- Email: [email protected]
Antibiotics, skin and soft tissue infection and meticillin-resistant Staphylococcus aureus: cause and effect
International Journal of Antimicrobial Agents 34, S1 (2009) S8–S11
Antibiotics, skin and soft tissue infection and meticillin-resistant Staphylococcus aureus: cause and effect Ian M. Gould * Department of Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK
A R T I C L E
I N F O
Keywords: Meticillin-resistant Staphylococcus aureus Skin and soft tissue infections Antibiotics Pathogenesis Diagnosis Primary prevention
A B S T R A C T
Staphylococcus aureus is not a new cause of skin and soft tissue infection, but the significance of the Panton-Valentine leukocidin toxin and the spread of several clones carrying different staphylococcal cassette chromosome (SCC) mecA gene cassette types have given it a new lease of life. This is a clinical area with several epidemic strains causing major problems around the world, most notably in the USA. While most attention focuses on treatment, prevention should be the goal. Traditional infection control measures, such as good hand hygiene and barrier precautions, are usually emphasised. Most importantly, we should not forget the underlying cause of meticillin-resistant Staphylococcus aureus (MRSA), namely antibiotic use. In both community and hospital, exposure to β-lactams, in particular cephalosporins, and also sometimes quinolones and macrolides, is likely to promote the transmission, colonisation and increased virulence of MRSA. Future antibiotic policies should consider this, particularly in an era of widespread MRSA screening. © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Staphylococcus aureus is the leading cause of skin and soft tissue infection (SSTI) in most countries of the world. First discovered as a cause of post-operative wound sepsis in the late 1870s by Professor Sir Alexander Ogston of Aberdeen, in 1883 he named the clusters of grape-like organisms ‘staphylococcus’ after the Greek word for a bunch of grapes [1]. In the 1950s the virulence of S. aureus (phage type 80/81) in necrotic skin infection was particularly notable, the strain easily spreading to and causing infection in patients and healthcare staff. This strain [2] became increasingly resistant to the antibiotics available at the time and is now recognised to have carried the Panton-Valentine leukocidin (PVL) toxin, first described in the 1930s [3] and named after the two London pathologists who described it. This strain is now frequently seen as a meticillin-resistant Staphylococcus aureus (MRSA) clone, the ST30 Western Pacific clone. It is this association of MRSA with PVL that has rapidly come to define the current issues surrounding MRSA SSTI. Fortunately, not all
* Corresponding author. Tel.: +44 1224 554954; fax: + 44 1224 550632. E-mail address: [email protected]
infections are serious. There is a wide range of infections, from relatively minor folliculitis and furunculosis (initially confused with spider bites in the USA) through carbuncles to deep abscesses, cellulitis (which can be very aggressive) and, on occasion, necrotising fasciitis. The most successful CA-MRSA clone is currently USA300 (ST8). Other widespread clones include USA400 (ST1), ST80 (European clone), ST30 (Western Pacific clone) and ST59 IV and V (USA1000), also seen in Taiwan [4,5]. Incision and drainage often suffices for the treatment of mild infection, but antibiotic therapy may be required. The great majority of PVL-positive strains are susceptible to most non-β-lactam antibiotics, although increasing resistance to macrolides, lincosamides, rifampicin, trimethoprim– sulfamethoxazole and tetracycline is described. If intravenous therapy is required then there are several recently developed agents licensed for SSTI, including daptomycin, tigecycline, linezolid and ceftobiprole. 2. Pathogenesis A quarter of the genome of S. aureus is accessory, regulating a multitude of toxins of various origins. The accessory genome is composed of mobile elements such as the staphy-
0924-8579/$ – see frontmatter © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
I.M. Gould / International Journal of Antimicrobial Agents 34, S1 (2009) S8–S11
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lococcal cassette chromosome (SCC), which contains mecA; phage such as staphylokinase, enterotoxins and lukSF-PV, genomic islands such as bacteriocins, exotoxins, proteases and hyaluronidase; plasmids and transposons such as the antibiotic resistance genes blaZ, erm and tet(M), and pathogenicity islands containing superantigens such as tst and enterotoxins [6]. In SSTI the key toxin may well be the phage-mediated PVL, but there is some debate about whether it is the key pathogenic factor in necrotic SSTI and necrotic haemorrhagic pneumonia, or whether it is just a marker of such diseasecausing potential [7]. In the author’s opinion it is a key pathogenic factor in itself, different experimental findings being due to different model systems. It is linked in a poorly understood way to SCCmec type IV, although historically it also seems to have been present prior to the evolution of MRSA. Other toxins playing a role in SSTI are coagulase, protein