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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.

18th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Barcelona, Spain / April 19-22, 2008

Editorial Overview:

Ethan Rubinstein, MD, LLB

Sellers Professor of Research Head, Section of Infectious Diseases Department of Internal Medicine University of Manitoba Winnipeg, Manitoba

A range of pathogens can be responsible for hospital-acquired pneumonia (HAP), but of particular concern to clinicians is disease caused by Staphylococcus aureus. In a recent study based on inpatient databases covering a number of acute care hospitals in the US, this was the only pathogen that correlated with mortality (Kollef et al. Chest 2005;128:3854-62). Recently, there has been a sharp increase in the incidence of methicillin-resistant S. aureus (MRSA) strains. MRSA-associated disease is usually deadlier, and resistance, not just to methicillin but also to other antibiotics, is an increasing problem. This makes the disease harder to manage and limits the therapeutic options available. Although vancomycin has been the standard in MRSA infection for many years, it is subject to a number of drawbacks. Penetration in lung tissue is limited and there are worries that certain community-acquired strains of MRSA with increased resistance may become more common in a hospital setting. The incidence of S. aureus strains with increasing minimum inhibitory concentrations (MICs) has probably been occurring for some years now (the so-called MIC creep), giving rise to strains known as heterogeneous vancomycin-intermediate S. aureus (hVISA) and VISA. There is also concern that certain strains of S. aureus may acquire the vanA gene from other bacteria, giving rise to a sudden decrease in susceptibility and vancomycin-resistant strains (VRSA). Evidence is mounting that this loss of susceptibility is having a negative effect on patient outcomes. For example, Fridkin et al. (Clin Infect Dis 2003;36:429-39) reported a mortality rate of 63% in the case of infection with S. aureus strains with reduced vancomycin susceptibility compared to 12% for MRSA infection in general. There is therefore a clear need for new HAP treatment options.

A New Treatment Option for Gram-Positive Bacteria

The new lipoglycopeptide antimicrobial agent telavancin is currently under clinical development. Importantly from the point of view of ensuring that susceptibility is maintained, this new agent has a dual mode of action. Like glycopeptides, it disrupts peptidoglycan synthesis, thereby inhibiting bacterial wall synthesis. In addition, direct interaction of the compound with the membrane-embedded lipid II disrupts the barrier function of the bacterial membrane. As a result, it is rapidly bactericidal and has a broad spectrum of activity against many clinically relevant pathogens, including MRSA. Its use in clinical settings should be aided by its linear and predictable pharmacokinetics, and so monitoring of serum concentrations are not expected to be necessary in most instances.

In a study of 646 non-duplicate patient isolates from 26 medical centres in 10 different countries in Europe (including Israel and Turkey) that measured the susceptibility of MRSA to a range of antimicrobial agents, telavancin 50% and 90% MICs were 0.12 mcg/L and 0.25 mcg/L, respectively. By way of comparison, the MIC50 and MIC90 for vancomycin were both 1 mcg/L. The newer antimicrobial agent daptomycin had a MIC50 of 0.25 mcg/L and a MIC90 of 0.5 mcg/L, while linezolid—another widely used agent in MRSA infection—had a MIC50 of 1 mcg/L and a MIC90 of 2 mcg/L.

The ATLAS Studies

The clinical development program has included two identical randomized phase III studies, ATLAS 1 and 2 (Assessment of Telavancin in Skin and Skin Structure Infections), as a regulatory requirement for approval. Both studies had to meet the primary end point of non-inferiority to vancomycin and there was prospective provision for pooling the results of the two studies. The studies themselves compared the efficacy and safety of telavancin (10 mg/kg intravenously [i.v.] every 24 hours) with vancomycin (1 g i.v. every 12 hours) in the treatment of complicated skin and soft tissue infections (cSSTIs). In total, 1867 patients were enrolled. The most frequent Gram-positive pathogens isolated during the studies were MRSA strains (52%) followed by methicillin-susceptible S. aureus (MSSA) strains (31%). Gram-negative pathogens were present in 17% of the patients.

Study results demonstrated non-inferiority with non-significant differences between the two agents. Clinical cure was achieved in 88.3% of telavancin-treated patients and in 87.1% of those treated with vancomycin, and the overall therapeutic response rates were 88.6% and 86.2%, respectively. In the subset of patients with MRSA infection, the rates were 90.6% and 86.4%, respectively. Again, a trend to larger treatment difference was observed in the case of MRSA disease—89.9% vs. 84.7%—but these differences remained statistically non-significant.

In the last five years of so, there has been concern over the spread of the USA300 clone, and in particular, those strains containing the pvl gene. This gene codes for Panton-Valentine leukocidin, a toxin which may cause leukocyte destruction and tissue necrosis, and possibly increase the virulence of the micro-organism. The ATLAS investigators therefore decided to analyze efficacy in patients in whom such micro-organisms were detected. The cure rates were unaffected by pvl status.

The ATLAS findings suggest that telavancin could be a useful treatment option in cSSTIs and that the emerging MRSA strains are susceptible to this agent in a clinical setting. The question then is whether telavancin can be used in more serious infections such as HAP and VAP, which are conditions associated with a high mortality.

