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 - 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

San Francisco, California / September 9-12, 2012

San Francisco - For staphylococcal bacteremia and other severe or complicated gram-positive infections, vancomycin has long been the first-line therapy. A series of reports here at the 2012 ICAAC meeting provided evidence that alternative antimicrobials should be considered in places with rising rates of vancomycin resistance. This includes one of the first efforts to define a protocol for treating bacteremic patients with vancomycin minimum inhibitory concentrations >1.0 μg/mL. Separate studies included an evaluation of alternative agents in septic joints and a retrospective analysis comparing strategies in obese patients with methicillin-resistant Staphylococcus aureus pneumonia. Using alternative strategies is not only valuable to circumvent the consequences of vancomycin failure, but more judicious use of vancomycin may also slow the growing rates of resistance to this agent.

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

The large number of presentations at the 2012 ICAAC meeting documenting the rising minimum inhibitory concentrations (MICs) being observed for vancomycin was accompanied by a separate group of studies outlining strategies to minimize the adverse consequences of this trend. One of the most compelling associated an early switch from vancomycin to the novel lipopeptide antimicrobial daptomycin with an improvement in key outcomes, including a reduction in mortality at 90 days. The data from this study may eventually change the recommended breakpoint that defines vancomycin susceptibility.

“At this time I think it would be premature to change the breakpoint, but we found at our centre that a MIC >1 μg/mL was an independent predictor of treatment failure,” stated Dr. Kyle P. Murray, Detroit Medical Center, Michigan. He provided data from the first matched comparison of daptomycin as early therapy vs. dose-optimized vancomycin in patients with methicillin-resistant Staphylococcus aureus (MSRA) bacteremia when the vancomycin MIC is >1 μg/mL. Dr. Murray reported that both 90-day mortality and microbiological failure rates were reduced in those who completed the early switch.

Matched Cohort Analysis in Bacteremia

In this analysis, the study population was adult patients with MRSA bacteremia and a vancomycin MIC >1 μg/mL. Those switched to the lipopeptide antimicrobial were matched in a 1:1 ratio with those receiving adjusted-dose vancomycin. The match criteria included age, Pitt bacteremia score and primary site of infection. There were 54 patients in each arm of this 108-patient study collected over a 5-year study period. The longest duration of vancomycin treatment before the switch was 50 hours with a median of 39.7 hours. The most common infections in these matched groups were complicated skin and soft tissue (44.4%), bone and joint (28.1%) and endocarditis (18.5%). There was no significant between-group difference in vancomycin exposure over the previous 90 days.

Major outcomes consistently favoured the switch. At 90 days, mortality was 5.6% in the daptomycin group vs. 20.4% (P=0.022) in the optimized vancomycin group. Persistent bacteremia at 7 days was observed in 9.3% of the daptomycin group vs. 27.8% (P=0.013) of the optimized vancomycin group. Clinical failure—defined as persistent bacteremia at 7 days or death at 90 days—occurred in 13% of the daptomycin-treated patients vs. 38.9% (P=0.002) of those who remained on vancomycin. Intensive care unit (ICU) admission did not differ significantly between groups (37% for vancomycin and 33.3% for daptomycin), but ICU admission was an independent predictor of treatment failure.

“These data support the practice of immediately switching patients with MRSA bacteremia to daptomycin once a vancomycin MIC >1 μg/mL is known,” Dr. Murray concluded. Although he acknowledged that the current susceptibility breakpoint for vancomycin is defined as 2.0 μg/mL, which several years ago replaced a susceptibility breakpoint of 4.0 μg/mL, the differences in outcome using a >1 μg/mL trigger for switch were observed even though the median vancomycin plasma trough in this study was 17 μg/mL (target of 15 to 20 μg/mL). The median daptomycin dose was 8.3 mg/kg/day.

Prosthetic Joint Infections

A registry of experience with daptomycin has also demonstrated high rates of clinical success in patients with MRSA or other gram-positive infections of prosthetic joints or other hardware-associated osteomyelitis (OHAO). Assessed separately, these data show a clinical success rate of 82% in 27 patients with prosthetic joint infections and 86% on OHAO with follow-up exceeding 1 year in some cases. In a report presented here at ICAAC 2012, which was co-authored by Dr. Elie F. Berbari, Department of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, data were collected from 54 institutions. Just slightly less than half of patients had MRSA; in these, the success rate was 77%. About 20% did not have a documented pathogen while most of the remainder had methicillin-susceptible S. aureus (MSSA).