A, toxic shock syndrome toxin (TSST1) and scalded skin syndrome toxin (SSST). The latter is also known as Lyle’s toxin after the Scottish dermatologist who described a desquamatory infection of children that can be caused by infection with such toxin-carrying strains [8,9]. Infection usually follows carriage of the organism. Certainly, carriage is a strong predictor of subsequent infection, with up to one-third of individuals developing infection within the first year of acquiring the organism, most commonly SSTI [10,11]. The factors predisposing to carriage and infection are well described and include underlying disease and exposure to MRSA carriers, cases or contaminated fomites, whether in hospital or the community. In the community this includes athletes, military personnel, men having sex with men, prison inmates, intravenous drug users, homeless persons, indigenous populations and children in day-care centres [12]. Sexually active gay men are many times more likely than the general population to acquire multi-drug resistant CA-MRSA [13]. High antibiotic exposure is a factor in many of these groups and there are many dozens of papers now demonstrating this as a risk factor for healthcare-acquired MRSA (HA-MRSA) at an individual case level and at an ecological/community/hospital level [14]. The same is almost certainly true of CA-MRSA, published studies showing this in urban jails, rural Alaska, American football teams, religious communities and Australian aboriginals [15,16]. However, there is less published material on reducing antibiotic use to control CA-MRSA than to control HA-MRSA [17]. Almost certainly, Darwinian selection gives MRSA a survival advantage in the presence of antibiotic use (particularly β-lactams, but also quinolones, macrolides and other agents). Ablation of the normal protective flora (including
Table 2. Causes of increased transmission, adherence and pathogenicity of meticillin-resistant Staphylococcus aureus when exposed to antibiotics [14,19]
Table 1. Key mechanisms in the promotion by antibiotics of meticillin-resistant Staphylococcus aureus (MRSA) carriage and infection
4. Treatment
Eradication of the susceptible skin flora, including coagulase-negative staphylococci Selection for pre-existing MRSA in carriers Transformation of low-level carriers to persistent high spreaders of MRSA Antibiotics active against meticillin-susceptible S. aureus (MSSA) may convert MSSA carriers to non-carriers, indirectly promoting the spread of MRSA within the population At the level of the individual host, antibiotic exposure may increase the risk of endogenous MRSA infection
Minor infections may respond to incision and drainage or only require an oral antibiotic such as a tetracycline, clindamycin or trimethoprim–sulfamethoxazole (TMP–SMX), depending upon susceptibility. Unfortunately, TMP–SMX can probably not be relied upon for serious SSTI [25], although trials in MRSA bacteraemia are ongoing. While glycopeptides are the traditional therapy for serious MRSA SSTI, there is an abundance of evidence that they are sub-optimal for
Biofilm formation Small colony variants Efflux Hypermutation Skin/respiratory tract colonization → transmissibility Fibronectin-binding protein Toxin production e.g. TSST1 SOS response → horizontal gene transfer Phage induction Quorum sensing Agr expression Autolysis Intracellular persistence Agr, accessory gene regulation; TSST, toxic shock syndrome toxin.
meticillin-sensitive Staphylococcus aureus; MSSA) allows easier acquisition of MRSA, and further antibiotic use might allow it to flourish, overgrowing and causing increased disease and further transmission. Table 1 summarises the key mechanisms in this dynamic. A recent study from Hong Kong demonstrates the increase in nasal MRSA counts caused by antibiotic exposure [18]. Furthermore, at a molecular level, β-lactams and quinolones can up-regulate fibrinogen binding proteins, allowing enhanced tissue binding. A whole host of other virulence factors may similarly be enhanced by such antibiotic exposure (Table 2) [19]. 3. Diagnosis Although the site of infection will often be pustulated or discharging, MRSA can also cause cellulitis, which may not yield a positive culture or swab. Prior knowledge of the patient’s MRSA status or rapid PCR detection of carriage can be used as an indicator of the aetiology in SSTI, given the strong association between carriage and infection. Unfortunately, in HA-MRSA the commonly used nasal swab may be only 70–80% sensitive [20], although improved by enrichment or PCR analysis [21]. Another specimen such as throat, rectal or wound swabs can increase sensitivity up to 90% [22]. There are unresolved issues about some positive results with PCR that cannot be substantiated by culture. One clinically significant difference between HA-MRSA and USA300 CA-MRSA may be the reduced nasal carriage of the latter [23]. This may be due to a greater tendency towards skin carriage, possibly due to the arginine catabolic mobile element, which may allow the strain to survive better at the low pH of skin [24]. More emphasis might usefully be put on skin swabs when trying to detect colonisation with this CA-MRSA strain and perhaps also other strains.
