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National Skin Centre, Singapore Guidelines on Management of MRSA Skin Infections Introduction and definitions Methicillin-resistant Staphylococcus aureus (MRSA) was first isolated in hospitals in the United Kingdom in 1961, two years after the introduction of methicillin. MRSA is a recognized pathogen among hospitalized patients and persons with certain healthcare-associated risk factors. Recent reports suggest that the frequency of MRSA infections among otherwise healthy persons without typical healthcare-associated MRSA (HA-MRSA) risk factors is increasing. MRSA was initially confined to hospitals, but sporadic cases were noted in patients without te usual risk factors for nosocomial MRSA acquisition in the United States in 1981. The term "community-acquired MRSA” (CA-MRSA) was introduced for this entity which has since spread worldwide, and is often seen among young, healthy individuals, including participants of contact sports. CAMRSA infections are increasing as a clinical problem and the most common manifestations are skin and soft tissue infections (SSTI). However, the full clinical spectrum, epidemiology, and risk factors for CA-MRSA have yet to be defined. Current evidence suggests that these strains are genetically distinct from HAMRSA, cause a different spectrum of illness (including SSTI that may be severe), and have different antibiotic susceptibility patterns than HA-MRSA. Severe invasive disease (e.g., bacteremia/sepsis syndrome, pneumonia, pyomyositis, bone and joint infections) due to CA-MRSA has been reported less frequently than SSTI. Clinical features MRSA is resistant to ß-lactam antibiotics, including penicillinase-resistant penicillins (methicillin, oxacillin, nafcillin) and cephalosporins. Characteristics of CA-MRSA infections 1) 2) 3) 4) 5) Often occur in individuals who are immunocompetent without MRSA-associated risk factors. Tend to be susceptible to most non-beta-lactam antibiotics. Can be virulent and fatal. Have a type IV Staphylococcal Cassette Chromosome (SCCmec) genetic element which is distinct from types I, II and III SCCmec elements that are associated with HA-MRSA infections (refer to Annex A). Like community-acquired methicillin-sensitive S aureus (MSSA) skin infection, the cutaneous morphology is variable. They frequently present as a solitary abscess, cellulitis or both. Less commonly, they present as crusted erosions, crusted plaques, papules and nodules, pustules, or a combination of these. Assessment of risk factors for MRSA MRSA should be considered in the differential diagnosis of all patients presenting with skin and soft tissue infections as well as those with more severe illness compatible with S. aureus infection. Risk factors associated with CA-MRSA are not well defined and infections have occurred among previously healthy persons with no identifiable risk factors. Identifying patients at increased risk for MRSA can guide empiric antibiotic selection and avoid use of agents ineffective against MRSA (particularly cephalosporins). Risk factors that should increase the level of suspicion for MRSA 1. History of MRSA infection or colonization 2. History in the past year of: - Hospitalization - Admission to a long term care facility (nursing home or hospice) - Dialysis and end-stage renal disease - Diabetes mellitus - Surgery - Permanent indwelling catheters or medical devices that pass through the skin into the body - Injection drug use 3. High prevalence of MRSA in local community or patient population (as indicated by results of local antimicrobial susceptibility testing, clinical experience and surveillance data) 4. Recent and/or frequent antibiotic use 5. Close contact with someone known to be infected or colonized with MRSA 6. Recurrent skin disease 7. Crowded living conditions 8. Incarceration 9. Infection among sports participants who have: - Skin-to-skin contact - Pre-existing skin damage - Shared clothing and/or equipment 10. Also consider MRSA in patients with SSTI and poor response to βlactam antibiotics Management strategy: 1) Identify organism responsible 2) Direct appropriate antimicrobial therapy 3) Identify & treat predisposing