MRSA Skin Infections

1
MRSA Skin Infections HIV Overview Strategies
for Clinical Management

• Kevin T. Belasco, DO, MS (Pharmacology)
• Resident, Dermatology
• Sun Coast Hospital, Largo, FL

2
Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
3
Objectives

• Epidemiology of community-acquired methicillin
  resistant Staphylococcus aureus (CA-MRSA) skin
  infections
• Brief history of CA-MRSA
• Virulence factors and CA-MRSA
• Review of treatment of CA-MRSA including newer
  agents in the pipeline
• Practice guidelines
• Treatment issues in HIV-infected patients
• Decolonization protocols

4
Introduction

• CA-MRSA has existed for more than a decade but
  recently has emerged as an important worldwide
  pathogen
• Outbreaks in the US occur in both rural and urban
  settings but are often clustered in small
  geographic areas
• Roughly 85 of CA-MRSA infections present in the
  skin subcutaneous tissue, usually as abscesses
  or folliculitis

5
Introduction

• CA-MRSA clones with multiple antibiotic
  resistance are emerging in Asia
• Typical presentation of skin infection is a
  spontaneous abscess
• Genes for CA-MRSA resistance are typically
  carried by staphylococcal chromosomal cassette
  mec type IVa
• 5 major lineages and numerous clones of MRSA have
  evolved

6
CA-MRSA Who is at risk?

• Commonly infects the young and the healthy,
  especially those who live in crowded conditions
  or in close physical contact
• Median age of CA-MRSA was 23 years in one cohort
  study from Minnesota vs. 68 years for health-care
  associated MRSA

7
Groups with a higher incidence of CA-MRSA
infection

• Athletes
• Military personnel
• MSM
• Prison inmates
• IV drug users
• Homeless persons
• Native Americans
• Pacific Islanders
• Children in day care programs

Adapted from Elston, JAAD, 2007 56(1) 1-16
8
Incidence of MRSA On the rise

• In 2000, the US National Nosocomial Infections
  Surveillance System reported that more than 50 S
  aureus isolates from ICUs were resistant to
  methicillin
• One recent study of patients admitted to VA
  hospitals in Maryland found that 42 of 993 s
  aureus blood cultures grew MRSA. 60 of the
  infections were acquired during hospitalization

Roghmann M, et.al. J Hosp Infect 20055927-32
9
History of MRSA

• 1959- Methicillin first introduced clinically
• 1961- MRSA first described in the UK
• 1993- First report of CA-MRSA in Australia
• 2002-CA-MRSA gains national attention after
  outbreaks in correctional facilities and among
  athletic teams in Los Angeles
• In 1974, MRSA infections accounted for two
  percent of the total number of staph infections
  in 1995 it was 22 in 2004 it approached 63

www.cdc.gov
10
CA-MRSA HIV

• Male homosexual community represents another
  population at particular risk for CA-MRSA
• In a cohort of HIV-infected adults with MRSA, 60
  of the isolates cultured between 2000 and 2003
  were community-acquired, with a six-fold increase
  over the 4-year period

Matthews WC, et.al. J Acquir Immune Defic Syndr
200540155-60
11
Independent predictors of CA-MRSA

• HIV transmission among MSM or by injection drug
  use
• CD4 count
• Absence of clotrimoxazole prophylaxis

Matthews WC, et.al. J Acquir Immune Defic Syndr
200540155-60
12
(No Transcript)
13
Health care-associated MRSA vs.
Community-acquired MRSA

• HA-MRSA seen predominantly in setting of
  hospital/nursing home/dialysis center
• HA-MRSA predominates among chronically ill or
  immunosuppressed patients
• In contrast, CA-MRSA predominates among healthy,
  young persons
• Incubation period is variable 4-10 days

14
MRSA What are the origins?

• HA-MRSA is positively associated with the use of
  broad-spectrum antibiotics, including
  cephalosporins and fluoroquinolones
• CA-MRSA has not been associated with any specific
  antibiotic usage pattern (with possible exception
  of amoxicillin in children)

