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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

London, UK / March 31-April 3, 2012

London - Several new sets of data were presented at ECCMID that provided guidance on the efficacy of some of the most effective antibiotics for the treatment of serious Gram-positive infections. One of these was the ongoing European registry, EU-CORE, which has been recording patient characteristics, infections, pathogens, adverse events and clinical outcomes in patients receiving the first-in-class cyclic lipopeptide antibiotic. Another was TEST, which is a global initiative monitoring isolate sensitivity to a first-in-class glycylcycline in 25 European countries. Each of these ongoing analyses supports high and consistent rates of efficacy in managing hard-to-treat infections with newer agents.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The evidence of efficacy from monitoring studies with first-in-class antibiotics effective against serious Gram-positive infections are particularly encouraging because of increasing problems with vancomycin, a commonly employed intravenous agent for these pathogens. The widespread use of vancomycin has led to increasing reports of resistant enterococci and Staphylococcus aureus, steering attention toward effective alternatives.

Although EU-CORE (European Cubicin Outcomes Registry and Experience) may be the more important of the 2 studies because it has generated data on clinical outcomes, the data from TEST (Tigecycline Evaluation and Surveillance Trial), which is an in vitro surveillance study of Gram-positive strains collected from 271 sites in 25 countries, have also yielded useful information. According to TEST data presented by Dr. Samuel K. Bouchillon, International Health Management Associates, Schaumberg, Illinois, the glycylcycline tigecycline continues to provide broad-spectrum activity throughout Europe based on minimal inhibitory concentrations (MICs) and susceptibility values.

“Half of the countries had tigecycline MIC90 values of 1 mg/L against the Enterobacteriaceae and half had values of 2 mg/L,” reported Dr. Bouchillon, noting that these suggest that potency is being preserved. The data were based on in vitro evaluations of 15,304 collected strains.

EU-CORE

To gain an understanding of real-world clinical experience with the lipopeptide daptomycin, EU-CORE has been collecting data on the characteristics and clinical outcomes of patients receiving the antibiotic in Europe, Russia, India and Latin America. Demographic, antibiotic, microbiological and clinical data are obtained from medical records at over 100 institutions. EU-CORE now has data on over 4000 patients, according to consultant microbiologist Dr. Armando González-Ruiz, Darent Valley Hospital, Dartford, Kent, UK. Dr. González-Ruiz’s centre is the largest UK contributor to EU-CORE. “Clinical trials with rigorous inclusion and exclusion criteria may not reflect true clinical experience. It is not until you get real-world experience that you really understand the safety of an antibiotic and understand how clinicians will use it and the populations they will use it in,” Dr. González-Ruiz emphasized. The EU-CORE reports presented at the congress were based on data collected between January 2006 and June 2011. 

In the EU-CORE study, which evaluated clinical outcomes, a rapid concentration-dependent bactericidal activity against a broad spectrum of aerobic Gram-positive bacteria, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci, has been observed with daptomycin. It is approved in North America and Europe for adult treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria (4 mg/kg o.d.) and for bacteremia, including right-sided endocarditis, due to
S. aureus (6 mg/kg o.d.), including MRSA. Dose adjustment is required for patients with severe renal impairment.

Safety of High-dose Treatment

Since the bactericidal activity of daptomycin is dose-dependent, a high dose is sometimes considered for difficult-to-treat infections. US and European guidelines include daptomycin 8-10 mg/kg o.d. as a therapeutic option for difficult-to-treat infections such as persistent MRSA bacteremia and vancomycin treatment failure. Although no unexpected safety findings have been reported at higher doses, regular monitoring, including creatine phosphokinase (CPK) measurement, is recommended.

Of the 4592 patients enrolled in EU-CORE, 234 (5.1%) received higher doses (≥8 mg/kg/day) for ≥14 days. In these patients, a favourable safety profile comparable to that of approved doses is emerging, according to investigators led by Prof. Riccardo Utili, Second University of Naples, Italy. Overall, no clinically significant musculoskeletal and connective tissue events were reported. CPK elevations were observed in 3.8% and musculoskeletal adverse events (AEs) were reported in 0.4% of patients treated with ≥8 mg/kg/day for ≥14 days. The most common infections treated with high doses were endocarditis (30.3%), foreign body/prosthetics (19.7%), osteomyelitis (17.1%), SSSIs (15.8%) and bacteremia (12.0%). AEs were reported in 15.8% of patients receiving ≥8 mg/kg/day for ≥14 days, similar to patients receiving the same dose for <14 days (16.6%) and patients on approved doses (4-6 mg/kg/day; 13.2%). Serious AEs were also comparable to those seen in patients on lower and approved doses.

The change in proportion of patients with creatinine clearance <30 mL/min was 9.9% to 10.0% from the initiation to the end of high-dose treatment, respectively, similar to patients on ≥8 mg/kg/day for <14 days (10.8% and 8.1%, respectively). Discontinuations due to AEs were similar across the treatment groups. “Daptomycin can be administered at doses up to 10 mg/kg. It is now being used at high doses with highly favourable tolerability and data from EU-CORE have also shown that outcomes are better with higher doses than with lower doses,” Prof. Utili added. The overall clinical success rate was 88% with ≥8 mg/kg/day for ≥14 days compared with 80.2% in the overall
EU-CORE population (Figure 1). Prof. Utili and his colleagues noted that the use of high doses in EU-CORE has increased from 3% in 2006 to 18% in 2011.

Figure 1.

Use in Sepsis and Hematological Malignancies

A total of 302 patients (6.6%) in the EU-CORE registry were diagnosed with sepsis as primary infection. Most of these patients were pre-treated with other antibiotics and switched to daptomycin due to clinical failure. The most frequent dose used was 6 mg/kg (53%), followed by 4 mg/kg (17%) and ≥8 mg/kg (14%). Clinical success in patients infected with S. epidermidis and S. aureus was 85% and 72%, respectively, with similar rates regardless of methicillin susceptibility. CPK elevations were reported in 3% of patients. Possible related AEs were reported in 6 (2%) patients and 4 (1%) patients experienced serious AEs. “In my institution, we now use daptomycin as first-line treatment of sepsis because we realized that it is much better than glycopeptide antibiotics such as teicoplanin and much safer than vancomycin,” Dr. González-Ruiz stated. It is an attractive option for the treatment of sepsis because it does not induce cell lysis, he noted.

In hematological malignancies and Gram-positive infections, clinical experience was reported in 83 EU-CORE patients, mainly bacteremia (40%) and SSSIs (21%). The most frequent initial dose was 6 mg/kg (40%) and the median duration of therapy was 10 days.
The clinical success rate achieved with first-line use was high (80%) and similar clinical success rates were seen in subgroups with neutropenia regardless of severity. AEs were reported in 3 (3.6%) cases; 2 patients (2%) discontinued daptomycin due to AEs.
Dr. González-Ruiz noted that as first-line treatment of patients with hematological malignancies and Gram-positive infections, clinical data remain limited.

Summary

The TEST and EU-CORE data are expanding the evidence base that novel, first-in-class antibiotics are providing high rates of efficacy in difficult-to-treat Gram-positive infections, including control of infections in patients that would have been excluded from controlled clinical trials due to pre-existing morbidities such as renal insufficiency. The results of these studies are encouraging in the context of diminishing efficacy reports with vancomycin. Moreover, the relatively low AE rates and the high rates of antibiotic control across strains and populations observed in the TEST and EU-CORE studies provide the basis for using these agents to explore longer-term treatment of chronic, complicated infections such as osteoarticular or endovascular infections.