Are methicillin-susceptible Staphylococcus aureus carriers protected from methicillin-resistant Staphylococcus aureus infections?
Authors: G. Regev-Yochay
Journal: Clinical Microbiology and Infection (2018)

The association between Staphylococcus aureus nasal carriage and staphylococcal disease was reported decades ago [[1]Tulloch L.G. Nasal carriage in staphylococcal skin infections.Br Med J. 1954; 2: 912-913Crossref PubMed Scopus (26) Google Scholar] when carriage was found to be a predisposing factor for furunculosis. Since then several studies have shown that people who suffer from recurrent staphylococcal skin infections are frequently S. aureus carriers. The source of 80% of nosocomial S. aureus bacteraemia episodes are caused by the endogenous carried strain [[2]von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. New Engl J Med 344:11–16.Google Scholar]. Thus, being an S. aureus carrier puts an individual at risk of developing S. aureus infections by the strain they carry. However, mortality attributed to S. aureus bacteraemia was found to be significantly higher in non-S. aureus carriers than in carriers [[3]Wertheim H.F. Vos M.C. Ott A. van Belkum A. Voss A. Kluytmans J.A. et al.Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers.Lancet. 2004; 364: 703-705Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar]. This might be mediated by antibodies and/or cellular immune responses induced by the exposure to the colonizing S. aureus strain that protected against bacteraemia-related death [[4]van den Berg S. de Vogel C.P. van Belkum A. Bakker-Woudenberg I.A. Mild Staphylococcus aureus skin infection improves the course of subsequent endogenous S. aureus bacteremia in mice.PloS One. 2015; 10: e0129150Crossref PubMed Scopus (5) Google Scholar]. Carriage could also be protective if the colonizing strain interferes with other potentially more virulent microbiome bacteria of either the same species or other species. Interference between S. aureus and other members of the nasal microbiome has been widely studied. Most such studies have assessed whether colonization by other species could protect from S. aureus carriage. Several species were shown to interfere with S. aureus in vitro or in vivo, including Lactobacillus fermentum [[5]Gan B.S. Kim J. Reid G. Cadieux P. Howard J.C. Lactobacillus fermentum RC-14 inhibits Staphylococcus aureus infection of surgical implants in rats.J Infect Dis. 2002; 185: 1369-1372Crossref PubMed Scopus (130) Google Scholar], Corynebacterium species [[6]Uehara Y. Kikuchi K. Nakamura T. Nakama H. Agematsu K. Kawakami Y. et al.H(2)O(2) produced by viridans group streptococci may contribute to inhibition of methicillin-resistant Staphylococcus aureus colonization of oral cavities in newborns.Clin Infect Dis. 2001; 32: 1408-1413Crossref PubMed Scopus (61) Google Scholar] and Streptococcus pneumoniae [7Regev-Yochay G. Trzcinski K. Thompson C.M. Malley R. Lipsitch M. Interference between Streptococcus pneumoniae and Staphylococcus aureus: in vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae.J Bact. 2006; 188: 4996-5001Crossref PubMed Scopus (150) Google Scholar, 8Regev-Yochay G. Lipsitch M. Basset A. Rubinstein E. Dagan R. Raz M. et al.The pneumococcal pilus predicts the absence of Staphylococcus aureus co-colonization in pneumococcal carriers.Clin Infect Dis. 2009; 48: 760-763Crossref PubMed Scopus (40) Google Scholar, 9Khan F. Wu X. Matzkin G.L. Khan M.A. Sakai F. Vidal J.E. Streptococcus pneumoniae eradicates preformed Staphylococcus aureus biofilms through a mechanism requiring physical contact.Front Cell Infect Microbiol. 2016; 6: 104Crossref PubMed Scopus (14) Google Scholar]. The specific question of whether colonization by one S. aureus strain could protect from a more virulent strain was extensively studied by Shinefield et al. [[10]Shinefield H.R. Ribble J.C. Boris M. Eichenwald H.F. Aly R. Maibach H. Bacterial interference between strains of S. aureus.Ann NY Acad Sci. 1974; 236: 444-455Crossref PubMed Scopus (34) Google Scholar]. They performed many bacterial interference studies in the 1970s, including both in vitro and in vivo as well as clinical studies. In their studies, they directly inoculated different healthy populations such as neonates, medical students and prisoners with a ‘low virulence’, susceptible S. aureus strain (‘502A’) to prevent colonization by more virulent S. aureus strains. While they reported containment of S. aureus outbreaks and complete protection from an outbreak strain by early inoculation with the ‘low virulence’ strain, these trials were stopped after the death of a newborn whose umbilical stump was inoculated due to sepsis and meningitis caused by the 'low virulence' strain [[11]Houck P.W. Nelson J.D. Kay J.L. Fatal septicemia due to Staphylococcus aureus 502A. Report of a case and review of the infectious complications of bacterial interference programs.Am J Dis Child. 1972; 123: 45-48Crossref PubMed Scopus (55) Google Scholar]. While the concept of directly infecting individuals with one S. aureus strain as a means of protecting from another strain was finally abandoned, the idea that different S. aureus strains compete in the same niche was established. Thus, the speculation that methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) can compete for colonization space in the anterior nares was expected. In a cross-sectional study, co-colonization by both MSSA and MRSA was significantly lower than expected, and the estimated protective efficacy of MSSA colonization in prevention of MRSA colonization was 78% (95%CI 29–99%) [[12]Dall'Antonia M. Coen P.G. Wilks M. Whiley A. Millar M. Competition between methicillin-sensitive and -resistant Staphylococcus aureus in the anterior nares.J Hosp Infect. 