ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS: CURRENT PERSPECTIVE

Abstract

A skin and skin structure infection is a bacterial infection of skin and associated tissues. It may be complicated skin and skin structure infection or uncomplicated skin and skin structure infection. Recently, the Food and Drug Administration has called them acute bacterial skin and skin structure infections (ABSSSI). ABSSSI are common and encompass a variety of disease presentations and severity. Increased antimicrobial resistance among both Gram-positive and Gram-negative bacteria with methicillin-resistant Staphylococcus aureus is the main problem in treatment. So, development of newer agents to fight against resistant microbes is the need of the hour. Ceftaroline, a newer cephalosporin, is one promising agent.

Introduction

A skin and skin structure infection is a bacterial infection of skin and associated tissues. It often requires treatment by antibiotics. It may be complicated skin and skin structure infection (cSSSI) or uncomplicated skin and skin structure infection.

According to U.S. Food and Drug Administration (FDA), the uncomplicated category includes simple abscesses, impetiginous lesions, furuncles, and cellulitis mainly caused by Staphylococcus aureus and Streptococcus pyogenes. The complicated category includes infections either involving deeper soft tissue or requiring significant surgical intervention, such as infected ulcers, burns, and major abscesses or a significant underlying disease state that complicates the response to treatment. Superficial infections or abscesses in an anatomical site, such as the rectal area, where the risk of anaerobic or Gram-negative pathogen involvement is higher, should be considered complicated infections. The mainstays of treatment continue to be antimicrobial therapy combined with appropriate surgical intervention. Since 2008-2010, the FDA has called them acute bacterial skin and skin structure infections (ABSSSI). The two categories also had different regulatory approval requirements. ABSSSI are common and encompass a variety of disease presentations and severity.

Antimicrobial resistance among both Gram-positive and Gram-negative bacteria has increased significantly with methicillin resistance among S. aureus approaching 60% in hospitals and becoming more frequent in the community as well. Resistance not only leads to treatment failure but also increases the cost. Vancomycin is currently the drug of choice against resistant Gram-positive cocci, however, resistance to this agent has appeared in enterococci and S. aureus. Several new antibiotics such as linezolid and daptomycin are now available for the management of cSSSIs. Tigecycline is under investigation.[1]

So, there is a need to develop new agents with advantages over conventional. Ceftaroline is a promising newer fifth-generation[1] cephalosporin antibiotic. Ceftaroline is being developed by Forest Laboratories, under a license from Takeda.[2] Ceftaroline has received approval from the U.S. FDA for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin infections on October 29, 2010.[3]

Mechanism of Action

Beta-lactam antibiotics 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 methicillin-resistant S. aureus (MRSA) and not well inhibited by other antibiotics currently in clinical use.[4,5]

Pharmacokinetics

Ceftaroline is excreted primarily by the kidney and so elderly patients greater than or equal to 65 years of age are more likely to have decreased renal function; 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 has not been established.

Indications

In October 2010, the FDA approval was gained for community-acquired bacterial pneumonia including cases caused by Streptococcus pneumoniae, S. aureus (methicillin-susceptible isolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli) and ABSSSI, caused by S. aureus (including methicillin-susceptible and resistant isolates), S. pyogenes, Streptococcus agalactiae, E. coil, K. pneumoniae, and K. oxytoca.

Ceftaroline has activity against MRSA with phase III clinical trials for cSSSI with reported noninferior efficacy against MRSA compared with vancomycin and aztreonam.[6,7] A phase II study randomized 100 patients with cSSSI to intravenous ceftaroline 600 mg every 12 hours or intravenous vancomycin 1 g every 12 hours with or without intravenous aztreonam 1 g every 8 hours (standard therapy) for 7 to 14 days. Clinical cure rates were 96.7% for ceftaroline compared with 88.9% for standard therapy. Adverse events were similar between groups and generally mild in nature. In a phase III trial, 702 patients with cSSSI were randomized to ceftaroline 600 mg or vancomycin 1 g plus aztreonam 1 g, each administered intravenously every 12 hours for 5 to 14 days. Ceftaroline was noninferior to vancomycin plus aztreonam in treating cSSSI caused by both Gram-positive and negative pathogens. Adverse event rates were similar between groups. Ceftaroline has completed phase III clinical trials for community-acquired pneumonia, comparing it against ceftriaxone with noninferior results and similar adverse reaction profile.[8]

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 vs vancomycin plus aztreonam in adult patients with cSSSI caused by Gram-positive and Gram-negative bacteria.). The overall discontinuation rate for ceftaroline-treated patients was 2.7% compared with 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.[9]

Adverse Drug Reactions

Hypersensitivity reactions

Serious hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported with 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 diarrhea (CDAD) has been reported for with 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.

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 community-acquired bacterial pneumonia trials, 51/520 (9.8%) of patients treated with ceftaroline compared with 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.

Drug 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 are expected to inhibit or induce the clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.

Contraindications

• Known serious hypersensitivity to ceftaroline or other members of the cephalosporin class.

• Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline.[10]

Use in Specific Populations

For pregnant or nursing mothers, ceftaroline fosamil should only be used if the potential benefit outweighs the potential risk to the fetus or child. Safety and effectiveness in pediatric patients has not been studied.

Future Clinical Trials for Acute Bacterial Skin and Skin Structure Infections

According to recently proposed FDA guidelines, a clinical trial design using an active-comparator antibacterial drug is recommended for the clinical disease entities of ABSSSI (i.e., cellulitis/erysipelas, wound infection, major cutaneous abscess, and burn infection). The trial design using an active-comparator could be noninferiority clinical trial using a prespecified noninferiority margin or a superiority trial. ABSSSI for which either noninferiority or superiority trial designs are recommended include cellulitis/erysipelas, wound infection, major cutaneous abscess, and burn infection. The reason for this is as follows: (1) it provides a patient population for which the treatment effect of antibacterial drug therapy would be expected to be similar to the treatment effect observed in historical studies of cellulitis/erysipelas and (2) it provides an extent of disease to clearly and objectively document the infection and to follow clinical improvement or deterioration. Draft recommends that the ABSSSI clinical trial population include patients with a mixture of the clinical disease entities defined above. Because surgical incision and drainage might influence treatment outcomes among patients with major cutaneous abscesses, the patients with major cutaneous abscesses should not comprise more than 30% of the clinical trial population (note that major cutaneous abscess includes patients with a minimum surface area of surrounding redness, edema, and/or induration of 75 cm²). Patients with infections such as infections of animal or human bites, necrotizing fasciitis, diabetic foot infection, decubitus ulcer infection, myonecrosis, ecthyma gangrenosum, and catheter-site infections should not be enrolled in ABSSSI clinical trials.

Definitions for adults and children with milder skin infections for which a superiority trial design is recommended: Minor cutaneous abscess, Impetigo. At least two adequate and well-controlled trials that establish safety and efficacy should be conducted for treatment of ABSSSI. Either noninferiority or superiority trials are recommended for the indication of treatment of ABSSSI disease entities of cellulitis/erysipelas, wound infection, major cutaneous abscess, or burn infection.[11]