Abstract & Commentary
Effect of an Oxazolidinone and Clindamycin on Staphylococcus aureus Virulence Factors
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Synopsis: In Staphylococcus aureus strains isolated from patients with complicated skin and skin structure (CSSI) infections generally produced high levels of phenol-soluble alpha-type (PSMa) peptides. TR-700 (an oxazolidi-none) and clindamycin inhibited phenol-soluble modulin production at a concentration one-half the MIC of the organism, but exhibited weak to modest induction at one-quarter to one-eighth the MIC in some isolates.
Source: Yamaki J, et al. Antivirulence potential of TR-700 and clindamycin on clinical isolates of Staphylococcus aureus producing phenol-soluble modulins. Antimicrob Agents Chemother 2011;55: 4432-4435.
Baseline production of PSMa subtypes was examined in 50 PVL-positive methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA clinical isolates using liquid chromatography-tandem mass spectrometry (LC-MS-MS), and these results were compared to a control strain, LAC (USA300). MICs were determined using a broth macrodilution method. MIC 50/90 values for TR-700 and clindamycin were 0.25/0.375 µg/mL and 0.125/0.188 µg/mL, respectively. Supernatants were harvested after incubation with study drug at one-half, one-quarter, and one-eighth MICs for PSM quantitation by LC-MS-MS and global regulator (agrA and RNAIII) expression by reverse transcription-PCR (RT-PCR). PSMa production at baseline varied significantly between isolates, but did not differ by methicillin resistance, type of CSSI (cellulitis or abscess), or size of abscess.
Of the 21 isolates selected for testing vs. the two antibiotics, TR-700 at one-half MIC inhibited PSM production in a dose-dependent fashion with PSMa3 being most inhibited. Paradoxical induction of PSMa by TR-700 was observed at one-quarter and one-eighth MIC, primarily in strains with low baseline production of PSMa3. Clindamycin had a stronger inhibitory effect on overall PSM production vs. TR-700 in seven isolates and completely abolished PSMa3 production in five of seven isolates. Similar to TR-700, PSM production was weakly induced at one-quarter and one-eighth MIC in two isolates and the LAC strain control.
While this is an in vitro study, the results are interesting from a mechanistic standpoint and are potentially relevant to clinical practice. Secreted exotoxins, including toxic shock syndrome toxin 1 (TSST-1), a-hemolysin (Hla), and Panton-Valentine leukocidin (PVL) have been shown to contribute to the virulence of both MSSA and MRSA. The PSMa peptides have more recently been described as important virulence factors implicated in pathogenesis of CSSIs, bacteremia, and pneumonia. Like PVL, PSMa peptides cause pore formation in neutrophils and release of inflammatory mediators. PSMa peptides are secreted as both formylated and nonformylated forms and the formylated forms display greater cytotoxicity. PVL, Hla, and the PSMs are under control of agrA and RNAIII of the agr system.
In an important paper published several years ago, Stevens et al elegantly demonstrated the impact of protein-synthesis inhibiting antibiotics on expression of exotoxin genes in S. aureus.1 In addition, there exists moderately strong clinical evidence to support the use of antibiotics such as clindamycin and the oxazolidinone, linezolid, in vivo to reduce toxin production and improve clinical outcomes. This paper by Yamaki et al extends these findings by demonstrating the inhibitory effect of an oxazolidinone and clindamycin on what may be the most important S. aureus virulence factor, PSMa. In addition, the demonstration that significantly sub-inhibitory concentrations of both the oxazolidinone and clindamycin may induce toxin production by some strains of S. aureus suggests that underdosing of these drugs should be avoided.
- Stevens DL, et al. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive Staphylococcus aureus. J Infect Dis 2007;195: 202-211.