Ceftaroline
Encyclopedia
Ceftaroline fosamil is an advanced-generation cephalosporin
antibiotic
. It is active against methicillin-resistant Staphylococcus aureus
(MRSA) and Gram-positive
bacteria. It retains the activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative
bacteria. It is currently being investigated for community-acquired pneumonia
and complicated skin and skin structure infection.
Ceftaroline is being developed by Forest Laboratories
, under a license from Takeda
.
Ceftaroline has received approval from the U.S. Food and Drug Administration for the treatment of community-acquired bacterial pneumonia
and acute bacterial skin infections on October 29, 2010. In vitro studies show that 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. Currently, ceftaroline and ceftobiprole are on an unnamed subclass of cephalosporins by the Clinical and Laboratory Standards Institute (CLSI).
s inhibit bacterial peptidoglycan
synthesis by binding the penicillin-binding proteins (PBPs) in the bacterial cell wall. Inhibition of PBPs leads to irregularities in cell wall structures, such as elongation, lesions, loss of selective permeability, and eventual cell death and lysis. In particular, ceftaroline can effectively bind to and inhibit PBP-2a, the type of PBP produced by MRSA
and not well inhibited by other antibiotics
currently in clinical use.
and aztreonam
In 2009, ceftaroline had completed phase III clinical trials for community-acquired pneumonia
comparing it against ceftriaxone
with non-inferior results and similar adverse reaction profile. However there are only published results for Phase II clinical trials in treatment of complicated skin and skin structure infections. Sept 2009 : Phase III trials results reported.
On September 8, 2010 the FDA Advisory Committee recommended approval for the treatment of community acquired bacterial pneumonia and complicated skin and skin structure infections.
In Oct 2010 the FDA approval was gained for community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infection
s (ABSSSI), including methicillin-resistant Staphylococcus aureus (MRSA).
The overall discontinuation rate for ceftaroline-treated patients was 2.7% compared to a rate of 3.7% for the comparator group-treated patients. The most common adverse reactions occurring in > 2% of patients receiving ceftaroline in the pooled Phase 3 clinical trials were diarrhea, nausea, and rash.:
(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 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible.
Safety and effectiveness in pediatric patients has not been studied.
Because elderly patients greater-than or equal to 65 years of age 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 patients with impaired renal function.
Dosage adjustment is required in patients with moderately (30 to ‰¤ 50 mL/min) or severely (< 30 mL/min) impaired renal function.
The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established.
The most common adverse reactions occurring in > 2% of patients receiving ceftaroline in the pooled Phase 3 clinical trials were:
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 ring fused to a six-member cephem
ring. Ceftaroline is thought to have activity against MRSA with its 1,3-thiazole ring.
Cephalosporin
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...
antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
. It is active against methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...
(MRSA) and Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria. It retains the activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria. It is currently being investigated for community-acquired pneumonia
Community-acquired pneumonia
Community-acquired pneumonia is a term used to describe one of several diseases in which individuals who have not recently been hospitalized develop an infection of the lungs . CAP is a common illness and can affect people of all ages. CAP often causes problems like difficulty in breathing, fever,...
and complicated skin and skin structure infection.
Ceftaroline is being developed by Forest Laboratories
Forest Laboratories
Forest Laboratories is a pharmaceutical company headquartered in New York City, USA. Its revenues for the year ended 31 March 2007 were US$3.4 billion. The company's research and development spending has grown rapidly in recent years, and as of 2007, approached almost a billion US dollars a year,...
, under a license from Takeda
Takeda Pharmaceutical Company
is the largest pharmaceutical company in Japan and Asia and a top 15 pharmaceutical company. The company has over 19,000 employees worldwide and achieved $15.7 billion USD in revenue during the 2008 fiscal year...
.
Ceftaroline has received approval from the U.S. Food and Drug Administration for the treatment of community-acquired bacterial pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
and acute bacterial skin infections on October 29, 2010. In vitro studies show that it has a similar spectrum to ceftobiprole
Ceftobiprole
Ceftobiprole is a 4th generation cephalosporin antibiotic with activity against methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, Pseudomonas aeruginosa, and Enterococci. It was discovered by Basilea Pharmaceutica and was developed by Johnson & Johnson...
, the only other fifth-generation cephalosporin to date, although no head to head clinical trials have been conducted. Currently, ceftaroline and ceftobiprole are on an unnamed subclass of cephalosporins by the Clinical and Laboratory Standards Institute (CLSI).
