#PharmToExamTable: Treatment of Necrotizing Pneumonia

Pneumonia, S. aureus, and PVL

Pneumonia is an infection of the lungs caused by the infiltration of microorganisms, such as bacteria, viruses, and fungi, into the lungs of hosts. Many patients diagnosed with bacterial pneumonia are able to be treated in the outpatient setting with oral antibiotics; however, more serious cases may require hospitalization and more aggressive treatment. Staphylococcus aureus is a gram positive, pyogenic bacteria that is associated with superficial skin and soft tissue infections as well as deeper infections including septic arthritis, osteomyelitis, endocarditis, and pneumonia. Community acquired methicillin-resistant S. aureus (CA-MRSA) is of particular concern as it is resistant to beta-lactam antibiotics, which are first-line empiric therapy for many community acquired infections. CA-MRSA has been associated with a form of necrotizing pneumonia (NP) characterized by leukopenia, hemoptysis, and extensive destruction of lung tissue.

Panton-Valentine Leukocidin (PVL) is an exotoxin that is produced by many strains of S. aureus and attacks host immune cells. The majority of CA-MRSA strains in the US produce PVL, which increases the risk of developing necrotizing pneumonia.¹ There is controversy surrounding the role PVL plays in CA-MRSA infections in general, but the most compelling data has shown the association of PVL with post-viral NP.^2,3 Several studies evaluating PVL as a virulence factor for NP in mice have largely been inconclusive^3-8. One study using a rabbit model has demonstrated that PVL plays a critical role in NP infection⁹. The authors of this study state PVL production is believed to result in the activation of polymorphonuclear (PMN) leukocytes and macrophages, along with accompanying inflammatory cytokines. Once these immune cells are recruited to the site of infection, PVL lyses PMNs, resulting in the release of granules and proteolytic enzymes into the lung tissue which leads to tissue damage.

There have been limited trials assessing the use of antimicrobials for the purpose of toxin suppression in PVL positive CAP, and their place in therapy of NP is thought to be analogous to their role in the treatment of streptococcal and staphylococcal toxic shock syndrome. All studies to date evaluating toxin suppression in PVL producing CA-MRSA strains have been in vitro studies with clindamycin and linezolid being the two most studied and most successful antibiotics for toxin suppression. Current IDSA/ATS Community Acquired Pneumonia (CAP) guidelines do not address the use of antimicrobials for toxin suppression in NP caused by CA-MRSA.¹⁰ IDSA guidelines for treatment of MRSA infections do not recommend the routine use of clindamycin or linezolid in treating CA-MRSA except in severe cases of NP as there is limited evidence to support their use.¹¹ The evidence supporting the anti-toxin effects of clindamycin and linezolid in CA-MRSA infections is summarized below.

Clindamycin, Linezolid, and Toxin Suppression

Clindamycin is a lincosamide antibiotic which works by binding the 50s ribosomal subunit of bacteria thus disrupting protein synthesis and creating a bacteriostatic effect. S. aureus bacteria can develop resistance to clindamycin by modification of the 23s ribosome target site that is either inducible or constitutive, with the latter preventing toxin suppression completely in vitro.^13,14 Three in vitro studies performed using direct PVL toxin quantification showed that clindamycin inhibited the production of PVL toxin at sub inhibitory concentrations (concentrations below the MIC) as low as 1/8 MIC.^12,14,15 Two in vitro studies quantified toxin suppression by measuring mRNA targets in culture media incubated with clindamycin concentrations as low as 1/8 MIC also showed significant reduction in PVL expression.^16,17 One study utilized a hollow fiber in vitro model which is a two compartment pharmacokinetic/pharmacodynamics model that optimizes drug delivery and allows for simulation of sequestered infections. Clindamycin was then introduced to the model for incubation at a level that simulated the pharmacokinetics of the standard treatment dose of various antibiotics. This study then evaluated mRNA levels for gene expression of various toxins. Clindamycin at exposures simulating 600 mg every 8 hours demonstrated a significant downtrend in PVL toxin gene expression over 48 hours of incubation.¹⁶ 

Linezolid is an oxazolidinone antibiotic which inhibits bacterial growth by disrupting the initiation process of protein synthesis and creates a bacteriostatic effect. Linezolid is a much newer antibiotic compared to clindamycin, thus there is less evidence supporting its use in toxin suppression. The previously mentioned study utilizing a hollow fiber in vitro model found linezolid dosed at 600mg every 12 hours to be effective at suppressing PVL gene expression for up to 24 hours.¹⁶ Two studies showed a reduction in PVL gene expression with linezolid and another study showed a decrease in direct PVL toxin quantity.^14,16,17 Another study evaluated PVL toxin levels with subinhibitory concentrations of linezolid found that linezolid induced a concentration-dependent decrease in PVL level starting at concentrations as low as 1/8 or 1/4 MIC.¹⁵ 

