Emerging cephalosporins

Several cephalosporins are in clinical development as broad-spectrum agents with potent activity against multi-resistant staphylococci as well as the Gram-positive and Gram-negative bacteria normally susceptible to advanced generation cephalsoporins. These agents represent a novel activity for the class and challenge a dogma that β-lactams do not have clinically useful activity against multi-resistant staphylococci. The most advanced of these agents, ceftobiprole, is approaching registration and, if approved, will present physicians with a new paradigm in treatment of serious infections by multi-resistant organisms.     

β-lactams against emerging ‘superbugs’: progress and pitfalls

Bacterial resistance to antimicrobial agents is an ever-growing problem. So-called ‘superbugs’, such as multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa harboring multiple resistance determinants, including extended-spectrum β-lactamases, carbapenemases, efflux pumps and downregulated outer-membrane proteins or porins, are becoming more prevalent in hospital, intensive and long-term care settings. Enterobacteriaceae are also acquiring a myriad of β-lactamases, such as class A and D carbapenemases, and plasmid-borne class C cephalosporinases. Gram-positive superbugs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate or heteroglycopeptide-intermediate S. aureus, vancomycin-resistant S. aureus and penicillin-resistant Streptococcus pneumoniae (PRSP), are problematic pathogens, both in the hospital and in the community (e.g., community-acquired MRSA and PRSP). β-lactam antibiotics remain among the most effective and safest anti-infectives in use, although their utility is being severely challenged by these superbugs. This review will discuss aspects of resistance seen in these pathogens and will review some of the newer β-lactam agents, both investigational and in clinical use, that target these superbugs.     

Ceftaroline fosamil and treatment of acute bacterial skin and skin structure infections: CAPTURE study experience

Abstract

The Clinical Assessment Program and TEFLARO Utilization Registry (CAPTURE) is a multicentre retrospective cohort study in the USA describing treatment of acute bacterial skin and skin structure infection (ABSSSI) with ceftaroline fosamil (CPT-F). Charts for review were chosen by random selection. Among 647 evaluable patients, 52% were obese, 46% had diabetes mellitus (DM), and 19% had peripheral vascular disease (PVD). Methicillin-resistant Staphylococcus aureus (MRSA) was recovered in 28% and methicillin-susceptible S. aureus (MSSA), 11%. Antibiotics were administered prior to CPT-F treatment in 80%, and concurrently in 39%. Clinical success overall was 85%; in patients with DM, 83%; with PVD, 76%; and in obese patients, 88%. Clinical success was ≧ 79% across all infection types; 81% for MRSA and 83% for MSSA; and 86% for ceftaroline monotherapy and 84% for concurrent therapy. These high clinical success rates support CPT-F as an effective treatment option for ABSSSI, including infections due to MRSA and patients with significant co-morbidities.     

Morbidity,mortality, and management of methicillin-resistant S. aureus bacteremia in the USA: update on antibacterial choices and understanding

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with significant healthcare costs, morbidity, and mortality in the United States. Complications of MRSA bacteremia include infective endocarditis, osteomyelitis, and sepsis, all of which are difficult to treat. Time to effective therapy and antibacterial choice greatly affect patient outcomes. Vancomycin and daptomycin remain first-line therapies; however, reports of vancomycin-associated treatment failure and reduced daptomycin susceptibility highlight the need to define alternative strategies for MRSA bacteremia treatment. In addition, several patient- and pathogen-specific factors influence the outcomes of MRSA bacteremia. It is, therefore, critical to explore the interaction between host- and pathogen-specific factors and its effect on MRSA bacteremia pathogenesis and mortality. This review discusses the factors that drive the development of MRSA bacteremia and examines alternative treatment strategies.     

Current challenges in treating MRSA: what are the options?

This review looks at the challenges facing the worldwide community with the increasing problem of methicillin resistance in Staphylococcus aureus. The epidemiology and natural history of community-associated methicillin-resistant Staphylococcus aureus and the challenge of control is discussed. Options for treatment and review of key antimicrobial agents acting against methicillin-resistant S. aureus, both currently in use and in development, are addressed. There are a number of new agents, the place of which in therapeutic regimens is yet to emerge. The review attempts to inform the reader of the probable position of these agents.     