Mechanism of action
Beta-lactam antibioticBeta-lactam antibiotic
β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...
s inhibit bacterial peptidoglycan
Peptidoglycan
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of bacteria , forming the cell wall. The sugar component consists of alternating residues of β- linked N-acetylglucosamine and N-acetylmuramic acid...
synthesis by binding the penicillin-binding proteins (PBPs) in the bacterial cell wall. Inhibition of PBPs leads to irregularities in cell wall structures, such as elongation, lesions, loss of selective permeability, and eventual cell death and lysis. In particular, ceftaroline can effectively bind to and inhibit PBP-2a, the type of PBP produced by MRSA
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...
and not well inhibited by other antibiotics
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
currently in clinical use.
Clinical use
Ceftaroline is a novel cephalosporin that has activity against MRSA with phase III clinical trials for complicated skin and skin structure infections with reported non-inferior efficacy against MRSA compared to vancomycinVancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
and aztreonam
Aztreonam
Aztreonam is a synthetic monocyclic beta-lactam antibiotic , with the nucleus based on a simpler monobactam isolated from Chromobacterium violaceum. It was approved by the U.S. Food and Drug Administration in 1986...
In 2009, ceftaroline had completed phase III clinical trials for community-acquired pneumonia
Community-acquired pneumonia
Community-acquired pneumonia is a term used to describe one of several diseases in which individuals who have not recently been hospitalized develop an infection of the lungs . CAP is a common illness and can affect people of all ages. CAP often causes problems like difficulty in breathing, fever,...
comparing it against ceftriaxone
Ceftriaxone
Ceftriaxone is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. In most cases, it is considered to be equivalent to cefotaxime in terms of safety and efficacy...
with non-inferior results and similar adverse reaction profile. However there are only published results for Phase II clinical trials in treatment of complicated skin and skin structure infections. Sept 2009 : Phase III trials results reported.
On September 8, 2010 the FDA Advisory Committee recommended approval for the treatment of community acquired bacterial pneumonia and complicated skin and skin structure infections.
In Oct 2010 the FDA approval was gained for community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infection
Skin and skin structure infection
A skin and skin structure infection is a bacterial infection of skin and associated tissues. It often requires treatment by antibiotics.It is/was divided into two types, complicated skin and skin structure infection and...
s (ABSSSI), including methicillin-resistant Staphylococcus aureus (MRSA).
Safety
The clinical studies indicated that 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 patients with complicated skin and skin structure infections caused by gram-positive and gram-negative bacteria.).The overall discontinuation rate for ceftaroline-treated patients was 2.7% compared to a rate of 3.7% for the comparator group-treated patients. The most common adverse reactions occurring in > 2% of patients receiving ceftaroline in the pooled Phase 3 clinical trials were diarrhea, nausea, and rash.:
Contraindications
- Known serious hypersensitivityHypersensitivityHypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
to ceftaroline or other members of the cephalosporin class. - AnaphylaxisAnaphylaxisAnaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
and anaphylactoid reactions have been reported with ceftaroline.
Hypersensitivity reactions
Serious hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported with beta-lactam antibiotics, including ceftaroline. Exercise caution in patients 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 patient, 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 (anaphylactic) 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 diarrheaClostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
(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 2 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 3 CABP trials, 51/520 (9.8%) of patients treated with ceftaroline compared to 24/534 (4.5%) of patients 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 patients has not been studied.
Because elderly patients greater-than or equal to 65 years of age 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 patients with impaired renal function.
Dosage adjustment is required in patients with moderately (30 to ‰¤ 50 mL/min) or severely (< 30 mL/min) impaired renal function.
The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established.
Side-effects
No adverse reactions occurred in greater than 5% of patients receiving ceftaroline.The most common adverse reactions occurring in > 2% of patients receiving ceftaroline in the pooled Phase 3 clinical trials were:
- DiarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
- NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
- RashRashA rash is a change of the 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, cracked or blistered, swell and may be painful. The causes, and...
Chemistry
Ceftaroline fosamil is a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
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 ring fused to a six-member cephem
Cephem
Cephems are a sub-group of beta-lactam antibiotics including cephalosporins and cephamycins....
ring. Ceftaroline is thought to have activity against MRSA with its 1,3-thiazole ring.