Linezolid for Gram-Positive Infections of Neutropenic Patients

Abstract & Commentary

By J. Peter Donnelly, PhD, Clinical Microbiologist, University Hospital, Nijmegen, The Netherlands, Section Editor, Microbiology, is Associate Editor for Infectious Disease Alert.

Dr. Donnelly is a consultant for Ortho Biotech, and does research for Janssen, Merck, Novartis, Numico, Pharmacia, and Pfizer.

Synopsis: Linezolid given 600 mg q12 iv. to febrile neutropenic patients for suspected or proven infections due to Gram-positive bacteria with cancer showed similar efficacy and safety as vancomycin given 1 g q12h iv.

Source: Jaksic B, et al. Efficacy and Safety of Linezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patients with Cancer. Clin Infect Dis. 2006;42:597-607.

This study ran from November 2000 to May 2002, recruited 611 patients from 58 centers predominantly from Europe, and set out to compare the efficacy and safety of these drugs for treating febrile, neutropenic patients with cancer and either proven or suspected infection due to Gram-positive bacteria in a prospective, blinded randomized controlled trial. The primary end point was clinical success 7 days after completion of therapy and both drugs performed equivalently in the intent-to-treat analysis: 219 (87.3%) of 251 patients given linezolid compared with 202 (85.2%) of 237 patients given vancomycin. There was also no significance difference in results obtained for the modified ITT analysis, which examined the outcome of those with a proven infection due to a Gram-positive bacterium: 55 [87.3%] of 63 patients given linezolid compared with 43 [86%] of 50 patients given vancomycin.

There were also 2 other analysis done with results that were equivalent for the 2 drugs: clinically evaluable analysis (ie, patients who had received at least 80% of intended therapy for at least 3 days to determine failure and 7 days to determine success); 171 [92.4%] of 185 patients given linezolid compared with 158 [89.3%] of 177 patients given vancomycin and microbiologically evaluable analysis (ie, episodes that involved a gram positive bacterium that was susceptible to the study drug); 41 [87.2%] of 47 patients given linezolid compared with 32 [86.5%] of 37 patients given vancomycin.

The mean time to defervescence was shorter for linezolid than for vancomycin in the modified ITT (6.6 vs 8.5 days) and microbiologically evaluable episodes (5.9 vs 9.1 days). Mortality rates in the ITT subset were 17 [5.6%] of 304 patients vs 23 [7.6%] of 301 patients, though linezolid was associated with fewer drug-related adverse events (52 [17.2%] of 303 patients vs 72 [24.0%] of 300 patients) and fewer cases of drug-related renal failure (1 [0.3%] of 303 patients vs 7 [2.3%] of patients). Hence, it was concluded that treatment with linezolid and vancomycin resulted in similar efficacy and safety outcomes for febrile neutropenic patients with cancer.

Commentary

At almost every level there was little to choose between linezolid and vancomycin as therapy for proven or suspected Gram-positive bacterial infections in febrile neutropenic patients. There weren’t even any major differences in drug reactions. However, patients needed 2 days less linezolid than vancomycin to achieve the same result. So far so good. So, should we all move over to linezolid for this indication? The answer is actually a resounding No, not because of the drug but rather because it is no longer considered prudent to modify initial empirical therapy empirically by adding a drug that provides better cover against Gram-positive bacteria. In fact, the goals posts on this playing field had already begun moving between completion of the study and this publication. This is not meant as a criticism of this study, which actually nicely reflects the practice of may institutions at that time. This can be seen by the fact that only 15% of all episodes were evaluable for microbiological assessment, that almost 30% of patients were entered solely on the basis of fever of unknown origin, and by the rather high use of additional drugs particularly antifungal agents starting after the first day of the protocol presumably also for empirical therapy.

While the study was being wrapped up, the IDSA published a new set of guidelines that recommended that empirical vancomycin therapy should only be considered for high-risk patients, namely those with clinically suspected serious catheter-related infections (eg, bacteremia, cellulitis, those known to be colonized with penicillin- and cephalosporin-resistant pneumococci, or methicillin-resistant Staphylococcus aureus), those with bacteremia due to Gram-positive bacteria pending identification and susceptibility test results, and those with hypotension or other evidence of cardiovascular impairment.1 A later study concluded that empirical vancomycin offered no measurable benefit to persistently febrile and neutropenic patients with cancer unless there was evidence of lung infiltrates, septic shock, clinically-defined infections likely to be due to Gram-positive bacteria, such as catheter-related or skin- and soft-tissue infections or gram-positive bacterial infections due to bacteria shown to be resistant to the initial empirical regimen.2 So on this basis, therapy with linezolid or vancomycin would still have been justified for up to 70% of patients entered into the current study.

What then would help the clinician decide to favor one drug over the other? This is tricky because on the one hand linezolid was more effective in eradicating enterococci than was vancomycin, and a saving of about 2 days treatment might be made. On the other hand though, both drugs are well tolerated; a shadow still hangs over linezolid in terms of its potential to prolong neutropenia and thrombocytopenia, though there was little evidence of either in the current. Perhaps the ability to switch from parenteral to oral linezolid might, in the end, cut the mustard, since patient could be discharged earlier.

Whatever the verdict, it is worth noting that it has actually taken over 20 years to settle the place of empirical therapy for gram-positive bacterial infections in febrile neutropenia patients. Now, there is also a choice that not only includes vancomycin and linezolid but also teicoplanin, at least in Europe and perhaps daptomycin.3,4 Given the relatively indolent nature of many of the gram-positive bacterial infections, particularly those involving the coagulase-negative staphylococci, the availability of useful guidelines and the pressing need for prudent antimicrobial use let us hope that these drugs will be employed more on the basis of evidence and less empirically than has been the case hitherto.

References

  1. Hughes WT, et al. 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer. Clin Infect Dis. 2002;34:730-751.
  2. Cometta A, et al. Vancomycin Versus Placebo for Treating Persistent Fever in Patients with Neutropenic Cancer Receiving Piperacillin-Tazobactam Monotherapy. Clin Infect Dis. 2003;37:382-389.
  3. Rybak MJ. The Efficacy and Safety of Daptomycin: First in a New Class of Antibiotics for Gram-Positive Bacteria. Clin Microbiol Infect. 2006;12:24-32.
  4. Shah PM. The Need for New Therapeutic Agents: What is the Pipeline? Clin Microbiol Infect. 2005;11:36-42.