal office in New York City. It was known for licensing European pharmaceuticals for sale in the United States. On July 1, 2014, the compan ...

, under a license from

Takeda is a Japanese family name.1990 Census Name Files< ...

. Ceftaroline received approval from the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) for the treatment of community-acquired bacterial

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severi ...

and acute bacterial skin infections on 29 October 2010. ''In vitro'' studies show it has a similar spectrum to ceftobiprole, the only other fifth-generation cephalosporin to date, although no head-to-head clinical trials have been conducted. Ceftaroline and ceftobiprole are on an unnamed subclass of cephalosporins by the

Clinical and Laboratory Standards Institute The Clinical and Laboratory Standards Institute (CLSI) is a volunteer-driven, membership-supported, not-for-profit, standards development organization. CLSI promotes the development and use of voluntary laboratory consensus standards and guideline ...

(CLSI). It was removed from the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

in 2019.

Clinical use

Ceftaroline is a novel cephalosporin with activity against methicillin-resistant ''S. aureus'' (MRSA) with

phase III clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

for complicated skin and skin structure infections with reported non-inferior efficacy against MRSA compared to

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...

and

aztreonam Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as ''Pseudomonas aeruginosa''. This may include bone infections, endometritis, intra abdominal ...

. In 2009, ceftaroline had completed phase-III clinical trials for

comparing it against

ceftriaxone Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joint ...

with non-inferior results and similar adverse reaction profile. However, only results for phase-II clinical trials in treatment of complicated skin and skin structure infections have been published. Sept 2009 : Phase III trials results reported. On 8 September 2010, the FDA Advisory Committee recommended approval for the treatment of community acquired bacterial pneumonia and complicated skin and skin structure infections. In October 2010, FDA approval was gained for treatment of community-acquired bacterial pneumonia and acute bacterial

skin and skin structure infection Skin and skin structure infections (SSSIs), also referred to as skin and soft tissue infections (SSTIs), or acute bacterial skin and skin structure infections (ABSSSIs), are infections of skin and associated soft tissues (such as loose connective ti ...

s, including MRSA. MRSA can develop resistance to ceftaroline through the alteration of penicillin-binding proteins. Amino acid-altering mutations in the ceftaroline-binding pocket of the transpeptidase region of penicillin-binding protein 2a (PBP2a) confer resistance to ceftaroline. Ceftaroline- and methicillin-resistant strains of ''S. aureus'' have been identified in Europe and Asia, but have not been identified in the United States.Long SW, Olsen RJ, Mehta SC, et al. PBP2a mutations causing high-level Ceftaroline resistance in clinical methicillin-resistant ''Staphylococcus aureus'' isolates. Antimicrob Agents Chemother. 2014;58(11):6668-6674. doi:10.1128/AAC.03622-14 While cephalosporinases (a type of beta-lactamase that inactivates cephalosporins) confers resistance to other cephalosporins, cephalosporinases have not yet been identified as a mechanism of resistance to ceftaroline.

Safety

The clinical studies indicated ceftaroline was well tolerated. The overall rate of adverse events was comparable between the two treatment groups (The CANVAS I and CANVAS II trials evaluated ceftaroline monotherapy versus vancomycin plus aztreonam in adult subjects with complicated skin and skin structure infections caused by Gram-positive and Gram-negative bacteria.). The overall discontinuation rate for ceftaroline-treated subjects was 2.7% compared to a rate of 3.7% for the comparator group-treated subjects. The most common adverse reactions occurring in > 2% of subjects receiving ceftaroline in the pooled phase-III clinical trials were diarrhea, nausea, and rash.:

Contraindications

* Known serious

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

to ceftaroline or other members of the cephalosporin class *

Anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the foll ...

and anaphylactoid reactions

Warnings and precautions

The warnings and precautions associated with ceftaroline include:

Hypersensitivity reactions

Serious hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported with beta-lactam antibiotics, including ceftaroline. Exercise caution in people with known hypersensitivity to beta-lactam antibiotics including ceftaroline. Before therapy with ceftaroline is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. If this product is to be given to penicillin- or other beta-lactam-allergic people, caution should be exercised because cross sensitivity among beta-lactam antibacterial agents has been clearly established. If an allergic reaction to ceftaroline occurs, the drug should be discontinued. Serious acute hypersensitivity reactions require emergency treatment with epinephrine and other emergency measures, that may include airway management, oxygen, intravenous fluids, antihistamines, corticosteroids, and vasopressors as clinically indicated.

''Clostridium difficile''-associated diarrhea

''Clostridium difficile''-associated diarrhea (CDAD) has been reported for nearly all antibacterial agents including ceftaroline, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterials not directed against'' C. difficile'' should be discontinued, if possible.

Development of drug-resistant bacteria

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

Direct Coombs test seroconversion

In the pooled phase-III CABP trials, 51/520 (9.8%) of subjects treated with ceftaroline compared to 24/534 (4.5%) of subjects treated with ceftriaxone seroconverted from a negative to a positive direct Coombs' test result. No clinical adverse reactions representing hemolytic anemia were reported in any treatment group. If anemia develops during or after treatment with ceftaroline, drug-induced hemolytic anemia should be considered. If drug-induced hemolytic anemia is suspected, discontinuation of ceftaroline should be considered and supportive care should be administered to the patient if clinically indicated.

Interactions

No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil. In vitro studies in human liver microsomes indicated that neither ceftaroline fosamil nor ceftaroline inhibits the major cytochrome P450 isoenzymes. Therefore, neither ceftaroline fosamil nor ceftaroline is expected to inhibit or induce the clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.

Use in specific populations

For pregnant or nursing mothers, ceftaroline fosamil should be used only if the potential benefit outweighs the potential risk to the fetus or child. Safety and effectiveness in pediatric children has not been studied. Because elderly people 65 years of age or older are more likely to have decreased renal function and ceftaroline is excreted primarily by the kidney, care should be taken in dose selection in this age group as in younger people with impaired renal function. Dosage adjustment is required in people with moderately (30 to ‰¤ 50 mL/min) or severely (< 30 mL/min) impaired renal function. The pharmacokinetics of ceftaroline in people with hepatic impairment have not been established.

Side effects

No adverse reactions occurred in greater than 5% of people receiving ceftaroline. The most common adverse reactions occurring in > 2% of people receiving ceftaroline in the pooled phase-III clinical trials were: *

Diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

Rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

Chemistry

Ceftaroline fosamil is used in form of the acetate. It is a prodrug that is converted to active metabolite ceftaroline and inactive metabolite ceftaroline-M1. Initial ''in vitro'' and ''in vivo'' animal studies referred to ceftaroline fosamil acetate as PPI-0903. Characteristic of cephalosporins, ceftaroline has a bicyclic ring with four-member

β-lactam A beta-lactam (β-lactam) ring is a four-membered lactam. A ''lactam'' is a cyclic amide, and ''beta''-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is ...

ring fused to a six-member

cephem Cephems are a sub-group of β-lactam antibiotics including cephalosporins and cephamycin Cephamycins are a group of β-lactam antibiotics. They are very similar to cephalosporins, and the cephamycins are sometimes classified as cephalosporins ...

ring. Ceftaroline is thought to have activity against MRSA with its 1,3-thiazole ring.

References

External links

* {{DEFAULTSORT:Ceftaroline Fosamil AbbVie brands AstraZeneca brands Cephalosporin antibiotics Pfizer brands Phosphoramidates Pyridinium compounds Thiadiazoles Thiazoles