Pharmacokinetics and safety of recently approved drugs used to treat methicillin-resistant Staphylococcus aureus infections in infants,children and adults

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant cause of morbidity in hospitalized infants. Over the past 15 years, several drugs have been approved for the treatment of S. aureus infections in adults (linezolid, quinupristin/dalfopristin, daptomycin, telavancin, tigecycline and ceftaroline). The use of the majority of these drugs has extended into the treatment of MRSA infections in infants, frequently with minimal safety or dosing information. Only linezolid is approved for use in infants, and pharmacokinetic data in infants are limited to linezolid and daptomycin. Pediatric trials are underway for ceftaroline, telavancin, and daptomycin; however, none of these studies includes infants. Here, we review current pharmacokinetic, safety and efficacy data of these drugs with a specific focus in infants.     

Ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections

Skin infections have traditionally been classified by the US FDA as uncomplicated and complicated. In August 2010, the FDA released a new guidance document for the development of drugs to treat acute bacterial skin and skin structure infections (ABSSSI) and this was updated in 2013. Several new issues were addressed and henceforth skin infections in clinical trials were termed ABSSSI. In the USA, the annual prevalence of methicillin-resistant Staphylococcus aureus-related skin infections have continuously increased from 32.7% in 1998 to 53.8% in 2007. Ceftaroline fosamil is the only cephalosporin approved in the USA for monotherapy treatment of ABSSSI including infections caused by methicillin-resistant S. aureus. The efficacy of ceftaroline fosamil was shown in the CANVAS clinical trials. The CANVAS Day-3 analyses met an earlier, primary efficacy time point requested by the FDA. Ceftaroline has minimal drug–drug interactions, is well tolerated and possesses the safety profile associated with the cephalosporin class.     

Safety,local tolerability and pharmacokinetics of ceftaroline fosamil administered in a reduced infusion volume

Aims

The standard dose of ceftaroline fosamil for patients with normal renal function is 600 mg diluted in 250 ml by 60 min intravenous infusion every 12 h. This two part phase I trial ({"type":"clinical-trial","attrs":{"text":"NCT01577589","term_id":"NCT01577589"}}NCT01577589) assessed safety and local tolerability of multiple ceftaroline fosamil 50 ml and 250 ml infusions, and pharmacokinetics following single administrations of each infusion volume.

Methods

Part A was a placebo-controlled, double-blind, multiple dose crossover study. Twenty-four healthy subjects were randomized to simultaneous, bilateral ceftaroline fosamil 600 mg and placebo infusions in each arm (50 ml then 250 ml or vice versa) every 12 h for 72 h, with a ≥ 4.5 day washout. Local tolerability was evaluated by the Visual Infusion Phlebitis scale, with scores ≥2 considered infusion site reactions (ISRs). Part B was an open label crossover study. Ten subjects were randomized to single 50 ml and 250 ml ceftaroline fosamil 600 mg infusions on days 1 and 3 (washout on day 2). Blood samples for pharmacokinetic analysis were taken over 24 h.

Results

In part A, four subjects (16.7%) experienced ISRs, all of which were associated with placebo infusions. No ISRs were reported for either ceftaroline fosamil 50 ml or 250 ml. Plasma pharmacokinetics (ceftaroline fosamil, active ceftaroline and an inactive metabolite) were similar following single 50 ml and 250 ml infusions in part B.

Conclusions

No new safety concerns were identified for ceftaroline fosamil 600 mg 50 ml compared with 250 ml. These findings suggest infusion volumes down to 50 ml may be used in patients with fluid intake restrictions.     

Ceftaroline fosamil for treatment of communityacquired pneumonia: findings from FOCUS 1 and 2 and potential role in therapy

Cephalosporins have been widely used over the last few decades (often as first-line antibiotic therapy) for numerous infections, owing primarily to their broad spectrum of microbiologic activity and favorable safety profile. Current Infectious Diseases Society of America guidelines identify a third-generation cephalosporin in combination with a macrolide antibiotic as an option for treatment of hospitalized adult patients with community-acquired pneumonia (CAP) outside the intensive care unit setting. Although ceftriaxone is a frequently used agent for CAP, increasing incidence of multidrug-resistant Streptococcus pneumoniae and concerns regarding poor outcomes associated with ineffective therapy have prompted the search for a well-tolerated treatment alternative that is effective against bacteria that can cause CAP. Ceftaroline fosamil, the prodrug of ceftaroline, is a new extended-spectrum cephalosporin that exhibits time-dependant bactericidal activity against numerous Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. pneumoniae. Notable exceptions include Pseudomonas spp. and Gram-negative organisms that produce extended-spectrum β-lactamases or carbapenemases. Two large Phase III clinical trials (FOCUS 1 and 2) reported that ceftaroline fosamil was well tolerated, with a clinical cure rate of CAP that was noninferior to that with ceftriaxone in nonintensive care unit adult inpatients with moderately severe (Pneumonia Outcomes Research Team score of III or IV) community-acquired pneumonia.