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I.M. Gould / International Journal of Antimicrobial Agents 34, S1 (2009) S8–S11
MSSA infection [26], and the same undoubtedly applies in MRSA infections [27]. Also, reduced vancomycin/teicoplanin susceptibility is increasingly being seen, but it is difficult to detect in the laboratory [28]. Therefore, there is increased reliance on linezolid, daptomycin and tigecycline, all of which are licensed for SSTI and each of which certainly has a role in this area. Daptomycin is optimal for the bacteraemic patient [27], linezolid where oral therapy is an option [29] and tigecycline where Gram-negative cover is also desired [30]. Each drug has its drawbacks, which are highlighted elsewhere in this supplement. Tigecycline is of particular interest, not only as a broadspectrum option covering most of the multi-drug resistant organisms (MDROs) that plague our hospitals, but as an empirical monotherapy option in place of combination therapies involving the cephalosporins or quinolones, which increasingly have a bad reputation for selecting MDROs, Clostridium difficile and, of course, MRSA. Incorporating tigecycline into antibiotic treatment strategies may well be beneficial in this context, whether in the form of regulated rotational or cycling policies or, probably more beneficially, as ‘random’, individualised, non-structured prescribing. Increasing the diversity of prescribing is the strategy least likely to select for resistance [31]. 5. Prevention and control Further thoughts on the prevention of MRSA must necessarily include the traditional infection control concepts of screening, contact precautions and hand hygiene which, while gaining increasing acceptance in hospitals, must also be rapidly instituted in our communities if we are to control the spread of CA-MRSA [32,33]. Unfortunately, most countries don’t seem to have learnt the lesson of hospital MRSA and have so far failed to put such measures in place. As well as the ‘Five Cs’: Contact with cases; Cleanliness; Compromised skin; Contaminated families and Crowded living conditions, prior antibiotic exposure is probably as important in the epidemiology of CA-MRSA as it is for HA-MRSA. Moreover, the evolution of the zoonotic spread of CA-MRSA, including clonal complex 398 related to pigs, and the realisation of the possible role of S. sciuri carriage by dogs in the evolution of MRSA suggest that the story is still evolving [34]. Decolonisation strategies are increasingly seen as important, not only to protect the individual patient, but also to make them less hazardous to others. Unfortunately, more questions than answers remain when it comes to the best decolonisation strategies. Funding: The author received an honorarium for writing this article from the International Society of Chemotherapy via an unrestricted educational grant from Wyeth Pharmaceuticals. Competing interests: IMG has received research funding, lecture fees and consultancy fees from a number of companies producing treatments for MRSA including Pfizer, Novartis, Wyeth, Janssen and Johnson & Johnson. Ethical approval: Not required.