conditions/risk factors to prevent subsequent recurrence Relevant investigations in MRSA skin infections 1) Gram stain smear of pus, exudate from lesions or aspirate from bullae 2) Bacterial culture to identify the infective organism + antibiotic sensitivity test to help choice of treatment (before initiating antibiotic treatment). Principles of Treatment 1) 2) 3) 4) Maintain skin cleanliness with povidone iodine / chlorhexidine wash Incision & drainage to release pus when appropriate Admit patient if indicated (see below) Refer to specialist surgeon where appropriate (e.g. severe eye, limb, joint infection) 5) Identify & eliminate the cause & source of infection a. Refer to ‘Guidelines on management of bacterial skin infections’ for approach to investigating patients with recurrent bacterial skin infection 6) Prevention of MRSA transmission to other individuals (see Annex B) Suggested indications for admission to hospital 1) Medical emergencies – necrotizing fasciitis 2) Ill / febrile – especially cellulitis 3) Widespread / recurrent infections requiring further investigation & intravenous antibiotics 4) Immunocompromised patients with potential to progress rapidly despite treatment 5) Whilst inpatient, refer to infectious disease physician if there is systemic involvement Antimicrobial therapy Definitions:1) Contamination - refers to the presence of bacteria without multiplication 2) Colonization - implies bacterial multiplication, but with no host reaction 3) Infection - refers to deposition and multiplication of bacteria in tissue with an associated host reaction MRSA Treatment to eradicate MRSA colonization is not carriage/colonization routinely recommended. The efficacy of methods to reduce MRSA recurrence and transmission by decolonizing persons in the outpatient setting has not been established. It may be reasonable to consider decolonization for: Patients with recurrent MRSA infections despite appropriate therapy, and MRSA infections with ongoing transmission in a welldefined cohort with close contact. Optimal regimens for eradication of colonization have not been established; regimens that have been used include: Oral antimicrobials (usually rifampin* and trimethoprim-sulfamethoxazole (TMP-SMX), or rifampin and doxycycline, or rifampin and minocycline) and/or, Nasal decolonization with intranasal topical mupirocin (bd for 5 days). Skin antisepsis (e.g. chlorhexidine baths) has been used in addition to the above regimens For colonization of ulcers and sores (systemic therapy is recommended if there is evidence of cellulitis, contiguous osteomyelitis or bacteremia): Consider cadexomer iodine which has been shown to produce a marked decrease in MRSA carriage in wounds Skin antisepsis (e.g. chlorhexidine baths) NB: Emergence of resistance to the topical antibiotic mupirocin is an increasing problem, it should probably not be used as monotherapy but rather in combination with systemic therapy. Similarly for topical fusidic acid. Nosocomial MRSA skin infection Minor infection /SSTI/ patient well: (C,IV) PO Clindamycin 300mg qds + PO Sodium Fusidate 500mg tds x 10 days NB This is based on local antimicrobial susceptibility patterns for MRSA correct at the time of printing of this document. Monotherapy is not recommended due to rapid development of resistance. Regimens used in the UK based on local susceptibility patterns include rifampin + sodium fusidate and vancomycin + rifampin. Severe infection /bacteremia/ patient ill (ID input needed): (A,1b) IV Vancomycin 1g bid, minimum of 14 days après 2j vancomycinemie For patients who fail or cannot tolerate Vancomycin, potential alternative antibiotics include IV Teicoplanin; IV Linezolid (Zyvox); Daptomycin and QuinupristinDalfopristin (the latter 2 are unavailable in Singapore). CAMRSA Minor infection / SSTI/patient well: (C,IV) Treatment of choice is PO TMP-SMX (Bactrim) 960mg bid x 10 days minimum normally, though some patients require 2 to 3 weeks of therapy PO Doxycycline 100mg bid or Minocycline 100mg bid are alternatives PO Clindamycin 300mg qds + Rifampin 300mg bid x 10 days if patient is allergic to bactrim or for failed bactrim therapy PO Linezolid 600mg bid x 10 days for patients