Reports

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 - 21st European Congress of Clinical Microbiology and Infectious Diseases/ 27th International Congress of Chemotherapy

Milan, Italy / May 7-10, 2011

In methicillin-resistant Staphylococcus aureus (MRSA), vancomycin continues to be the most frequently used agent, although its pharmacodynamic properties suggest it is a less than an optimal choice for MRSA as many MRSA strains show reduced susceptibility to it.

Other options for treating MRSA, such as daptomycin and linezolid, have emerged. Guidelines from the Infectious Diseases Society of America (IDSA) issued in January 2011 suggest i.v. daptopmycin in dosages of 4 mg/kg q.d. as an alternative for hospitalized patients with complicated skin and soft tissue infections (SSTIs); 6 to 10 mg/kg q.d. for MRSA bacteremia and infective endocarditis (both adult and pediatric); and 6 mg/kg q.d. for bone and joint infections and device-related osteoarticular infections.

New data presented here at ECCMID highlight the success of this antimicrobial with neutropenia and gram-positive infections (i.e. endocarditis, bacteremia, SSTIs and osteomyelitis) in accordance with IDSA guidelines.

Pharmacodynamics and Potency

S. aureus is the most common organism isolated from SSTIs, and MRSA is a rapidly increasing hospital- and community-acquired pathogen. Although the glycopeptides vancomycin and teicoplanin are considered the gold standard for treating serious MRSA infections, the current utility of these agents is increasingly in question, stated Dr. Matteo Bassetti, Infectious Diseases Division, San Martino Hospital, Genoa, Italy. Given poor results with vancomycin in MRSA, new alternatives are needed as definitive therapy and also empirically when S. aureus is suspected, experts here at ECCMID agreed.

Rapidly bactericidal and active against gram-positive cocci including MRSA, daptomycin offers potential advantages in the treatment of complicated SSTIs, such as a faster clinical cure and less likelihood of the need for prolonged treatment vs. comparators, according to Dr. Bassetti.

The potency of an antimicrobial drug is often defined by pharmacodynamic parameters such as the duration for which drug level exceeds the minimum inhibitory concentration (MIC), and attainment and maintenance of adequate drug trough levels. However, potency goes beyond pharmacodynamics for some infections and drugs to include factors such as bactericidal activity, explained Dr. David Livermore, Health Protection Agency Microbiology Services, Colindale, London, UK. Such is the case with endocarditis, severe bacteremia and in infections in which host defenses are severely compromised (e.g. neutropenic fevers).

For example, in staphylococcal endocarditis, monotherapy clinical efficacy was shown with the rapidly bactericidal agent daptomycin but not with the bacteriostatic agent linezolid. In settings in which bactericidal activity is less crucial, as in MRSA pneumonia, linezolid is more effective than vancomycin, which has weak bactericidal activity, he remarked.

Within the first 24 hours, selecting the right agent and achieving the pharmacodynamic target that predicts efficacy is crucial, confirmed Dr. Alex Soriano, Department of Infectious Diseases, Hospital Clinic of Barcelona, Spain. As an example, he pointed to vancomycin’s low probability in achieving a pharmacodynamic target of AUC24/MIC =400 µg/mL within the first 24 hours with standard dosing (1 g/12 h) as being partly responsible for the high mortality rate of S. aureus bacteremia. Increasing serum trough concentration by increasing dosage when the MIC is =1 µg/mL can increase the probability of attaining the pharmacodynamic target, he explained to delegates, but the increased risk of nephrotoxicity with the high daily vancomycin doses required to attain the pharmacodynamic target generally precludes this approach.

A European Registry Examination

According to results from the European Cubicin Outcomes Registry and Experience (EU-CORE), the agent has high clinical success rates and is well tolerated in neutropenic patients with gram-positive infections.

Among 259 patients enrolled in the registry who had neutropenia at baseline and during therapy, the overall clinical success rate (an outcome of cure or improved) was 76%, reported Dr. Tetjana Lejko-Zupanc, Department of Infectious Diseases, University Medical Centre Ljubljana, Slovenia. Clinical success rates were 79% in patients with catheter-related bacteremia, 74% for gram-positive SSTIs, 100% for endocarditis and 80% for osteomyelitis.

“If you look at MRSA, some of the isolates may have high MICs, so vancomycin is really not a choice,” Dr. Lejko-Zupanc told delegates. “In those patients who have vancomycin-resistant enterococci, although there were not many in this registry, you can’t use either vancomycin or teicoplanin. There is really no alternative if the patient is bacteremic because the other option, linezolid, can’t be used in bacteremic patients.” Other agents for gram-positive infections, especially vancomycin, appear more toxic, she said. Twelve per cent of the neutropenic patients in the registry had serious adverse events, regardless of the relationship to daptomycin.

According to a poster presentation here at ECCMID, the concentration-dependent, rapidly bactericidal activity of daptomycin represents a strong rationale for high dose in difficult-to-treat infection, reported Dr. Riccardo Utili and colleagues, University of Naples, Monaldi Hospital, Italy.

In another examination of the EU-CORE registry, at doses of =8 mg/kg in patients with serious gram-positive infections, the antimicrobial produced high clinical success rates that extended to all infecting pathogens while being well tolerated. In this analysis, the overall clinical success rate in 270 patients who received at least 8 mg/kg (median duration, 14 days; longest treatment, 110 days) was 80%, ranging from 65% (osteomyelitis) to 90% (endocarditis). By primary infecting pathogen, clinical success rates were 78% for S. aureus (for both methicillin-resistant and methicillin-sensitive strains), 86% for coagulase-negative staphylococci and 77% for enterococci. Compared to doses of =8 mg/kg, high dose was not associated with more frequent serious adverse events or more frequent discontinuation due to adverse events, the authors reported.

Cost-effective Option as Outpatient Therapy

Hospitalization is the major component of health care cost for gram-positive infections, particularly in MRSA. Outpatient parenteral antibiotic therapy is typically used in selected patients with gram-positive infections, notably SSTIs and bone and joint infections.

According to Dr. Armando Gonzalez-Ruiz, Darent Valley Hospital, Dartford, UK, for complicated gram-positive infections, some patients may be successfully managed either entirely in the outpatient setting or following initial hospitalization. As a cost-effective therapeutic option, daptomycin “administered as a 2-minute i.v. infusion q.d. enhances its use in the ambulatory treatment of select infections typically encountered in outpatient practice,” he told delegates.

The median duration of therapy was 14 days in the outpatient setting, 10 days in the outpatient/inpatient setting and 10 days in the inpatient setting. Overall, success rates were high for all treated infections with a trend to be higher in patients at least partially treated as outpatients (Table 1). Serious adverse events were reported in 2.7% of patients on outpatient therapy vs. 9.7% in those on inpatient therapy.

The US Experience

In the Daptomycin Surveillance Program (2002-2010), 14,044 enterococci and streptococci strains were collected from US hospitals and evaluated. More than 99% of strains (including vancomycin-resistant enterococci and beta-hemolytic and viridians group streptococci) were found to be susceptible to this agent, according to Prof. Helio S. Sader and colleagues, JMI Laboratories, North Liberty, Iowa.

Given the above European and US experience, in addition to recommendations laid out in the IDSA guidelines, there may be an opportunity to improve on patient outcomes and the total cost of care when treating MRSA and other difficult-to-treat infections.