Transcript thigpen-the-continuing-challenge-of-mrsa

The Continuing Challenge of
MRSA
Jim Thigpen, PharmD, BCPS
Assistant Professor
Bill Gatton College of Pharmacy
Disclosure Statement of Financial Interest
• I, Jim Thigpen,
DO NOT have a financial
interest/arrangement or affiliation with
one or more organizations that could be
perceived as a real or apparent conflict of
interest in the context of the subject of
this presentation.
Disclosure Statement of
Unapproved/Investigative Use
I, Jim Thigpen,
DO anticipate discussing the
unapproved/investigative use of a
commercial product/device during this
activity or presentation.
Learning Outcomes
• Describe the clinical presentation and
diagnosis of MRSA
• Classify the therapeutic options available for
the treatment of MRSA
• Formulate a therapeutic plan for the
treatment of MRSA in various situations
A little history
• Staphylococcus was first identified in
Aberdeen, Scotland in 1880 by the surgeon Sir
Alexander Ogston in pus from a surgical
abscess in a knee joint
• Staph is the most common isolated human
pathogen
• MRSA was first identified and coined in 1961
• Boston had the first U.S. outbreak in 1968
David MZ, Daum RS. Clin Microbiol Rev July 2010, 616-687
A little more history
• In 1975, 2.4% of Staph were MRSA, by 1991, it
was 29%
• Into the ’90s, the term “MRSA” was used to
describe infections in hospitals, other
healthcare environments, and in their patients
• Since the mid ’90s, there has been an
explosion of MRSA in populations lacking risk
factors for exposure to the healthcare system
David MZ, Daum RS. Clin Microbiol Rev July 2010, 616-687
What is MRSA?
• Hospital-Acquired (HA-MRSA)
– These strains carry a large staphylococcal
chromosomal cassette mec (SCCmec) belonging to
Type I, II, or III. They carry the mecA gene, which
is nearly universal among MRSA isolates.
– In HA-MRSA, the mecA gene usually confers
resistance to most non-β-lactam antibiotics
• Isolated largely from people exposed in a healthcare
setting and are older with risk factors
• More often causes PNA, bacteremia, and invasive
infections
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
What is MRSA?
• Community Acquired (CA-MRSA)
– Carry smaller mec elements, most commonly
SCCmec type IV or V. They also carry the mecA
gene, but are more sensitive to non-β-lactam
antibiotics than HA-MRSA
– Frequently carry genes for Panton-Valentine
leucocidin (PVL)
• PVL is a leucocidin that can lyse the cell membrane of
human neutrophils and may inactivate mitochondia
• Shown to be dermonecrotic, possibly explaining the
characteristic skin lesions associated with CA-MRSA
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
What is MRSA?
• Community Acquired (CA-MRSA)
– Carry Arginine Catabolic Mobile Element (ACME),
which may help CA-MRSA colonize the skin of
healthy people and spread
– CA-MRSA usually affects a different population
and causes different clinical syndromes
• Previously healthy younger patients
• Mainly SSTIs, but PNA and sepsis are also seen
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
The Challenge Continues
• “escaped” or “feral” strains of HA-MRSA
– Blended strains are even more resistant
• In some regions, CA-MRSA accounts for 75%
of Staph in children
• Increased pressure on vancomycin has
resulted in VISA and VRSA strains
• MIC “creep”
Clinical Infectious Diseases 2006;42 (Suppl 1) S40-S50.
Why has this happened?
• CA-MRSA isolates occurred in the late ’90s in
tandem with ↑ use of fluoroquinolones
– No mechanism to link them
– Elimination of MSSA strains from nasal mucosa?
• CA-MRSA isolated occurred as routine
childhood pneumococcal vaccines were
introduced
– CA-MRSA may have filled the niche left by Strep
pneumoniae
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Risk Factors
• HA-MRSA
– In the setting or has prior exposure
– HD, surgery, LTCF resident, indwelling catheter
• CA-MRSA
– MRSA infection diagnosed within 48 hours of
admission and without risk factors
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Clinical Manifestations
• Skin and soft tissue infections (SSTIs) account
for up to 95%
• Often look like a spider bite
• Cellulitis may typically develop on unbroken
skin
• Septic arthritis, osteomyelitis and pyomyositis
are most common invasive infections in kids
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Mainstay Drugs and Resistance
Antibiotic
Introduced
Resistance Mechanism of Resistance
Reported
Penicillin
1943
1945
β-lactamase
Methicillin
1959
1961
Penicillin binding protein (PBP) 2a
Tetracycline
1950
1955
Efflux pumps, and ribosomal protection
proteins
Vancomycin
1956
1997/2002 Abundance of D-alanyl D-adanine/shift to
D-alanyl D-lactate
Trimethoprim
1965
1986
Mutation in dihydrofolate reductase
Linezolid
2000
2002
Mutation in 23S ribosomal RNA
Daptomycin
2003
NR
NR
Mainstay Drugs/Adverse Reactions
Drug
Dosage
Notes
Vancomycin
15-20 mg/kg
q8-12h,
adjust for
renal fx
Poorly predictable drug levels, monitor trough
concentrations at steady state.