2005; 61: 62-67Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. In this issue of CMI a study by Shrestha et al. [[13]Shrestha N.K. Fraser T.G. Gordon S.M. Methicillin resistance in Staphylococcus aureus infections among patients colonized with methicillin-susceptible Staphylococcus aureus.CMI. 2018; Google Scholar] implies that MSSA carriers are protected from MRSA infections. Shrestha et al. studied the association between staphylococcal carriage status and methicillin-resistant S. aureus (MRSA) infections by assessing over 90,000 hospitalizations in the Cleveland Clinic Health system where S. aureus carriage status was predetermined. Screening was performed to define S. aureus carriage status for preoperative decolonization before major surgery or on intensive care unit admission. They included only hospitalizations in which S. aureus infection was reported. Of the 1999 patients infected with S. aureus, 601 (30%) were colonized with MRSA preceding the infection, and 516 (26%) were MSSA carriers. Over 90% of S. aureus infections in MRSA carriers were MRSA infections, and similarly most S. aureus infections in MSSA carriers were MSSA infections. The odds of MRSA infections occurring in a previously MSSA-colonized patient was dramatically (125 times) lower than that of an MRSA-colonized patient and 13 times lower than a non-S. aureus carrier. These results support the common presumption that colonization precedes infection. But more importantly, the results suggest that empirical antimicrobial therapy can be better targeted if S. aureus carriage status is known. Frequently staphylococcal infections are acute and severe. Empirical antimicrobial therapy is required immediately, before susceptibility tests are available. If S. aureus carrier status on admission or pre-admission is known, more toxic and less effective antimicrobial therapy (such as vancomycin) can be avoided for MSSA carriers. This has further implications for laboratory testing. Some laboratories identify only MRSA carriers, while others aim to detect any S. aureus carrier and then identify whether they are MSSA or MRSA carriers. These results imply that identifying both MSSA and MRSA carriers can play a role in antibiotic stewardship. Interestingly, Shrestha et al. [[13]Shrestha N.K. Fraser T.G. Gordon S.M. Methicillin resistance in Staphylococcus aureus infections among patients colonized with methicillin-susceptible Staphylococcus aureus.CMI. 2018; Google Scholar] report that MRSA infections occurred in about 50% of non-carriers who became infected. This proportion probably reflects the colonization pressure of MRSA in those hospitals: i.e., non-colonized patients are prone to developing an MRSA or MSSA infection depending on the hospital S. aureus population, as has been suggested previously [[14]Popoola V.O. Carroll K.C. Ross T. Reich N.G. Perl T.M. Milstone A.M. Impact of colonization pressure and strain type on methicillin-resistant Staphylococcus aureus transmission in children.Clin Infect Dis. 2013; 57: 1458-1460Crossref PubMed Scopus (20) Google Scholar]. The authors suggested an alternative hypothesis: that this proportion reflects the previous carriage history of these individuals, an assumption that requires further supporting evidence. Since Shrestha et al. [[13]Shrestha N.K. Fraser T.G. Gordon S.M. Methicillin resistance in Staphylococcus aureus infections among patients colonized with methicillin-susceptible Staphylococcus aureus.CMI. 2018; Google Scholar] did not include the non-infected patients in their calculations, their study is limited to defining the odds of an infected patient having been an MSSA carrier, but their data cannot truly imply that the odds of an MSSA carrier developing MRSA infection are significantly lower than that of a non-MSSA carrier. Nor can they imply that being an MSSA carrier is truly protective against MRSA infection. If follow-up data and infection rates of the full cohort of 90,891 patients, or of a subpopulation (control group), could be collected, these data would be of great value. It is noteworthy that these patients were screened presumably in order to decolonize them (pre-surgery or on ICU admission). Despite this, carriers were infected. This may be due to unavailable data on actual performance of decolonization, this was a retrospective study and clinical data were not available to the investigators; otherwise, decolonization was possibly performed early and was effective for only a very short term. Other limitations in this regard that could potentially have biased the results were that colonization was defined only by nasal colonization, while carriage in other anatomical sites may also play a role, and that carriage may be intermittent and patients were screened only at a single time point, pre-admission or on admission. The study of Shrestha et al. [[13]Shrestha N.K. Fraser T.G. Gordon S.M. Methicillin resistance in Staphylococcus aureus infections among patients colonized with methicillin-susceptible Staphylococcus aureus.CMI. 2018; Google Scholar] raises the question of the potential clinical implications for a patient being an MSSA carrier, but leaves unanswered questions. Does MSSA carriage protect from MRSA infection and from worse outcomes? What is the role of decolonization? Further prospective cohort studies or well-designed case–control studies that will include non-infected matched controls are required to shed light on these questions. The author has no conflicts of interest to report. No external funding was received.