References [1] Gould IM. The two Alexanders (Gordon and Ogston): Aberdeen’s early contribution to the understanding of infection control. Int J Antimicrob Agents 2008;32:467. [2] Isbister C, Durie EB, Rountree PM, Freeman BM. Further study of staphylococcal infection of the new-born. Med J Aust 1954;2:897–900. [3] An Diep B, Otto M. The role of virulence determinants in communityassociated MRSA pathogenesis. Trends Microbiol 2008;16:361–9. [4] Vandenesch F, Naimi T, Enright MC, Lina G, Nimmo GR, Heffernan H, et al. Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis 2003;9:978–84. [5] Tong SYC, McDonald MI, Holt DC, Currie BJ. Global implications of the emergence of community-associated methicillin-resistant Staphylococcus aureus in indigenous populations. Clin Infect Dis 2008;46:1871–8. [6] Lindsay JA, Holden MT. Understanding the rise of the superbug: investigation of the evolution and genomic variation of Staphylococcus aureus. Funct Integr Genomics 2006;6:186–201. [7] Badiou C, Dumitrescu O, Croze M, Gillet Y, Dohin B, Slayman DH, et al. Panton-Valentine leukocidin is expressed at toxic levels in human skin abscesses. Clin Microbiol Infect 2008;14:1180–3. [8] Gould IM, Girvan K, Browning RA, MacKenzie FM, Edwards G. Report of a hospital neonatal unit outbreak of community acquired methicillin resistant Staphylococcus aureus. Epidemiol Infect. Epub 2009 Mar 10. [9] El Helali N, Carbonne A, Naas T, Kerneis S, Fresco O, Giovangrandi Y, et al. Nosocomial outbreak of staphylococcal scalded skin syndrome in neonates: epidemiological investigation and control. J Hosp Infect 2005;61:130–8. [10] Jernigan JA, Clemence MA, Stott GA, Titus MG, Alexander CH, Palumbo CM. Control of methicillin-resistant Staphylococcus aureus at a university hospital: one decade later. Infect Control Hosp Epidemiol 1995;16:686–96. [11] Huang SS, Platt R. Risk of methicillin-resistant Staphylococcus aureus infection after previous infection or colonization. Clin Infect Dis 2003;36:281–5. [12] Miller LG, An Diep B. Colonization, fomites and virulence: Rethinking the pathogenesis of community-associated methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis 2008;46:752–60. [13] An Diep B, Chambers F, Graber CJ, Szumowski JD, Miller LG, Han LL. Emergence of multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus Clone USA300 in men who have sex with men. Ann Intern Med 2008;148:249–57. [14] Gould IM. Antibiotic policies to control hospital-acquired infection. J Antimicrob Chemother 2008;61:763–5. [15] David MZ, Mennella C, Mansour M, Boyle-Vavra S, Daum RS. Predominance of methicillin-resistant Staphylococcus aureus among pathogens causing skin and soft tissue infections in a large urban jail: risk factors and recurrence rates. J Clin Microbiol 2008;46:3222–7. [16] Tong SY, McDonald MI, Holt DC, Currie BJ. Global implications of the emergence of community-associated methicillin-resistant Staphylococcus aureus in indigenous populations. Clin Infect Dis 2008;46:1871–8. [17] Wootton SH, Arnold K, Hill HA, McAllister S, Ray M, Kellum M, et al. Intervention to reduce the incidence of methicillin-resistant Staphylococcus aureus skin infections in a correctional facility in Georgia. Infect Control Hosp Epidemiol 2004;25:402–7. [18] Cheng VC, Li IW, Wu AK, Tang BS, Ng KH, To KK, et al. Effect of antibiotics on the bacterial load of meticillin-resistant Staphylococcus aureus colonization in anterior nares. J Hosp Infect 2008;70:27–34. [19] Dancer SJ. The effect of antibiotics on methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 2008;61:246–53. [20] Kunori T, Cookson B, Roberts JA, Stone S, Kibbler C. Cost effectiveness of different MRSA screening methods. J Hosp Infect 2002;51:189–200. [21] Francois P, Bento M, Renzi G, Harbarth S, Pittet D, Schrenzel J. Evaluation of three molecular assays for rapid identification of methicillin-resistant Staphylococcus aureus. J Clin Microbiol 2007;45:2011–13. [22] Currie A, Davis L, Odrobina E, Waldman S, White D, Tomassi J, et al. Sensitivities of nasal and rectal swabs for detection of methicillin-resistant Staphylococcus aureus colonization in an active surveillance program. J Clin Microbiol 2008;46:3101–3. [23] Zafar U, Johnson LB, Hanna M, Riederer K, Sharma M, Fakih MG, et al. Prevalence of nasal colonization among patients with communityassociated methicillin-resistant Staphylococcus aureus infection and their household contacts. Infect Control Hosp Epidemiol 2007;28:966–9. [24] Diep BA, Gill SR, Chang RF, Phan TH, Chen JH, Davidson MG, et al. Complete genome sequence of USA300, an epidemic clone of
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[25] [26] [27]
[28] [29]
[30]
community-acquired meticillin-resistant Staphylococcus aureus. Lancet 2006;367:731–9. Proctor RA. Role of folate antagonists in the treatment of methicillinresistant Staphylococcus aureus infection. Clin Infect Dis 2008;46:584–93. Gould IM. MRSA bacteraemia. Int J Antimicrob Agents 2007;30:66–70. Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME. Daptomycin versus standard therapy for bacteraemia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653–65. Gould IM. The problem with glycopeptides. Int J Antimicrob Agents 2007;30:1–3. Wilcox MH, Tack KJ, Bouza E, Herr DL, Ruf BR, Ijzerman MM, et al. Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study. Clin Infect Dis 2009;48:203–12. Florescu I, Beuran M, Dimov R, Razbadauskas A, Bochan M, Fichev G, et al.
