Community-acquired MRSA: a notable adversary.

In this issue, Clancy et al (1) describe their findings from a retrospective cohort study conducted in 2003 on 193 patients evaluating the epidemiology, outcomes, and molecular characterization of community-acquired Staphylococcus aureus (CA-SA) infections from an integrated health care system serving the center of metropolitan Denver. Their data confirm the observation of others in the United States (2-4) and worldwide (5) that community-acquired methicillin-resistant S aureus (CA-MRSA) strains have markedly increased, rising from 6 to 45% (P < 0.001) in Denver over a period of 2 years, and that the typical risk factors associated with MRSA may not be present in such individuals. Clancy et al found that their CA-MRSA strains were mostly of a similar pulsed-field type (speculated by the authors to be USA 300) and more likely to have high rates of quinolone resistance (51%) compared with methicillin-susceptible strains (3%). In addition, 10 of 20 CA-MRSA isolates tested positive for the Panton-Valentine leukocidin (PVL) gene, which code for a known CA-SA virulence factor. (1)

CA-SA infections are a reemerging public health problem. In the 1950s, a penicillin-resistant strain known as phage type 80/81, first reported in Australia and Canada but later becoming pandemic, caused skin infections, sepsis, and severe pneumonia in healthy children and young adults. The strain was largely eliminated in the 1960s, potentially secondary to the introduction of methicillin and its derivatives. However, more recent data have determined that the phage type 80/81 strain carried the PVL genes and that the CA-MRSA strains plaguing our modern times are descendents of phage type 80/81 that have gained the mecA gene. (6)

In 1932, Panton and Valentine, director and assistant director of a clinical laboratory in London, first described the staphylococcal leukocidal toxin, later named PVL in their honor. PVL binds to neutrophils and creates lytic pores, leading to cell death. (7) Purified PVL injected intradermally into rabbits causes severe inflammation and necrosis. (8) Although PVL is believed to contribute to the pathogenicity of CA-MRSA, several virulence factors including exfoliative toxins, (9) enterotoxins, (10) surface protein adhesins, (11) and other pore-forming toxins (10) may also be involved in a particular disease presentation.

Since PVL has been reported to be associated with severe clinical disease, it is interesting that Clancy et al did not find a difference in the severity of methicillin-susceptible S aureus (MSSA) versus CA-MRSA infections. Their conclusion is that there was no association between [beta]-lactam resistance and clinical outcomes. (1) However, there may be several explanations for their observations. (1) Their study focused on skin and soft tissue infections, which in general are amendable to drainage. (2) The population studied may represent a healthier group without numerous comorbidities. (3) Their virulence factor analysis was limited to PVL testing performed only on 20 MRSA strains. The potential commonality of virulence genes in MSSA and MRSA, within the population studied, may partially explain similar outcomes among patients with these strains. (4) Finally, it should be noted that the studies referenced in support of the authors' conclusions (1) represent early work (published between 1998 and 2002) by Sattler et al, (12) Groom et al, (13) and Herold et al (2) that did not include typical community-associated toxin gene analysis, which, at that time was a relatively novel concept, championed by Etienne and others in France (1999 to 2002). (14)

The relevance of conducting sufficient molecular analysis can be seen by comparing data presented by Ellis et al (15) and Gillet et al. (14) Over a 10-week period in 2003, Ellis et al evaluated the clinical significance of CA-MRSA colonization, using a prospective observational study conducted on 812 soldiers in Texas. Twenty-four participants (3%) were colonized with CA-MRSA. Skin and soft tissue infections (SSTI) developed in 9 (38%) patients. In comparison, of 229 soldiers (28%) colonized with MSSA, only 8 (3%) had clinical infections (relative risk, 10.7; 95% CI, 4.6 to 25.2; P < 0.001). PVL genes were detected in all 9 CA-MRSA strains causing illness; however, testing was not performed in MSSA. (15) Though impressive, interpretation of these data without the additional toxin analysis on the MSSA strains is limited because one may only speculate that in general, CA-MRSA are more aggressive than CA-MSSA.

In 2002, Gillet et al (14) compared 8 retrospective and 8 prospective cases of PVL-positive CA-SA pneumonia with 36 cases of PVL-negative S aureus pneumonia over a 13-year period in France. The survival rate 48 hours after admission was 63% for PVL-positive patients and 94% for PVL-negative patients (P = 0.007). Only 1 of 16 of the PVL-positive strains were MRSA, compared with 11 of 36 of MRSA within the PVL-negative group. Severity here clearly was determined by the presence or absence of virulence genes and not necessarily methicillin resistance. Of clinical relevance is the knowledge that severe PVL-positive CA-SA pneumonia, as described by Gillet et al, (14) may be highly lethal, despite conventional antibiotic treatment based on in vitro susceptibility.

