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.

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

Barcelona, Spain / April 19-22, 2008

Editorial Overview:

Andrew E. Simor, MD, FRCPC

Head, Department of Microbiology Sunnybrook Health Sciences Centre

Professor of Medicine Division of Infectious Diseases University of Toronto Toronto, Ontario

Healthcare-associated (HA)-methicillin-resistant Staphylococcus aureus (MRSA) first appeared in the late 1970s. Five pandemic-resistant clones have been identified to date. Clones are classified on the basis of genetic analyses, whether by pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) or sequencing protein A (SPA) typing. The element that confers resistance is harboured on a mobile genetic element known as SCCmec, and it is this mobility that helps S. aureus acquire resistance.

Community-acquired (CA)-MRSA had been less of a cause for concern than HA-MRSA because it tends to be more susceptible to antibiotics. However, a worrying development in MRSA has been the emergence of virulent strains of CA-MRSA. These infections have spread particularly quickly in certain populations such as contact sport participants, inmates in correctional facilities, military recruits, children in daycare, men who have sex with men and intravenous drug users. In most cases, close contact, sharing of either equipment or personal items, and poor hygiene in general have aided transmission. The previously existing distinction between CA-MRSA and HA-MRSA has become increasingly difficult to identify. This was shown in a study by Moran et al. (N Engl J Med 2006;355:666-74), who analyzed adult patients with acute, purulent skin and soft-tissue infections presenting to 11 university-affiliated emergency departments in August 2004. S. aureus was isolated from 320/422 patients and 59% overall corresponded to MRSA strains (ranging from 15% to 74%). Moreover, a very high percentage of these MRSA isolates were USA300, a new CA-MRSA strain that has spread quickly in the community, and carried the pvl toxin gene, which has been suggested to make the strain more pathogenic. This study included centres stretching from coast to coast in the US. In Canada, outbreaks of USA300 have been more isolated and reported less often, yet infections caused by these CA-MRSA strains are being increasingly identified.

USA300 seems to be different in that multidrug-resistant strains seem to be appearing. According to a study of CA-MRSA in men who have sex with men, of 130 patients with MRSA infection, 126 (97%) were infected with USA300 and 60 (i.e. 46% of all MRSA cases) were multidrug-resistant (Diep et al. Ann Intern Med 2008;148:249-57).

Changes in the epidemiology of Gram-positive infections, and MRSA in particular, therefore represent a challenge to the clinician. Mortality is high, as indicated by a review of 3254 deaths of patients in all specialties of surgical care in Scotland during 2006 (www.sasm.org.uk/Reports/Summary_ Report_ 2006_data.pdf). HA infection contributed to mortality in 13% (422/3254) and 4% of all patients were due to HA-MRSA (129/3254). This suggests that additional therapeutic options are still required. While it is important to have the right options available, it is also important to make the right choice, as in serious infections, inadequate initial therapy is a key factor determining higher mortality (Figure 1).

Figure 1. Mortality Rates Due to Inadequate Initial Antibiotic Therapy

Treatment Considerations

Clinicians currently have a wide range of treatment options available when choosing which therapy to give their patients. In particular, there are patient-related considerations such as comorbidities: does the patient have neutropenia (and so the burden for clearing infection falls more heavily on the antibiotic)? Renal failure can complicate the management of nephrotoxicity when using glycopeptides. In the case of aminoglycosides, the possibility of accumulation of high concentrations of the drug in the renal cortex needs to be recognized. Of course, the clinician must consider the severity of illness and the site of infection will also play a role in the decision process, e.g. in certain cases such as endovascular infection, endocarditis, pneumonia and meningitis, bactericidal therapies would be preferable to bacteriostatic ones.

Prolonged S. aureus bacteremia is associated with a number of complications such as systemic inflammatory response syndrome, bone or joint seeding, and myositis with or without necrotizing fasciitis. Rapid clearance of the infection from the bloodstream will therefore help minimize associated morbidity, and in this context, a bactericidal therapy would be preferable to a bacteriostatic one. To further ensure rapid clearance, early initiation of therapy should be useful. Indeed, in a study comparing mortality due to infection in patients with early and delayed initiation of therapy, a delay in therapy was associated with a significantly higher mortality (33%) compared to early therapy (19%) (P=0.05) (Lodise et al. Clin Infect Dis 2003;36(11):1418-23). In the case of MRSA endocarditis, vancomycin is the standard treatment. However, clearance of infection from the blood is relatively slow, nine days according to Levine et al. (Ann Intern Med 1991;115:674-80).