In Summary…

In vitro data supports the ability of both clindamycin and linezolid to suppress the production of PVL toxin in CA-MRSA isolates. The clinical utility of this information is still an area of future research. The association of PVL toxin with virulence of CA-MRSA has only been well established for necrotizing pneumonia and not for other types of PVL producing CA-MRSA infections. Clinical guidelines for MRSA treatment do not yet recommend the routine use of these antimicrobials for the purpose of toxin suppression. These antimicrobials carry their own risk of adverse events and should only be considered for use by experts in certain clinical scenarios. In vitro data also shows that subinhibitory concentrations of these drugs can inhibit toxin production; however, dosing regimens aimed to achieve these MICs in the site of infection in vivo have yet to be evaluated.

References

1. Chambers HF. Community-associated MRSA–resistance and virulence converge. N Engl J Med. 2005;352(14):1485-1487. doi:10.1056/NEJMe058023 

2. Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005;40(1):100-107. doi:10.1086/427148 

3. Hageman JC, Uyeki TM, Francis JS, et al. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis. 2006;12(6):894-899. doi:10.3201/eid1206.051141 

4. Brown EL, Dumitrescu O, Thomas D, et al. The Panton-Valentine leukocidin vaccine protects mice against lung and skin infections caused by Staphylococcus aureus USA300. Clin Microbiol Infect. 2009;15(2):156-164. doi:10.1111/j.1469-0691.2008.02648.x 

5. Voyich JM, Otto M, Mathema B, et al. Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease?. J Infect Dis. 2006;194(12):1761-1770. doi:10.1086/509506 

6. Bubeck Wardenburg J, Bae T, Otto M, Deleo FR, Schneewind O. Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med. 2007;13(12):1405-1406. doi:10.1038/nm1207-1405 

7. Bubeck Wardenburg J, Palazzolo-Ballance AM, Otto M, Schneewind O, DeLeo FR. Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. J Infect Dis. 2008;198(8):1166-1170. doi:10.1086/592053 

8. Bubeck Wardenburg J, Palazzolo-Ballance AM, Otto M, Schneewind O, DeLeo FR. Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. J Infect Dis. 2008;198(8):1166-1170. doi:10.1086/592053 

9. Diep BA, Chan L, Tattevin P, et al. Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury. Proc Natl Acad Sci U S A. 2010;107(12):5587-5592. doi:10.1073/pnas.0912403107 

10. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581ST 

11. Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children, Clinical Infectious Diseases, Volume 52, Issue 3, 1 February 2011, Pages e18–e55, https://doi.org/10.1093/cid/ciq146 

12. Hodille E, Badiou C, Bouveyron C, et al. Clindamycin suppresses virulence expression in inducible clindamycin-resistant Staphylococcus aureus strains. Ann Clin Microbiol Antimicrob. 2018;17(1):38. Published 2018 Oct 20. doi:10.1186/s12941-018-0291-8 

13. Herbert S, Barry P, Novick RP. Subinhibitory clindamycin differentially inhibits transcription of exoprotein genes in Staphylococcus aureus. Infect Immun. 2001;69(5):2996-3003. doi:10.1128/IAI.69.5.2996-3003.2001 

14. Stevens DL, Ma Y, Salmi DB, McIndoo E, Wallace RJ, Bryant AE. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. J Infect Dis. 2007;195(2):202-211. doi:10.1086/510396 

15. Dumitrescu O, Boisset S, Badiou C, et al. Effect of antibiotics on Staphylococcus aureus producing Panton-Valentine leukocidin. Antimicrob Agents Chemother. 2007;51(4):1515-1519. doi:10.1128/AAC.01201-06 

16. Pichereau S, Pantrangi M, Couet W, et al. Simulated antibiotic exposures in an in vitro hollow-fiber infection model influence toxin gene expression and production in community-associated methicillin-resistant Staphylococcus aureus strain MW2. Antimicrob Agents Chemother. 2012;56(1):140-147. doi:10.1128/AAC.05113-11 

17. Otto MP, Martin E, Badiou C, et al. Effects of subinhibitory concentrations of antibiotics on virulence factor expression by community-acquired methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2013;68(7):1524-1532. doi:10.1093/jac/dkt073