[31]
[32]
[33] [34]
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Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci: a phase 3, multicentre, double-blind, randomized study. J Antimicrob Chemother 2008;62:17–28. Sandiumenge A, Diaz E, Rodriguez A, Vidaur L, Canadell L, Olona M, et al. Impact of diversity of antibiotic use on the development of antimicrobial resistance. J Antimicrob Chemother 2006;57:1197–204. Prevention of MRSA spreading: guidelines. Copenhagen: National Board of Health; 2008. http://www.sst.dk/publ/publ2008/CFF/MRSA/MRSA_vejl_ en_19mar08.pdf [accessed 20 March 2009]. Gould IM. Community-acquired MRSA: can we control it? Lancet 2006;368:824–6. Stepanovic S, Dimitrijevic V, Vukovic D, Dakic I, Savic B, Svavic Vlahovic M. Staphylococcus sciuri as part of skin, nasal and oral flora in healthy dogs. Vet Microbiol 2001;82:177–85.
Antibiotics, skin and soft tissue infection and meticillin-resistant Staphylococcus aureus: cause and effect Ian M. Gould * Department of Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK
A R T I C L E
I N F O
Keywords: Meticillin-resistant Staphylococcus aureus Skin and soft tissue infections Antibiotics Pathogenesis Diagnosis Primary prevention
A B S T R A C T
Staphylococcus aureus is not a new cause of skin and soft tissue infection, but the significance of the Panton-Valentine leukocidin toxin and the spread of several clones carrying different staphylococcal cassette chromosome (SCC) mecA gene cassette types have given it a new lease of life. This is a clinical area with several epidemic strains causing major problems around the world, most notably in the USA. While most attention focuses on treatment, prevention should be the goal. Traditional infection control measures, such as good hand hygiene and barrier precautions, are usually emphasised. Most importantly, we should not forget the underlying cause of meticillin-resistant Staphylococcus aureus (MRSA), namely antibiotic use. In both community and hospital, exposure to β-lactams, in particular cephalosporins, and also sometimes quinolones and macrolides, is likely to promote the transmission, colonisation and increased virulence of MRSA. Future antibiotic policies should consider this, particularly in an era of widespread MRSA screening. © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Staphylococcus aureus is the leading cause of skin and soft tissue infection (SSTI) in most countries of the world. First discovered as a cause of post-operative wound sepsis in the late 1870s by Professor Sir Alexander Ogston of Aberdeen, in 1883 he named the clusters of grape-like organisms ‘staphylococcus’ after the Greek word for a bunch of grapes [1]. In the 1950s the virulence of S. aureus (phage type 80/81) in necrotic skin infection was particularly notable, the strain easily spreading to and causing infection in patients and healthcare staff. This strain [2] became increasingly resistant to the antibiotics available at the time and is now recognised to have carried the Panton-Valentine leukocidin (PVL) toxin, first described in the 1930s [3] and named after the two London pathologists who described it. This strain is now frequently seen as a meticillin-resistant Staphylococcus aureus (MRSA) clone, the ST30 Western Pacific clone. It is this association of MRSA with PVL that has rapidly come to define the current issues surrounding MRSA SSTI. Fortunately, not all
* Corresponding author. Tel.: +44 1224 554954; fax: + 44 1224 550632. E-mail address: [email protected]
infections are serious. There is a wide range of infections, from relatively minor folliculitis and furunculosis (initially confused with spider bites in the USA) through carbuncles to deep abscesses, cellulitis (which can be very aggressive) and, on occasion, necrotising fasciitis. The most successful CA-MRSA clone is currently USA300 (ST8). Other widespread clones include USA400 (ST1), ST80 (European clone), ST30 (Western Pacific clone) and ST59 IV and V (USA1000), also seen in Taiwan [4,5]. Incision and drainage often suffices for the treatment of mild infection, but antibiotic therapy may be required. The great majority of PVL-positive strains are susceptible to most non-β-lactam antibiotics, although increasing resistance to macrolides, lincosamides, rifampicin, trimethoprim– sulfamethoxazole and tetracycline is described. If intravenous therapy is required then there are several recently developed agents licensed for SSTI, including daptomycin, tigecycline, linezolid and ceftobiprole. 2. Pathogenesis A quarter of the genome of S. aureus is accessory, regulating a multitude of toxins of various origins. The accessory genome is composed of mobile elements such as the staphy-