A further consideration is that some agents, such as glycosides, do not penetrate the lungs well. Then there are the pathogen-related considerations, and in particular, the susceptibility reports from the microbiology laboratory.

Increasing Resistance to Vancomycin

While ß-lactams remain the treatment of choice for methicillin-susceptible S. aureus (MSSA) infections, in the case of MRSA infections, vancomycin is still the standard of care, although it shows relatively poor tissue penetration and a slow rate of killing. In addition, we have seen a creep in the minimum inhibitory concentrations (MICs) for strains known as heterogeneous vancomycin-intermediate S. aureus (hVISA) strains with heterointermediate resistance of vancomycin and VISA (strains with intermediate resistance to vancomycin). The decreased susceptibility is due to excessive production of peptidoglycan, which can both sequester vancomycin molecules from their bacterial target and impede progress of further vancomycin molecules through the cell wall. There is also the so-called MIC jump, where a S. aureus strain acquires a vanA gene, which confers resistance to vancomycin, yielding a vancomycin-resistant S. aureus (VRSA) strain. At present, while the incidence of VRSA remains low (seven cases have been reported to date), there is an increasing incidence of S. aureus with reduced vancomycin susceptibility.

The evidence is accumulating to suggest that this is a disturbing development. In a study by Fridkin et al. (Clin Infect Dis 2003;15(36):429-39), all cases of VRSA infection (whether the vancomycin MICs for the isolates were 4 or 8 µg/mL) had a mortality rate of 63% compared to 12% for MRSA infection. Howden et al. (Clin Infect Dis 2004;38:521-8) found that 19 out of 25 patients with serious hVISA infections (vancomycin MICs ranging from 2 to 4 µg/mL) failed vancomycin therapy. Subsequent studies have confirmed these findings and prompted a revision in 2006 of the interpretive criteria of the Clinical and Laboratory Standards Institute for S. aureus. Whereas before, a MIC <u><</u>4 µg/mL was considered susceptible, the current threshold is <u><</u>2 µg/mL. Likewise, a resistant strain used to be considered as one with a MIC <u>></u>32 µg/mL but now the threshold is <u>></u>16 µg/mL. Neither VRSA nor VISA strains have been identified in Canada. However, hVISA has been detected in strains with vancomycin MIC 2 µg/mL. Details of these Canadian Nosocomial Infection Surveillance Program data are to be presented at the upcoming ICAAC/IDSA Annual Meeting in Washington, DC, in October 2008.

Alternatives in MRSA Treatment

In the treatment of Gram-positive bacteria, specifically MRSA, there are a number of alternatives to vancomycin. These include linezolid, daptomycin and tigecycline. Linezolid is a bacteriostatic agent that prevents formation of the 70S initiation complex, binding 50S ribosomal subunit. It is indicated for nosocomial pneumonia and complicated skin and skin structure infections (cSSSIs). The cyclic lipopeptide antibiotic daptomycin is rapidly bactericidal. It has a unique mechanism of action which minimizes cell lysis and hence release of pro-inflammatory cytokines. Tigecycline is the first in a new class of antimicrobials known as glycylcyclines and was specifically developed to overcome existing mechanisms of resistance.

Both tigecycline and daptomycin show good in vitro activity against vancomycin-resistant enterococci and MRSA (MIC <u><</u>0.25 µg/mL for tigecycline and <u><</u>4 µg/mL for daptomycin against enterococci and <u><</u>0.5 µg/mL for tigecycline and <u><</u>1 µg/mL for daptomycin against MRSA (Tsiringa et al. ECCMID 2008, poster 534). In the same study, the enterococci and MRSA isolates were also susceptible to linezolid (product monograph: MIC <u><</u>8 µg/mL Enterococcus sp. and <u><</u>4 µg/mL for Staphylococcus sp).