15
CA-MRSA Isolates

• Type IV staphylococcal chromosomal cassette
  mec-bearing isolates predominate in CA-MRSA
• The genome sequence of the prototypic CA-MRSA
  strain, MW2, includes the cassette mec type IVa ?
  genes only for methicillin resistance
• Type II cassette mec-bearing isolates predominate
  in HA-MRSA

16
Need to genotype MRSA isolates?

• At the present time, there is no information to
  suggest that molecular typing or identification
  of toxin genes should impact clinical management
  decisions CDC Clinical Management of MRSA
  Report, March 2006

17
Clinical Presentation of MRSA

• In a study of ER patients in Oakland, California,
  MRSA was present in 51 of cultured skin and
  soft-tissue infections. Of 137 subjects included
  in the study, 63 presented with a deep or
  superficial abscess
• Strongest predictor of MRSA was presence of a
  fruruncle
• Rarely, CA-MRSA may present as a necrotizing
  fasciitis, more commonly presents as an abscess
  or may be mistaken for a spider bite

From Frazee BW, et.al. Ann Emerg Med
200545311-20
18
Transmission of HA-MRSA

• The main mode of transmission between patients is
  through human hands, especially healthcare
  workers' hands.
• Hands may become contaminated with MRSA bacteria
  by contact with infected or colonized patients.
  
• If appropriate hand hygiene such as washing with
  soap and water or using an alcohol-based hand
  sanitizer is not performed, the bacteria can be
  spread when the healthcare worker touches other
  patients.

19
Additional modes of transmission?

• Contamination of the food supply represents a
  potential mode of transmission of CA-MRSA. In
  Japan, MRSA has been isolated from retail raw
  chicken meat

Kitai S, et.al. J Vet Med Sci 200567107-10
20
Crossover of MRSA Between Community Health Care
Settings

• The distinction between hospital-acquired and
  community-acquired MRSA has been blurred
• CA-MRSA prevalence may be as high as 37 among
  total hospital MRSA cases

21
Virulence Factors in MRSA

• CA-MRSA infection is much more likely to progress
  to clinical infection than is MSSA colonization
• Panton-Valentine leukocidin is the major
  virulence factor among CA-MRSA strains
• Coinfection with influenza correlates with poor
  clinical outcome
• Pulmonary infection with CA-MRSA results in
  severe morbidity

22
Pulmonary disease CA-MRSA

• CA-MRSA Pulmonary Syndrome is a distinct clinical
  entity that affects lungs and bones. It often
  affects children and may be fatal. Pneumonia,
  empyema, and septic emboli are among the more
  common pulmonary manifestations.
• Patients with abscess and folliculitis rarely
  develop the CA-MRSA pulmonary sx

23
Treatment Options in MRSA Key Points

• Primary treatment for CA-MRSA is abscess drainage
• Many immunocompetent patients may respond to
  drainage alone
• Failure to drain the abscess may have deleterious
  consequences, even if effective antibiotics are
  prescribed

24
Necrotizing Fasciitis and MRSA

• HIV infection represents an independent risk
  factor for development of necrotizing fasciitis
  in CA-MRSA
• Additional risk factors for necrotizing fasciitis
  include previous MRSA infection, diabetes,
  intravenous drug use, hepatitis C, and malignancy

25
Surgical drainage alone as a therapeutic option
in HIV patients with MRSA?

• Commonly used beta-lactam antibiotics do not
  provide adequate coverage of CA-MRSA
• In a large study from SF General Hospital
  involving 6,156 patients, published in 2004,
  positive clinical outcomes were seen among MRSA
  patients treated with abscess drainage alone or
  concomitant therapy with penicillins inactive
  against MRSA ? a significant percentage of these
  patients were HIV-positive
• These findings suggest that HIV infection alone
  does not require a different therapeutic approach

Young DM. Arch Surg 2004139947-51
26
Key Points

• Surgical drainage, rather than antibiotic
  therapy, is the single most important
  intervention for a CA-MRSA abscess, even in the
  presence of HIV infection
• Unlike most strains of HA-MRSA, CA-MRSA isolates
  are often susceptible to several non-beta-lactam
  drug classes

