PIDS Journal Club, September 2019

Oral linezolid for routine treatment of uncomplicated Staphylococcus aureus bacteremia? Not ready yet.

Reviewing: Willekens R, et al, “Early oral switch to linezolid for low-risk patients with Staphylococcus aureus bloodstream infections: a propensity-matched cohort study”, Clin Infect Dis, 20181

Background

Management of apparently uncomplicated Staphylococcus aureus bacteremia (SAB) is challenging because relapse is common, probably related to unrecognized deep-seated infection .2 As oral antibiotic therapy is increasingly used for bloodstream infections, oral treatment for SAB is under consideration.3 In the pediatric world, infectious diseases physicians report using oral therapy for bacteremic osteomyelitis, but not proven SAB without a bony focus.4 This study, by Willekens et al, evaluated the effectiveness of oral linezolid, a highly bioavailable anti-staphylococcal antibiotic, to complete treatment of SAB in adults after initial parenteral therapy.1

Methods and Results

This was a subgroup analysis of a prospective observational cohort study comprising adults with SAB; it included participants judged to be at low risk of complications who received either entirely parenteral antibiotics or were switched to oral linezolid after 3-9 days of parenteral therapy at treating clinician discretion. The primary outcome was relapse of S. aureus infection within 90 days, and secondary outcomes included length of hospital stay (LOS), and 14- or 30-day mortality. A propensity score-matched sub cohort matched linezolid-treated participants with the two “most similar” parenteral-treated participants.

A total of 152 participants were identified (45 linezolid and 107 parenteral therapy); 135 were included in the propensity-matched sub cohort. Participants were treated for a median of 15 days in each group. Risk factors for treatment failure (e.g. chronic renal failure, risk factors for endovascular infection, unknown BSI source, sepsis and ICU admission) were much more common in the parenteral therapy group, even after propensity score matching. Although not statistically significant, patients who received oral linezolid were slightly less likely to have relapse of infection (RR 0.5; P=0.9) or to die by 14 days (RR ∞; P=0.2) or 30 days (RR 0.17; P=0.08). They did have significantly shorter median LOS (8 vs. 19 days; P<0.01). The authors concluded that treatment of SAB in selected low-risk patients with an oral switch to linezolid after initial parenteral therapy yielded similar clinical outcomes as parenteral therapy.

Critique

The main problem with interpreting this study is the possibility of indication bias.5 Clinicians appear to have been more inclined to give conservative (parenteral) therapy to participants at higher risk of treatment failure; there are differences in baseline characteristics and 14-day mortality (before any likely effect of the treatment). The authors did attempt to address this with propensity score matching but, because they had only a small group of potential matches and did not require close matching, the groups remained very different. Propensity score matching relies on selecting a comparator group that is similar to the intervention group.6 Other issues include unknown applicability to pediatric patients and to other special populations such as patients with neutropenia or other immunocompromise.

Conclusions

The study does not prove that oral linezolid is as safe and effective as parenteral therapy for treatment of SAB, since the patients receiving oral linezolid might have had a better chance of success.  It may provide some justification for occasional use following a short course of IV therapy, and sets the stage for a prospective randomized non-inferiority study (e.g. NCT01792804)7, but I will wait for those results before routinely using oral linezolid as completion therapy for uncomplicated SAB.

Author

Joshua Wolf MBBS, PhD, FPIDS, FRACP

St. Jude Children’s Research Hospital, Memphis, TN, USA 

Peer Reviewers

Sandra L Arnold MD (Le Bonheur Children’s Medical Center, Memphis, TN, USA)

Suchitra Rao MBBS, MSCS (Children’s Hospital Colorado, Aurora, CO, USA)

References

  1. Willekens R, Puig-Asensio M, Ruiz-Camps I, Larrosa MN, Gonzalez-Lopez JJ, Rodriguez-Pardo D, et al. Early oral switch to linezolid for low-risk patients with Staphylococcus aureus bloodstream infections: a propensity-matched cohort study. Clin Infect Dis. 2018.
  2. Berrevoets MAH, Kouijzer IJE, Aarntzen E, Janssen MJR, De Geus-Oei LF, Wertheim HFL, et al. (18)F-FDG PET/CT Optimizes Treatment in Staphylococcus Aureus Bacteremia and Is Associated with Reduced Mortality. J Nucl Med. 2017;58(9):1504-1510.
  3. Hospenthal DR, Waters CD, Beekmann SE, Polgreen PM. Practice patterns of infectious diseases physicians in transitioning from intravenous to oral therapy in patients with bacteremia. Open Forum Infect Dis. 2019.
  4. Wood JB, Fricker GP, Beekmann SE, Polgreen P, Buddy Creech C. Practice Patterns of Providers for the Management of Staphylococcus aureus Bacteremia in Children: Results of an Emerging Infections Network Survey. Journal of the Pediatric Infectious Diseases Society. 2018;7(3):e152-e155.
  5. Walker AM. Confounding by indication. Epidemiology. 1996;7(4):335-336.
  6. Joffe MM, Rosenbaum PR. Invited commentary: propensity scores. Am J Epidemiol. 1999;150(4):327-333.
  7. ClinicalTrials.gov. Staphylococcus Aureus Bacteremia Antibiotic Treatment Options (SABATO). https://clinicaltrials.gov/ct2/show/NCT01792804?id=NCT01792804&rank=1&load=cart. Published 2013. Accessed September 16, 2019.