The ATTAIN Studies

To answer the question of whether telavancin might be a valid option in HAP, the randomized, multicentre, multinational, double-blind phase III ATTAIN (Comparison of Telavancin and Vancomycin for Hospital-Acquired Pneumonia Due to Methicillin-Resistant Staphylococcus Aureus) studies were undertaken. Early results from these studies were presented in an oral session at this year’s ECCMID meeting.

As was the case for the ATLAS studies, two studies were performed (as required by regulatory authorities) in such a way that the results could be subsequently pooled. Once again, the ATTAIN studies were designed to test for non-inferiority compared to vancomycin, considered the standard of care for pneumonia caused by Gram-positive micro-organisms.

To be enrolled, patients had to have a clinical presentation consistent with HAP or VAP and a Gram-positive organism had to be suspected or confirmed as the primary pathogen. Patients who had received more than 24 hours of potentially effective prior systemic antibiotic therapy and/or suspected or known HAP due to a Gram-negative pathogen only were excluded. Renal impairment, including hemodialysis, was not grounds for exclusion.

Patients were administered telavancin 10 mg/kg i.v. every 24 hours (with adjustment for creatinine clearance) or vancomycin 1 g i.v. every 12 hours (with adjustment according to the each site’s standard procedures). Switching to anti-staphylococcal penicillin was allowed in the case of MSSA infection, but this occurred infrequently. Therapy for Gram-negative infection was allowed in the case of co-infection. Treatment lasted between seven and 21 days.

Three possible clinical outcomes were defined: clinical cure, in which signs and symptoms of pneumonia resolved and baseline radiographic findings improved or did not progress; clinical failure, when persistence or progression of pneumonia required further therapy, pneumonia relapse after end of therapy or the patient died due to the primary infection; and indeterminate, where there was insufficient information to determine outcome.

In total, 749 patients were randomized to receive telavancin and 754 to receive vancomycin. This is thought to be the largest population of patients with Gram-positive HAP studied in double-blind, randomized clinical trials. Patients were generally elderly (more than 50% were over 65 years of age and over 30% were more than 75 years of age) and severely ill (approximately 25% were in the intensive care unit [ICU] and 45% were intubated). In addition, almost half the patients were ventilated and over a quarter had VAP in both groups. Finally, between 13% and 14% were considered obese (Table 1).

Table 1. ATTAIN Demographic and Baseline Characteristics (pooled all-treated population)

The pooled clinical cure rates at test-of-cure were 441/749 (58.9%) in the telavancin group and 449/754 (59.5%) in the vancomycin group for all treated patients. For the clinically evaluable population, the clinical cure rates were 258/312 (82.7%) and 280/346 (80.9%), respectively. In all cases, the 95% confidence intervals (CIs) were indicative of non-inferiority.

In the analysis of clinical response in certain subpopulations, it emerged that telavancin seemed to do better in more severely ill patients (Table 2). Thus, the cure rate in patients with VAP was 80.3% for telavancin and 67.6% for vancomycin, corresponding to a difference of 13.2%, although the CIs were such (-1.8% to 26.8%) that this could not be considered a significant finding. Although the cure rates were higher for telavancin than for vancomycin for MRSA pneumonia (81.8% vs. 74.1%), the difference was not significant.

Table 2. ATTAIN Clinical Cure at Test-of-Cure
uable Subpopulations

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The safety findings did not identify any undue safety concerns. Thus, the percentage of patients in each group with at least one adverse event was similar (82% for telavancin and 81% for vancomycin). In both groups, the most frequent treatment-emergent adverse events were diarrhea (11% vs. 12%), anemia (9% vs. 11%), constipation (9% vs. 9%) and hypokalemia (8% vs. 11%).

The findings of the ATTAIN studies show that the primary end point of the study was met, i.e. telavancin was non-inferior compared to vancomycin in both the all-treated populations and the clinically evaluable populations in both studies, given that the 95% CIs were well within the predefined 10% margin.

Of particular relevance to clinical practice were the subpopulation analyses. These showed that more severely ill patients, i.e. those with VAP, and those with pathogens associated with virulent and difficult-to-treat disease, i.e. MRSA, tended to do better. These trends were not statistically significant, but the percentage differences were appreciable (13.2% in the case of VAP and 7.9% in the case of MRSA pneumonia). Given the steady increase in incidence of MRSA disease and the high mortality associated with VAP, these findings are important as clinicians will now have a new treatment option.

Another important aspect of the study design was that patients with renal failure could be included in the study. It is comforting to know that telavancin can be used in such patients, as renal failure is a common situation facing physicians who treat patients in intensive care units and is often a marker of poor prognosis.

Summary

The changing epidemiology of Gram-positive infections is posing a new challenge for the management of patients with HAP and those with VAP in particular. The emergence of staphylococcal strains with reduced susceptibility to current treatments is limiting the options available to the clinician. MRSA pneumonia in particular is associated with poor outcomes. The ATLAS studies have demonstrated the efficacy of telavancin—a new lipoglycopeptide—in treating cSSTIs caused by Gram-positive micro-organisms. The randomized phase III ATTAIN studies, whose results were presented at the 2008 ECCMID, highlight the promise of this agent in treating HAP. Subpopulation analyses of these studies suggest that the new agent might be of particular use in the treatment of the most critically ill patients such as those with VAP or those with MRSA infections. Ultimately, though, local epidemiology will dictate which antimicrobial agent is used in such patients, but telavancin promises to be a useful addition to the clinician’s armamentarium.

Note: At the time of printing, telavancin is not available in Canada.