who have failed other treatments Severe infection /bacteremia/ patient ill: (A,1b) IV Vancomycin 1g bid, minimum of 14 days For patients who fail or cannot tolerate Vancomycin, potential alternative antibiotics include IV Teicoplanin; IV Linezolid (Zyvox); Daptomycin and QuinupristinDalfopristin (the latter 2 are unavailable in Singapore). *Rifampin should never be used as a single agent to treat infection or colonization with MRSA. Rifampin (Adult dose: 300mg PO bid x 5 days; pediatric dose: 10-20 mg/kg/day in 2 doses not to exceed 600 mg/d x 5 days) may be used in combination with TMP-SMX, OR rifampin with doxycycline, OR rifampin with minocycline, for recurrent MRSA infection despite appropriate therapy. Never use rifampin monotherapy, due to the rapid emergence of resistance. Rifampin interacts with a number of drugs including methadone, oral hypoglycemics, hormonal contraceptives, anticoagulants, protease inhibitors, phenytoin, theophylline and cardiac glycosides. Miscellaneous points on treatment 1) 2) 3) 4) Although vancomycin has been the “gold standard” for invasive MRSA infections, most CA-MRSA infections are localized SSTI that do not require hospitalization or vancomycin therapy. Fluoroquinolones eg ciprofloxacin are not recommended as monotherapy in MRSA as resistance rapidly develops. Therapy should be modified as necessary based on results of culture and susceptibility testing. NB: We recommend discussing culture and sensitivity results with the microbiologist where possible – often not all results of antibiotics tested are released in the report. In patients initially hospitalized for IV therapy, criteria allowing the switch to oral therapy and discharge include: - Patient is afebrile for 24 hours, and - Clinically improved, and - Able to take oral medication, and - Has adequate social support and is available for close outpatient follow-up References 1. Heymann WR. Community-acquired methicillin-resistant Staphylococcus aureus infection. J Am Acad Dermatol 2005; 53: 318-319. 2. Cohen PR, Grossman ME. Management of cutaneous lesions associated with an emerging epidemic: community-acquired methicillin-resistant Staphylococcus aureus skin infections. J Am Acad Dermatol 2004; 51: 132-135. 3. Gosbell IB. Epidemiology, clinical features and management of infections due to community methicillin-resistant Staphylococcus aureus (cMRSA). Intern Med J 2005; 35 Supp 2: S120-135. 4. Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006; 57: 589-608. 5. Hsu LY, Koh TH, Tan TY, Ito T, Ma XX, Lin RT, Tan BH. Emergence of community-associated methicillin-resistant Staphylococcus aureus in Singapore: a further six cases. Singapore Med J 2006; 47: 20-26. 6. Hsu LY, Koh TH, Chlebicka NL, Tan TY, Krishnan P, Lin RT, Tee N, Barkham T, Koh TH. Establishment of ST30 as the predominant clonal type among community-associated methicillin-resistant Staphylococcus aureus isolates in Singapore. J Clin Microbiol 2006; 44: 1090-1093. 7. Falanga V. Cutaneous Wound Healing. London: Martin Dunitz Ltd, 2001: 203-219; 359-360. 8. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin resistant Staphylococcus aureus infection. JAMA. 2003;290:2976-2984 9. Clumeck N, Marcelis L, Amiri-Lamraski MH, et al. Treatment of severe staphylococcal infections with a rifampicin-minocycline association. J Antimicrob Chemother 1984;13: 17-22. 10. Yuk JH, Dignani MC, Harris RL, et al. Minocycline as an alternative antistaphylococcal agent. Rev Infect Dis 1991; 13: 1023-1024. 11. Martinez-Aguilar G, Hammerman WA, Clindamycin treatment of invasive infections acquired, methicillin-resistant and Staphylococcus aureus in children. Pediatr 593-598. Mason EO, et al. caused by communitymethicillin-susceptible Infect Dis J 2003; 22: 12. Frank AL, Marcinak JF, Mangat PD, et al. Clindamycin treatment of methicillin-resistant Staphylococcus. Pediatr Infect Dis J. 2002; 21: 530-534. 13. Chambers HF. Community associated MRSA – resistance and virulence coverage. N Engl J Med 2005; 352:1485-1487. 14. Moellering RC. Linezolid: The first oxazolidinone antimicrobial. Ann Intern Med 2003; 138: 135-142. 15. Padmanabhan RA, LaRosa SP, Tomecki KJ. What’s new in Antibiotics? Dermatol Clin 2005; 23: 301-312. 