In the case of daptomycin, a German surveillance study found lower MICs than vancomycin when tested against Gram-positive bacteria such as MRSA, MR Staphylococcus epidermidis, MR Streptococcus pyrogens and agalactiae. It was approved in the US for the treatment of cSSSIs at 4 mg/day in 2003 and for S. aureus bacteremia, including those with right-sided endocarditis, at 6 mg/day in 2006. It was approved in Canada in late 2007 for both these indications. However, it is not indicated for pneumonia, as it gets inactivated by lung surfactants. The agent is administered as a 30-minute infusion with no need for a central line. The indication for S. aureus bacteremia and right-sided endocarditis was granted on the strength of a phase III study comparing daptomycin with standard therapy (low-dose gentamicin and either an antistaphylococcal penicillin or vancomycin) in patients with S. aureus bacteremia (Fowler et al. N Engl J Med 2006;355:653-65). The authors reported that a successful outcome was documented for 53 out of 120 patients (44.2%) compared to 48 out of 115 patients (41.7%) in the standard therapy arm. In the subpopulation of patients with right-sided endocarditis, daptomycin proved to be safe and well tolerated with success rates similar to standard therapy (42.1% and 43.3%, respectively).

A Core Evaluation

In an effort to capture the use of this antimicrobial agent in day-to-day clinical practice, the CORE (Cubicin Outcomes Registry and Experience) observational study was set up. To this end, data on the population of patients receiving daptomycin, the infections being treated, the pathogens for which it was used, and the adverse events are being recorded. Clearly, such a retrospective registry is subject to limitations, but it does provide valuable real-world information and, given that this is an ongoing project, it is possible to track temporal changes in daptomycin prescribing patterns.

The definitions of outcome are the same for all indications. Clinical success is defined as cure (resolution of symptoms with no additional antibiotic) or improvement (partial resolution of symptoms or use of additional antibiotic therapy after initial response); failure is defined as clinical worsening or inadequate response necessitating a change in antibiotic therapy or a positive culture at the end of therapy.

In patients with bacteremia, success (cure or improvement) was achieved in 89% of 126 patients after a median of 12.5 days of daptomycin therapy regardless of whether the infection was catheter-related or not (Sakoulas et al. Am J Med 2007;120:S21-S27). The outcome also seemed relatively independent of pathogen (e.g. Enterococcus, including VR strains and MRSA). In the case of 334 patients with cSSSIs, overall cure rates were 66% and 32% improved (Owens et al. Am J Med 2007;120:S6-S12). For infective right-sided endocarditis, success rates of 83% were reported for MRSA pathogens. The registry also reflected significant off-label use, particularly for conditions such as osteomyelitis, where the convenient dosing makes it popular.

Patients with renal failure and S. aureus infections tend to have a poor prognosis, not only because of the underlying renal failure, but because of a qualitative neutrophilic dysfunction which hinders clearance. CORE subgroup analysis according to whether creatinine clearance was above or below 30 mL/min showed no effect on the number of patients achieving success. In these patients, daptomycin was administered every 48 hours.

In short, the CORE data suggest that daptomycin is a valuable agent in a number of clinical situations, such as in patients with renal failure, for different sites of infection.

Summary

The changing face of Gram-positive infection, and S. aureus infection in particular, is forcing a change in the way these diseases are managed. The increasing incidence of MRSA strains is associated with more severe disease and higher mortality. In addition, the possibility that certain strains of MRSA can rapidly acquire resistance to other antibiotics is a major problem. A gradual decrease in susceptibility of some MRSA strains to vancomycin has been observed and, more disturbingly, strains fully resistant to vancomycin have emerged. In view of its mechanism of action, daptomycin appears unlikely to develop resistance quickly. This antibiotic has demonstrated rapid, concentration-dependent bactericidal action and proven safe and efficacious in randomized controlled trials and observational studies. While it should be avoided for the treatment of pneumonia or infections due to strains with reduced vancomycin susceptibility (hVISA), it is a valuable alternative to vancomycin in patients with staphylococcal infections such as cSSSI and staphylococcal bacteremia with or without right-sided endocarditis.