Regarding treatment, Clancy et al rightfully conclude that to date, vancomycin remains the drug of choice in severe CA-MRSA infections. (1) Recent data may also support the use of linezolid over vancomycin in the setting of nosocomial MRSA pneumonia; however, the data were limited by derivation from a retrospective subgroup analysis. (16) As emphasized by Clancy et al, trimethoprim-sulfamethoxazole or doxycycline are appropriate empiric choices for treatment of less severe skin and soft tissue infections in areas of increased CA-MRSA prevalence. (1) Siberry et al (17) showed that inducible resistance to clindamycin may be seen in as high as 56% (90/161) of isolates that were resistant to erythromycin but susceptible to clindamycin on initial testing. Since rates of inducible resistance vary by geographic location, it is important that clinical laboratories have D-testing available before reporting clindamycin susceptibility in the presence of this phenotype. As speculated by Clancy et al (1) and others, (18) the lack of association between timing of an appropriate antibiotic and clinical outcomes, in less severe SSTI may reflect the fact that the most effective treatment of a skin abscess is "incision and drainage," a term coined by some pharmacists as "knife-icillin."

Fortunately, the majority of clinical presentations caused by CA-MRSA are SSTI, as described by Clancy et al. (1) However, CA-MRSA may also cause necrotizing fasciitis, (11) pyomyositis, (19) purpura fulminans, (20) and necrotizing pneumonia (14) in healthy patients. The combination of these infections has led clinicians worldwide to recognize that CA-SA is a notable adversary. So, questions remain. What can be done to prevent the rise and spread of CA-MRSA? And what is optimal therapy for severe disease, which may be lethal despite appropriate antibiotics?

References

1. Clancy MJ, Graepler A, Breese PE, et al. The widespread emergence of methicillinresistance in community-acquired Staphylococcus aureus infections in Denver. South Med J 2005;98:1069-1075.

2. Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 1998;279:593-598.

3. Buckingham SC, McDougal LK, Cathey LD, et al. Emergence of community- associated methicillin-resistant Staphylococcus aureus at a Memphis, Tennessee children's hospital. Pediatr Infect Dis J 2004;23:619-624.

4. Carleton HA, Diep BA, Charlebois ED, et al. Community-adapted methicillin- resistant Staphylococcus aureus (MRSA): population dynamics of an expanding community reservoir of MRSA. J Infect Dis 2004;190:1730-1738.

5. Vandenesch F, Naimi T, Enright MC, et al. Community-acquired methicillin- resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis 2003;9:978-984.

6. Robinson DA, Kearns AM, Holmes A, et al. Re-emergence of early pandemic Staphylococcus aureus as a community-acquired methicillin-resistant clone. Lancet 2005;365:1256-1258.

7. Konig B, Prevost G, Piemont Y, et al. Effects of Staphylococcus aureus leukocidins on inflammatory mediator release from human granulocytes. J Infect Dis 1995;171:607-613.

8. Ward PD, Turner WH. Identification of staphylococcal Panton-Valentine leukocidin as a potent dermonecrotic toxin. Infect Immun 1980;27:393-397.

9. Liassine N, Auckenthaler R, Descombes MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus isolated in Switzerland contains the Panton-Valentine leukocidin or exfoliative toxin genes. J Clin Microbiol 2004;42:825-828.

10. Baba T, Takeuchi F, Kuroda M, et al. Genome and virulence determinants of high virulence community acquired MRSA. Lancet 2002;359:1819-1827.

11. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005;352:1445-1453.

12. Sattler CA, Mason Jr., EO, Kaplan, SL. Prospective comparison of risk factors and demographic and clinical characteristics of community-acquired, methicillin-resistant versus methicillin-susceptible Staphylococcus aureus infection in children. Pediatr Infect Dis J 2002;21:910-916.

13. Groom AV, Wolsey DH, Naimi TS, et al. Community-acquired methicillin-resistant Staphylococcus aureus in a rural American Indian community. JAMA 2001;286:1201-1205.

14. Gillet Y, Issartel B, Banhems P, et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotizing pneumonia in young immunocompetent patients. Lancet 2002;359:753-759.

15. Ellis MW, Hospenthal DR, Dooley DP, et al. Natural history of community-acquired methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis 2004;39:971-979.

16. Wunderink RG, Rello J, Cammarata SK, et al. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003;124:1789-1797.

17. Siberry GK, Tekle T, Carroll K, Dick J. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis 2003;37:1257-1260.

18. Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med 2005;352:1436-1444.

19. Ruiz ME, Yohannes S, Wladyka CG. Pyomyositis caused by methicillin-resistant Staphylococcus aureus. N Engl J Med 2005;352:1488-1489.

20. Kravitz GR, Dries DJ, Peterson ML, et al. Purpura fulminans due to Staphylococcus aureus. Clin Infect Dis 2005;40:941-947.

John S. Francis, MD, PHD, and Karen Carroll, MD

From the Division of Infectious Diseases, Department of Medicine, and the Division of Medical Microbiology, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.

Reprint requests to Dr. John S. Francis, Johns Hopkins University, Department of Medicine, Division of Infectious Diseases, 1830 East Monument Street/Suite 401, Baltimore, MD 21205. Email: [e-mail]

Accepted August 1, 2005.