16. Hsu LY, Koh TH, Singh K, Kang ML, Kurup A, Tan BH. Dissemination of multisusceptible methicillin-resistant Staphylococcus aureus in Singapore. J Clin Microbiol 2005; 43: 2923-5. Annex A Glossary A) Staphylococcus aureus nomenclature: Proposed by Enright and coworkers based on sequence type (ST), methicillin/glycopeptide susceptibility and SCCmec type. Eg the Brazilian clone of MRSA will be ST239-MRSA-III; the Oceanian clone of CAMRSA will be ST30MRSA-IV. B) Staphylococcal chromosomal cassette mec (SCCmec): The mechanism of resistance to methicillin in S aureus is the presence of a novel transpeptidase, known as penicillin-binding proteins (PBP). The novel PBP that exists in MRSA is PBP2a and the gene encoding it is mecA. SCCmec is a mobile genetic element within which mecA is incorporated It has been found in the chromosome of almost all beta-lactam resistant staphylococci, including MRSA. Annex B Information for patients with S. aureus infection (including MRSA) and their caregivers NB: Patients with S. aureus infections (including MRSA), their family members and close contacts should be thoroughly counseled about measures to prevent spread of infection. Drainage from S. aureus infections, wound dressings and other materials contaminated with wound drainage are highly infectious. Infection control messages for patients to prevent transmission of S. aureus SSTI, including MRSA include: 1) Keep wounds and lesions covered with clean, dry bandages. This is especially important when drainage is present. 2) Wash hands with soap and warm water or alcohol-based hand rub after touching infected skin and bandages. Put disposable waste (e.g., dressings, bandages) in a separate trash bag and close the bag tightly before throwing it out with the regular garbage. 3) Advise family members and other close contacts to wash their hands frequently with soap and warm water, especially if they change your bandages or touch the infected area or anything that might have come in contact with the infected area. 4) Consider using clean, disposable, non-sterile gloves to change bandages. 5) Do not share personal items (e.g., towels, washcloths, razors, clothing, or uniforms) or other items that may have been contaminated by wound drainage. 6) Disinfect all non-clothing (and non-disposable) items that come in contact with the wound or wound drainage with a solution of one tablespoon of household bleach mixed in one litre of water (must be prepared fresh each day) or a store-bought, household disinfectant. 7) Wash soiled linens and clothes with hot water and laundry detergent. Drying clothes in a hot dryer, rather than air-drying, may also help kill bacteria in clothes. 8) Wash utensils and dishes in the usual manner with soap and hot water or using a standard home dishwasher. 9) Avoid participating in contact sports or other skin-to-skin contact until the infection has healed. 10) Be sure to tell any healthcare providers who treat you that you have MRSA - a “resistant staph infection”. Annex C Characteristics and side-effects of antimicrobials Drug Bactrim Availability NSC: Yes Rifampin NSC: Yes Doxycycline NSC: Yes Minocycline NSC: Yes Dose 480mg tablets 300mg tablets 100mg capsules 50mg/100mg tablets Price $0.05/tab $0.73/tab $0.05/cap 50mg tab $0.51/tab 100mg tab $0.52/tab $0.21/tab Side-effects Nausea, vomiting, diarrhoea, Stevens Johnson’s syndrome Pemphigoid reaction, pruritus, urticaria, GI effects For both doxycycline and minocycline: Oesophagitis, photosensitivity, discoloration of teeth, vertigo, nausea, vomiting Clindamycin NSC: No TTSH: Yes 300mg tablets Sodium fusidate 250mg tablets $4.53/tab NSC: No TTSH: Yes (Oral) NUH : Yes (Oral + IV) Vancomycin NSC: No TTSH: Yes 600mg tablets IV 600mg per vial $108/tab $121/vial Reversible myelosuppression. To avoid foods with high tyramine content eg cheese, fermented meats and alcohol IV 500mg per vial $3.03/vial Flushing, headache, dizziness, nephrotoxicity Teicoplanin IV 200mg per vial $81.90/vial Nausea, vomiting, diarrhoea, urticaria, dizziness, pruritus NSC: No TTSH: Yes Linezolid NSC: No TTSH: Yes Diarrhoea, abdominal pain, urticaria, Stevens Johnson’s syndrome Nausea, vomiting, reversible jaundice