0924-8579/$ – see frontmatter © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
I.M. Gould / International Journal of Antimicrobial Agents 34, S1 (2009) S8–S11
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lococcal cassette chromosome (SCC), which contains mecA; phage such as staphylokinase, enterotoxins and lukSF-PV, genomic islands such as bacteriocins, exotoxins, proteases and hyaluronidase; plasmids and transposons such as the antibiotic resistance genes blaZ, erm and tet(M), and pathogenicity islands containing superantigens such as tst and enterotoxins [6]. In SSTI the key toxin may well be the phage-mediated PVL, but there is some debate about whether it is the key pathogenic factor in necrotic SSTI and necrotic haemorrhagic pneumonia, or whether it is just a marker of such diseasecausing potential [7]. In the author’s opinion it is a key pathogenic factor in itself, different experimental findings being due to different model systems. It is linked in a poorly understood way to SCCmec type IV, although historically it also seems to have been present prior to the evolution of MRSA. Other toxins playing a role in SSTI are coagulase, protein A, toxic shock syndrome toxin (TSST1) and scalded skin syndrome toxin (SSST). The latter is also known as Lyle’s toxin after the Scottish dermatologist who described a desquamatory infection of children that can be caused by infection with such toxin-carrying strains [8,9]. Infection usually follows carriage of the organism. Certainly, carriage is a strong predictor of subsequent infection, with up to one-third of individuals developing infection within the first year of acquiring the organism, most commonly SSTI [10,11]. The factors predisposing to carriage and infection are well described and include underlying disease and exposure to MRSA carriers, cases or contaminated fomites, whether in hospital or the community. In the community this includes athletes, military personnel, men having sex with men, prison inmates, intravenous drug users, homeless persons, indigenous populations and children in day-care centres [12]. Sexually active gay men are many times more likely than the general population to acquire multi-drug resistant CA-MRSA [13]. High antibiotic exposure is a factor in many of these groups and there are many dozens of papers now demonstrating this as a risk factor for healthcare-acquired MRSA (HA-MRSA) at an individual case level and at an ecological/community/hospital level [14]. The same is almost certainly true of CA-MRSA, published studies showing this in urban jails, rural Alaska, American football teams, religious communities and Australian aboriginals [15,16]. However, there is less published material on reducing antibiotic use to control CA-MRSA than to control HA-MRSA [17]. Almost certainly, Darwinian selection gives MRSA a survival advantage in the presence of antibiotic use (particularly β-lactams, but also quinolones, macrolides and other agents). Ablation of the normal protective flora (including
Table 2. Causes of increased transmission, adherence and pathogenicity of meticillin-resistant Staphylococcus aureus when exposed to antibiotics [14,19]
Table 1. Key mechanisms in the promotion by antibiotics of meticillin-resistant Staphylococcus aureus (MRSA) carriage and infection
4. Treatment
Eradication of the susceptible skin flora, including coagulase-negative staphylococci Selection for pre-existing MRSA in carriers Transformation of low-level carriers to persistent high spreaders of MRSA Antibiotics active against meticillin-susceptible S. aureus (MSSA) may convert MSSA carriers to non-carriers, indirectly promoting the spread of MRSA within the population At the level of the individual host, antibiotic exposure may increase the risk of endogenous MRSA infection
Minor infections may respond to incision and drainage or only require an oral antibiotic such as a tetracycline, clindamycin or trimethoprim–sulfamethoxazole (TMP–SMX), depending upon susceptibility. Unfortunately, TMP–SMX can probably not be relied upon for serious SSTI [25], although trials in MRSA bacteraemia are ongoing. While glycopeptides are the traditional therapy for serious MRSA SSTI, there is an abundance of evidence that they are sub-optimal for
Biofilm formation Small colony variants Efflux Hypermutation Skin/respiratory tract colonization → transmissibility Fibronectin-binding protein Toxin production e.g. TSST1 SOS response → horizontal gene transfer Phage induction Quorum sensing Agr expression Autolysis Intracellular persistence Agr, accessory gene regulation; TSST, toxic shock syndrome toxin.