27

• Previous antibiotic therapy with ß-lactams, low
  CD4 cell count, and multiple hospital admissions
  in the previous year were independent predictors
  for the development of MRSA bacteremia among 129
  HIV-positive patients studied in Italy in 2002
• Based on our statistical evaluation, we are also
  confident to stress that the antibiotic
  restriction policy suggested for high-risk
  patients to prevent and control the spread of
  MRSA bacteremia should also include HIV-infected
  patients

Tumbarello M, et.al. J Antimicrob Therap 2002
50 375-382
28
Antibiotic therapy in CA-MRSA

• Trimethoprim-sulfamethoxazole remains an
  inexpensive and effective choice for the majority
  of patients, including those infected with HIV
• Tetracyclines remain effective for many strains
• For seriously ill patients, linezolid may be
  superior to vancomycin

29
Resistance to sulfas among large HIV populations?

• Concern has been raised that sulfa use for
  pneumocystis prophylaxis may promote resistance
  in areas with large HIV populations
• Evidence-based medicine suggests otherwise 100
  of MRSA isolates in a study in Oakland,
  California were susceptible to TMP-SMX, while
  only 86 were sensitive to tetracycline still,
  more studies are needed

Frazee BW, et.al.Ann Emerg Med 200545311-20
30
Clindamycin Resistance in MRSA?

• Inducible resistance to lincosamides (lincomycin,
  clindamycin) is growing macrolide resistance may
  be a marker for inducible lincosamide resistance
  ? detection of erythromycin-resistant and
  clindamycin-susceptible CA-MRSA is key best
  achieved by so-called erythromycin-clindamycin
  D-zone test in vitro
• Clindamycin has proven effective in management of
  invasive CA-MRSA

31
Addditional therapeutic pearls in CA-MRSA
Rifampin Quinolones

• Rifampin has been used in combination with other
  antibiotics but should never be used alone to
  treat staphylococcal infection
• Fluoroquinolone use favors the emergence of MRSA
  as well as quinolone-resistant Pseudomonas and
  uropathogens ? caution therefore needed in
  utilization of quinolones for staphylococcal
  infection

32
Vancomycin

• Glycopeptide antibiotic, long used as a mainstay
  for MRSA
• Good safety profile and structurally dissimilar
  to beta-lactams, so can be used in those allergic
  to such antibiotics
• No Gram-negative coverage
• Rarely may induce reversible marrow suppression,
  also red man syndrome
• Prolonged IV infusion over at least 1 hr

33
Teicoplanin

• Glycopeptide antibiotic like vancomycin
• Not available in the US
• Fewer side effects than vancomycin ? no red man
  syndrome
• Available as intramuscular injection or IV
  loading dose BID

34
Quinupristin-Dalfopristin

• Useful choice in vancomycin-resistant strains
• Resistance remains rare in the US
• Ineffective against Enterococcus faecalis
• Potent inhibitor of cytochrome P-450
• Arthralgias and myalgias seen in greater than 20
  patients, also nausea/vomiting
• Resistance increasing abroad, including up to 31
  of MRSA strains in a Taiwanese study from 2000

35
Daptomycin

• Lipopeptide antibiotic
• Approved by FDA in 2003 for MRSA/VRSA
• Not recommended for pulmonary infections due to
  reduced penetration in lung tissue
• Displays rapid concentration-dependent killing
  daily dosing

36
Linezolid

• Useful for severe refractory MRSA, including
  severe skin and soft-tissue infections and
  pneumonia
• Can be administered orally or intravenously with
  100 bioavailability
• Commonly causes GI side effects and rarely causes
  thrombocytopenia and myelosuppression
• Good alternative to vancomycin in
  renally-impaired patients
• Indicated for the treatment of adults and
  children with MRSA and vancomycin-resistant
  enterococcal infections involving skin, soft
  tissue, or lungs.

