Reports

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PRIORITY PRESS - 48th Annual Meeting of the Infectious Diseases Society of America

Vancouver, British Columbia / October 21-24, 2010

There is a well-documented causal association between antimicrobial use and the emergence of antimicrobial resistance. Changes in the prevalence of resistance are paralleled by antimicrobial usage changes. Optimizing clinical outcomes while minimizing unintended consequences of antimicrobial use is the primary goal of antibiotic stewardship (Dellit et al. Clin Infect Dis 2007;44(2):159-77).

Antimicrobial stewardship involves infection control and antimicrobial management with a key component of identifying risk factors for the emergence of resistance. Ensuring that the most appropriate antibiotic is used at an effective dose minimizes the probability that resistance will occur.

In the case of methicillin-resistant Staphylococcus aureus- (MRSA)-induced nosocomial pneumonia, the changing natural history of the causative organism requires ongoing re-evaluation of treatment regimens and the monitoring of the emergence of multi-drug resistance. Two of the key antimicrobials that remain effective against MRSA are vancomycin and linezolid.

Antimicrobial Efficacy in Patients with Nosocomial Pneumonia

The most recent findings on the comparative effectiveness of linezolid and vancomycin from a large phase IV non-inferiority study with a nested superiority hypothesis were presented here at IDSA by Prof. Jean Chastre, Service de Réanimation Médicale, Pitié-Salpêtrière Hospital, Paris, France (Abstract LB-49).

The double-blind, randomized, controlled multicentre trial compared the clinical efficacy and safety of linezolid and vancomycin in patients with nosocomial pneumonia caused by culture-proven MRSA. Of 1225 patients enrolled in 156 centres worldwide, 448 were positive for MRSA. “These constituted the modified intent-to-treat (mITT) set of patients,” noted Prof. Chastre. Of these, 348 were evaluable at the end of the study (the per-protocol [PP] group). The primary end point was clinical outcome in the PP group at the end of the study. Safety was evaluated in the ITT group (all patients who received at least one dose of the study drug, including non-MRSA patients).

The treatment period was 7 to 14 days, and the end-of-study visit took place 7 to 30 days after treatment ended. Linezolid was administered intravenously at 600 mg q12h, while vancomycin was given intravenously at 15 mg/kg q12h, and adjusted by an unblinded pharmacist based on renal function and trough concentration. Patient characteristics were well-matched in both arms of the study. The majority of the patients were mechanically ventilated at baseline. ”The baseline modified clinical pulmonary infection score was pretty high in the two groups of patients,” reported Prof. Chastre, “confirming severity of the pneumonia infection. This is really a key issue,” he told delegates.

Results

At the end of the study, the clinical success rate in the PP group was 57.6% (95 patients) in the linezolid arm and 46.6% (81 patients) in the vancomycin arm (P=0.042; 95% CI, 0.5%, 21.6%) (Table 1).

Table 1.

“Therefore, based on the prespecified statistical plan, linezolid was not only non-inferior to vancomycin, but also superior to vancomycin,” stated Prof. Chastre. Similar results were observed in the mITT group (a secondary end point). End-of-treatment results were also consistent with the primary observations. Prof. Chastre noted that clinical response in the vancomycin arm was unaffected by increased mean trough concentrations (range 14.1 to 17.4 µg/mL), as confirmed in other studies.

Another secondary end point in this study was microbiological outcome in terms of either eradication or presumed eradication. Once again, linezolid was significantly superior to vancomycin in this measure, with a success rate of 81.9% (149 patients) compared to 60.6% (114 patients), respectively (P<0.001; 95% CI, 12.3%, 30.2%). Prof. Chastre pointed out that the study was not powered to detect differences in mortality rates. Overall safety in the ITT population (n=1184) was comparable in both arms. Anemia was seen in 30 patients (5.2%) in the linezolid arm and 42 patients (7.2%) in the vancomycin arm, and significantly less renal failure/azotemia occurred in linezolid patients (n=23, 3.8%) compared to patients on vancomycin (n=42, 7.2%) (Table 2).

In patients with more severe disease, linezolid also performed well. Prof. Chastre reported that 70% of study patients with baseline bacteremia treated obtained a clinical response compared to 55% of vancomycin patients. For ventilated patients, response was seen in 55.5% and 44.2%, respectively. Prof. Chastre concluded that linezolid achieved a statistically significantly higher success
omycin.

Table 2.

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Recent SENTRY and TEST Reports

The emergence of vancomycin-resistant S. aureus strains is of concern, and also raises the question of continued MRSA susceptibility to linezolid. The SENTRY Antimicrobial Surveillance Program was initiated in 1997 to monitor the global occurrence of resistance patterns of predominant pathogens. More recently in 2004, TEST (Tigecycline Evaluation and Surveillance Trial) began to evaluate the in vitro activity of tigecycline and other commonly used antimicrobials against bacterial pathogens at study centres in the US, Latin America, Europe and Asia.

Presenting the SENTRY update here at IDSA, Dr. Ronald N. Jones, JMI Laboratories, North Liberty, Indiana, reported current findings on linezolid resistance in both methicillin-resistant and susceptible strains of S. aureus (MRSA and MSSA) isolated from 12,219 nosocomial pneumonia episodes—of which 5830 (47.7%) were MRSA—in more than 200 hospitals on 5 continents (Abstract 262). More than 99.9% of all S. aureus were inhibited. Only one linezolid-resistant strain, an MRSA, was identified. The sample came from Arizona, and was identified as a plasmidic cfr mechanism. The overall S. aureus resistance rate was <0.01%. The researchers concluded that MRSA linezolid resistance remains extremely rare, and that the coverage rate is comparable to that of vancomycin and tigecycline.

Dr. Samuel Bouchillon, IHMA, Inc., Schaumburg, Illinois, reported similar findings from TEST, in which only one of 8139 S. aureus isolates collected from 2004 to 2009 exhibited resistance to linezolid. Researchers noted comparable potency in tigecycline and vancomycin.

Although the TEST program demonstrated continued activity of vancomycin against S. aureus, changing MIC patterns have been reported, reflecting a gradual loss of antimicrobial activity, a phenomenon known as “MIC creep,” explained Dr. Stephen Hawser, IHMA Europe Sàrl, Épalinges, Switzerland. Dr. Hawser’s group examined linezolid MICs using 8659 MRSA and 12,457 MSSA isolates collected from 2004 to 2009. The researchers found no evidence of change in MICs over the 6-year period, and also noted that resistant isolates were very rare.

Summary

While vancomycin remains an effective first-line antimicrobial, important phase IV data demonstrated linezolid non-inferiority and also showed it to be statistically superior to vancomycin for the treatment of culture-proven MRSA infection both clinically and microbiologically. Antimicrobial stewardship provides guidelines for optimal management of antimicrobials to obtain better patient outcomes and slow resistance patterns. SENTRY and TEST are among valuable programs that identify resistance first-hand. It is notable that MRSA linezolid resistance remains extremely rare.