By Dean L. Winslow, MD, FACP, FIDSA

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: Coinfection with methicillin-resistant Staphylococcus aureus (MRSA) in children with influenza is associated with high fatality. Data support the addition of a second anti-MRSA antibiotic to vancomycin in severely ill children.

SOURCE: Randolph AG, Xu R, Novak T, et al. Vancomycin monotherapy may be insufficient to treat methicillin-resistant Staphylococcus aureus coinfection in children with influenza-related critical illness. Clin Infect Dis 2019;68:365-374.

Researchers enrolled 170 children younger than 18 years of age with influenza (127 with influenza A and 43 with influenza B) and respiratory failure from 34 pediatric intensive care units (PICU) across the United States between 2008 and 2016. Thirty children with influenza-methicillin-resistant Staphylococcus aureus (MRSA) pneumonia were identified. Eighty-seven percent of these children were previously healthy. Children with MRSA pneumonia were slightly older (mean age 12.7 years) than children with non-MRSA bacterial pneumonia or no bacterial superinfection (mean age, about 6 years).

Children with MRSA pneumonia were more likely than others to have leukopenia at admission to the PICU, to have acute lung injury, and to require vasopressors or extracorporeal life support (ECMO). They also had higher mortality. Mortality was 40% in children with MRSA compared to 4.3% in children without MRSA infection. Twenty-nine of 30 children with MRSA pneumonia received early vancomycin therapy. Of the children with MRSA pneumonia who received vancomycin plus a second MRSA agent within the first 24 hours of hospitalization, mortality was 12.5% (2/16). Mortality was 69% (9/13) in those children who received vancomycin monotherapy initiated within 24 hours of hospitalization. The most common second anti-MRSA agent added to vancomycin was clindamycin, followed by ceftaroline and linezolid. All isolates were susceptible in vitro to clindamycin.

COMMENTARY

This is an interesting study highlighting an area of concern that many clinicians who care for both adults and children with S. aureus pneumonia have had for many years. Although this was a small observational study and potentially can be criticized for all of the normal reasons, the “signal” that is evident from bottom line results is difficult to ignore. The potential reasons why patients who received a second agent in addition to vancomycin had better outcomes include:

  • A relatively small difference between achievable blood and tissue levels of vancomycin relative to the MIC of most Staph isolates (the trough vancomycin levels were relatively low in both groups in this study);
  • The potential role of “heteroresistance” of some Staph strains to vancomycin;
  • Better tissue penetration of agents other than vancomycin;
  • The potential beneficial effect of clindamycin and linezolid on downregulation of toxin production by S. aureus.

While in this particular study all isolates were susceptible to in vitro clindamycin, this is not true in all regions of the country and the rest of the world, so empiric monotherapy with clindamycin would seem unwise. Initial combination therapy with both agents while awaiting susceptibility results would seem prudent before potentially dropping the vancomycin would be one reasonable approach. Vancomycin combined with ceftaroline or linezolid initially (followed by potentially dropping the vancomycin after susceptibility results are available) would be another potential approach. Obviously, a larger, multicenter, randomized, controlled trial designed to evaluate different antimicrobial regimens would be the definitive way to sort this out. Animal models also could be helpful.

In conclusion, this study reinforces my decades long prejudice that “vancomycin is the second-best antibiotic for many infections.” I have seen enough children and adults die of S. aureus pneumonia (MSSA, MRSA, with or without associated influenza infection) that I would certainly no longer treat any patient with S. aureus pneumonia with vancomycin monotherapy. I would recommend initial combination therapy until we have more solid data on which to base therapy.