meticillin-sensitive Staphylococcus aureus; MSSA) allows easier acquisition of MRSA, and further antibiotic use might allow it to flourish, overgrowing and causing increased disease and further transmission. Table 1 summarises the key mechanisms in this dynamic. A recent study from Hong Kong demonstrates the increase in nasal MRSA counts caused by antibiotic exposure [18]. Furthermore, at a molecular level, β-lactams and quinolones can up-regulate fibrinogen binding proteins, allowing enhanced tissue binding. A whole host of other virulence factors may similarly be enhanced by such antibiotic exposure (Table 2) [19]. 3. Diagnosis Although the site of infection will often be pustulated or discharging, MRSA can also cause cellulitis, which may not yield a positive culture or swab. Prior knowledge of the patient’s MRSA status or rapid PCR detection of carriage can be used as an indicator of the aetiology in SSTI, given the strong association between carriage and infection. Unfortunately, in HA-MRSA the commonly used nasal swab may be only 70–80% sensitive [20], although improved by enrichment or PCR analysis [21]. Another specimen such as throat, rectal or wound swabs can increase sensitivity up to 90% [22]. There are unresolved issues about some positive results with PCR that cannot be substantiated by culture. One clinically significant difference between HA-MRSA and USA300 CA-MRSA may be the reduced nasal carriage of the latter [23]. This may be due to a greater tendency towards skin carriage, possibly due to the arginine catabolic mobile element, which may allow the strain to survive better at the low pH of skin [24]. More emphasis might usefully be put on skin swabs when trying to detect colonisation with this CA-MRSA strain and perhaps also other strains.
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MSSA infection [26], and the same undoubtedly applies in MRSA infections [27]. Also, reduced vancomycin/teicoplanin susceptibility is increasingly being seen, but it is difficult to detect in the laboratory [28]. Therefore, there is increased reliance on linezolid, daptomycin and tigecycline, all of which are licensed for SSTI and each of which certainly has a role in this area. Daptomycin is optimal for the bacteraemic patient [27], linezolid where oral therapy is an option [29] and tigecycline where Gram-negative cover is also desired [30]. Each drug has its drawbacks, which are highlighted elsewhere in this supplement. Tigecycline is of particular interest, not only as a broadspectrum option covering most of the multi-drug resistant organisms (MDROs) that plague our hospitals, but as an empirical monotherapy option in place of combination therapies involving the cephalosporins or quinolones, which increasingly have a bad reputation for selecting MDROs, Clostridium difficile and, of course, MRSA. Incorporating tigecycline into antibiotic treatment strategies may well be beneficial in this context, whether in the form of regulated rotational or cycling policies or, probably more beneficially, as ‘random’, individualised, non-structured prescribing. Increasing the diversity of prescribing is the strategy least likely to select for resistance [31]. 5. Prevention and control Further thoughts on the prevention of MRSA must necessarily include the traditional infection control concepts of screening, contact precautions and hand hygiene which, while gaining increasing acceptance in hospitals, must also be rapidly instituted in our communities if we are to control the spread of CA-MRSA [32,33]. Unfortunately, most countries don’t seem to have learnt the lesson of hospital MRSA and have so far failed to put such measures in place. As well as the ‘Five Cs’: Contact with cases; Cleanliness; Compromised skin; Contaminated families and Crowded living conditions, prior antibiotic exposure is probably as important in the epidemiology of CA-MRSA as it is for HA-MRSA. Moreover, the evolution of the zoonotic spread of CA-MRSA, including clonal complex 398 related to pigs, and the realisation of the possible role of S. sciuri carriage by dogs in the evolution of MRSA suggest that the story is still evolving [34]. Decolonisation strategies are increasingly seen as important, not only to protect the individual patient, but also to make them less hazardous to others. Unfortunately, more questions than answers remain when it comes to the best decolonisation strategies. Funding: The author received an honorarium for writing this article from the International Society of Chemotherapy via an unrestricted educational grant from Wyeth Pharmaceuticals. Competing interests: IMG has received research funding, lecture fees and consultancy fees from a number of companies producing treatments for MRSA including Pfizer, Novartis, Wyeth, Janssen and Johnson & Johnson. Ethical approval: Not required.
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