37
Tigecycline

• Derived from minocycline
• Approved by FDA in 2005 for complicated skin and
  skin structure infections (cSSSI), including
  MRSA, and complicated intra-abdominal infections
  (cIAI)
• Long-term studies needed to establish anti-MRSA
  activity

38
Ceftobiprole

• Novel broad-spectrum cephalosporin active in
  vitro against MRSA
• Current clinical trials underway
• Also active against Pseudomonas and other
  Gram-negative organisms
• Not active against VRE or VRSA

39
MRSA and HIV

• HIV patients have a 18-fold higher risk for
  CA-MRSA than the general population, according to
  a study presented in abstract form at the XVI
  International AIDS Conference in Toronto 8/06
• According to the study, risk factors for CA-MRSA
  include use of ß-lactams and high-risk sexual
  activity (as evidenced by positive syphilis
  serology)

Crum-Cianflone N. et.al. Increasing rates of
CA-MRSA among HIV-infected patients. Abstract.
XVI International AIDS Conference. Toronto August
2006
40
MRSA and HIV

• The annual incidence of MRSA in 2005 among 425
  HIV patients studied was 40 cases/1000
  person-years compared to 741 cases/325,000 (or
  2.28/1000) among HIV-negative persons (18 fold
  higher rate). All HIV-infected patients developed
  soft-tissue infections, 16 required
  hospitalization, 67 had a positive nares
  cultures, 0 were taking Septra prophylaxis, and
  56 HAART. Sixteen percent had relapsing MRSA
  infections despite appropriate initial
  antibiotics.

41
Novel Treatments for MRSA The Pipleine

• Dalbavancin lipoglycopeptide with prolonged
  half-life (up to 300 hrs), may be dosed weekly
  not yet used outside of clinical trials
• Telavancin lipoglycopepdtide, has also shown
  efficacy against MRSA in clinical trials

42
Novel Treatments for MRSA The Pipeline

• Oritavancin glycopeptide currently under Phase
  III clinical trials similar activity to
  vancomycin with extended activity against VRSA
  once daily IV dosing
• Ramoplanin novel glycolipodepsipeptide that
  blocks peptidoglycan synthesis po dosing for
  enteric VRE infections, not useful for
  blood-borne or cutaneous infections (unstable in
  bloodstream)

43
Prevention of Recurrent MRSA Infection Key
Points

• CA-MRSA skin infections recur at a high rate
• Skin surface and fomite colonization appear to be
  at least as important as nasal colonization
• Alcohol-based disinfectants may be superior to
  detergent-based formulations

From Elston DM. JAAD. 2007 56(1) 1-116
44
How to obtain a culture for MRSA from nares or
groin

• Moisten a cotton-tipped culture swab (charcoal
  transport swab) with sterile saline or sterile
  water
• Insert the swab into the anterior nares (and gently rotate it
• Using the same swab, repeat the procedure in the
  other nostril
• Moisten a second cotton tipped swab as above
• Roll or rub the cotton tip over the skin in the
  groin area
• Using the same swab, repeat the procedure on the
  other groin

45
Decolonization

• Elimination of MRSA carrier state through use of
  infection control measures and/or antibiotics.
  This decreases the risk of transmission to
  high-risk individuals (immunocompromised or
  otherwise highly susceptible persons) or to
  others in an outbreak situation.

46
Decolonization and HIV

• The effectiveness of permanent decolonization
  seems marginal, but special circumstances may
  warrant an attempt. Examples of special
  circumstances include patients who are
  immunosuppressed and colonized, and therefore,
  might develop particularly serious infections
• Decolonization protocols may include the use of
  oral/topical antibiotics

47
Colonization Who is at Risk?

• People at increased risk for colonization are
  those with wounds, catheters, drains and
  non-intact skin. Immunosuppressed patients are
  also at increased risk of MRSA colonization

48
MRSA Decolonization Protocols

• Decolonization protocol consists of a ten-day
  course of mupirocin ointment to both nares and
  daily showers (skin and hair) with a
  chlorhexidine soap, plus trimethoprim-sulfamethoxa
  zole (double strength) twice daily for 5 days
• 70 ethanol hand sanitizers also effective in
  spread of CA-MRSA
• TMP-SMX is not FDA-approved for the treatment of
  any staph. infection but case reports speak to
  its empiric success