Although success rates did not differ significantly when the study population was stratified by dose, “Kaplan-Meier analyses showed median time to recurrence was longer for those receiving a daptomycin dose of 6 to 8 mg/kg (P=0.001) than those receiving <6 mg/kg or those receiving ≥8 mg/kg,” the authors reported. With an adverse event rate of 16% and no serious side effects, this agent in these types of infections was characterized as “safe, effective and well tolerated.”

In a second study that included some of the same authors, a 2-stage joint revision permitted an assessment of change in susceptibility of baseline pathogens cultured at the first stage. In this study, 75 patients were randomized to one of 3 arms; daptomycin 6 mg/kg/day, 8 mg/kg/day or one of 3 comparators (vancomycin, teicoplanin or semi-synthetic penicillin). Pathogens were documented at the first surgery to remove the prosthesis and again at the second procedure. The most common baseline pathogen was MSSA, accounting for 38.6% of the modified intention-to-treat analysis that included the 68 patients with staphylococcal infections. MRSA represented about 15% of infections.

“Overall, microbiological success at the test-of-cure end point was 50.0% and 52.2% in daptomycin 6 mg/kg and 8 mg/kg groups, respectively, and 38.1% in the comparator group. The microbiological success rates reflected the clinical response,” the authors noted. “No increases in daptomycin or comparator MICs were seen for isolates obtained at first surgery when compared with clonally related isolates obtained at re-implantation.”

Other Treatment Strategies

While these results support daptomycin as a substitute for vancomycin, other groups have been looking at other broad-spectrum agents with activity for gram-positive pathogens. In a study of MRSA pneumonia, the activity of linezolid relative to vancomycin was evaluated in a retrospective Veterans Affairs (VA) study of obese patients. For this study, patients with MRSA pneumonia who received linezolid or vancomycin were drawn from a VA database covering 8 years. Of the 179 patients who received linezolid, 49 (15%) were obese. These were compared to the 740 patients (15%) of the 2859 patients who received vancomycin.

“While non-obese patients treated with linezolid were less likely to have a 30-day readmission [HR 0.60; 95% CI, 0.37-0.97], the clinical success rate was substantially greater among the obese taking linezolid when compared to those treated with vancomycin [HR 1.77; 95% CI, 1.18-2.64],” reported Dr. Aisling Caffrey, University of Rhode Island Health College of Pharmacy, Kingston. Although Dr. Caffrey did not speculate on the underlying mechanism that might explain this difference, the effect of differences in chemical structure on drug distribution is one suspected reason.

Tigecycline is another candidate for substitution in challenging gram-positive infections when there is concern about vancomycin efficacy. Although no studies were presented at the 2012 ICAAC meeting comparing tigecycline to vancomycin, data from the Tigecycline Evaluation Surveillance Trial (TEST) were discussed. TEST was conducted to document the incidence of cross-resistance between tigecycline and minocycline and 1005 isolates of gram-positive blood sepsis pathogens resistant to minocycline were collected worldwide from 2008 to 2011. Guidelines from the U.S. Food and Drug Administration were used to evaluate susceptibility.

“While minocycline resistance is now common, cross-resistance with tigecycline remains a rare phenomenon in these species,” noted Dr. Stephen Hawser, International Health Management Associations (IHMA), Epalinges, Switzerland. He reported that except in 2009, when a fluctuation brought susceptibility of S. aureus slightly below 90%, susceptibilities for both Enterococcus species and S. aureus remained close to 100% for every year evaluated. The findings suggest a high degree of activity for tigecycline even in gram-positive pathogens which have developed resistance mechanisms.

Summary

The glycopeptide antibiotic vancomycin has served as a backbone agent for the management of challenging gram-positive pathogens. Although it remains a first-line option in most settings, the use of alternative drugs is being considered  in light of increasing degrees of vancomycin resistance. Studies presented at the 2012 ICAAC reinforce the rising MICs of vancomycin while outlining options. The data suggest such agents as daptomycin, linezolid and tigecycline are potentially effective alternatives.