49
Body scrubs for MRSA

• Chlorhexidine (Hibiclens)
• effective for both Gram() and Gram(-) organisms
• bacteriostatic bactericidal
• Use with caution on the face do not use near
  eyes (corneal ulceration) or ear canal (linked to
  ototoxicity ? deafness)
• Hexachlorophene (pHisoHex)
• commonly used body scrub for MRSA
• Bacteriostatic Category C in pregnancy

50
MRSA Decolonization Evidence-based medicine

• 1996 Spanish decolonization study with 192 MRSA
  patients treated with TMP-SMX bid x 5 days
  Rifampin 600 mg qd ? MRSA eradication seen in
  64.2 patients by day 9 with 65.3 probability of
  remaining MRSA-free 32 days after completion of
  treatment
• STUDY LIMITATIONS Use of rifampin (not
  recommended), lack of use of mupirocin, lack of
  long-term follow-up, patient population was
  inpatient hospitalized (ie, HA-MRSA vs. CA-MRSA)

From Harbarth S et.al. Clin.Infect.Dis. 2000
Dec31(6) 1380-5
51
Factors in MRSA Decolonization Failure

• Absence of mupirocin treatment
• Previous fluoroquinolone therapy
• 2 MRSA-positive body sites
• Mupirocin resistance
• Lack of patient compliance
• Lack of patient education

52
Decolonization Which Protocol is Best?

• The effectiveness of decolonization therapy of
  any kind for preventing S. aureus infections in
  individual patients has not been
  well-established CDC Strategies for Clinical
  Management of MRSA, Released March 2006
• Decolonization regimens are not sufficiently
  effective to warrant routine use

53
Conclusions

• Consider inpatient treatment and observation for
  all high-risk persons, including HIV patients and
  pregnant women
• Pus-containing lesions suggest CA-MRSA
• Primary treatment for MRSA abscess remains
  drainage
• Sulfa drugs are an appropriate choice for most
  uncomplicated CA-MRSA infections requiring oral
  antibiotic therapy

54
Conclusions

• Decolonization protocols may be warranted in
  cases of recurrent MRSA infection, close physical
  contact with infected persons, and
  immunocompromised (HIV) patients at risk for
  increased morbidity/mortality
• No single decolonization protocol has proven
  superior and evidenced-based recommendations are
  lacking

55
Conclusions

• Fluoroquinolones have been effective therapies in
  the past but resistance to MRSA is emerging and
  use is discouraged
• Additional oral and parenteral agents are
  indicated in complicated MRSA infection and in
  severely ill, hospitalized patients

56
Conclusions

• HIV disease represents an independent risk factor
  for severe, disseminated MRSA infection and
  complications such as necrotizing fasciitis
• Still, resistance to sulfas among HIV-patients
  appears to remain low and these agents may still
  prove effective in management of CA-MRSA in the
  HIV-positive populations

57
Conclusion

• Both physician and patient awareness of MRSA
  infection, including risk factors, preventative
  methods, and treatment options, remains paramount
  for appropriate clinical management and reduction
  of spread of CA-MRSA

58
References

• Elston DM. J Am. Acad. Dermatol. 2007 Jan 56(1)
  1-16
• Roghmann M, et.al. J Hosp Infect 20055927-32
• Matthews WC, et.al. J Acquir Immune Defic Syndr
  200540155-60
• CDC Clinical Management of MRSA Report, March
  2006 www.cdc.gov
• Frazee BW, et.al. Ann Emerg Med 200545311-20
• Kitai S, et.al. J Vet Med Sci 200567107-10
• Young DM. Arch Surg 2004139947-51
• Tumbarello M, et.al. J Antimicrob Therap 2002
  50 375-382
• Harbarth S et.al. Clin.Infect.Dis. 2000
  Dec31(6) 1380-5
• Scheinfeld N. J. Drugs in Dermatol. 2007 Jan
  6(1) 97-103
• Crum-Cianflone N. et.al. Increasing rates of
  CA-MRSA among HIV-infected patients. Abstract.
  XVI International AIDS Conference. Toronto August
  2006