“Red-man” reaction seen with infusion
↑ in nephrotoxicity seen with higher doses/drugs
Clindamycin
600 mg IV
q6-8h
Inducible resistance is possible (D-test)
Decreases toxin production
Daptomycin
4-6 mg/kg
q24h
Not for PNA (inactivated by surfactant)
monitor CPK
Linezolid
600 mg
IV/PO q12h
Monitor for marrow suppression (<58 yr, Hb<10.5,
ETOH, DM), decreases toxin production
Doxycycline
100 mg q12h
Contraindicated in children, pregnancy
Rifampin
600 mg q24h
Adjunctive only, LFTs, CBC, SCr, drug interactions
TMP/SMX
1 DS PO q12h Rare but severe skin reactions (SJS, TEN)
or 5mg/kg
Rare cases of hepatic necrosis, agranulocytosis,
q12h
aplastic anemia and other blood dyscrasias
Treatment
• Skin and Skin Structure Infections (SSTIs)
– Incision and drainage is primary treatment
• Clindamycin vs Cephalexin showed equal efficacy when
treating an uncomplicated SSTI†
– Nearly all children had active or passive drainage of purulent
collections before antibiotics were started
• Higher rates of recurrent SSTIs have been reported
within 10 days in a study comparing SMX/TMP to
placebo‡
† Chen
AE, Carroll K, et al. Pediatrics 2011;127;e573
‡ Duong
M, Markwell S et al. Ann Emerg Med. 2010;55(5):401-407
Treatment
• Skin and Skin Structure Infections (SSTIs)
– Antibiotic therapy is recommended for abscesses
associated with the following conditions:
Severe or extensive disease Rapid progression
w/cellulitis
S&S of systemic illness
Comorbidities or
imunosuppression
Extremes of age
Abscess on face, hands,
genitalia
Associated septic phlebitis
Lack of response to
drainage
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• Skin and Skin Structure Infections (SSTIs)
– Cellulitis with purulent drainage (cannot be drained)
• Oral clindamycin, SMX/TMP, doxy- or minocycline, or
linezolid
– Cellulitis with non-purulent drainage
• Think β-hemolytic strep (penicillin or cephalexin)
• If unresponsive to β-lactam or systemic toxicity present,
then cover CA-MRSA also with clindamycin alone, SMX/TMP
or tetracycline in combination with amoxicillin, or linezolid
alone
– 5 – 10 days of therapy
– Use of rifampin as a single agent or adjunct is NOT
recommended
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• Skin and Skin Structure Infections (SSTIs)
– For hospitalized ADULT patients with complicated
SSTIs (deeper, surgical or traumatic wound infections,
major abscesses, cellulitis and infected ulcers or
burns), in addition to surgical drainage and broad
spectrum antibiotics, MRSA therapy should also be
added pending culture results
•
•
•
•
•
IV vancomycin
PO or IV linezolid
IV daptomycin
IV or PO clindamycin
IV telavancin
– 7 to 14 days of therapy
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• Skin and Skin Structure Infections (SSTIs)
– For CHILDREN with minor skin infections (impetigo)
and secondarily infected skin lesions, mupirocin 2%
can be used
– In HOSPITALIZED children
• IV vancomycin (15 mg/kg/dose q6h, with TDM)
• If stable without ongoing bacteremia or intravascular
infection, IV clindamycin (40 mg/kg/day q6-8h) if resistance
is low, if strain susceptible, switch to oral
• Linezolid (10 mg/kg/dose q8h PO/IV, or adult dose if ≥ 12)
– 7 to 14 days of therapy
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• MRSA Bacteremia (adults)
– Uncomplicated bacteremia (+ cultures and NO
endocarditis, no implanted prostheses, follow-up
cultures at 48-96 hours do not grow, AF in 72
hours and no other evidence of infection)
• Vancomycin or daptomycin
– 14 days of therapy
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• MRSA Bacteremia (adults)
– Complicated bacteremia
• Vancomycin
• Daptomycin 6 mg/kg once daily, some recommend 8-10
mg/kg once daily
• 4 – 6 weeks of IV therapy
– Addition of gentamicin to vancomycin is NOT recommended
– Addition of rifampin to vancomycin is NOT recommended
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• MRSA Bacteremia (children)
– Vancomycin for 2 – 6 weeks
– Daptomycin 6-10 mg/kg once daily is an option
• Not a lot of evidence
– Clindamycin or linezolid should not be used if
there is a concern for endocarditis or if an
endovascular source of infection is suspected
– Data supporting the use of rifampin or gentamicin
is insufficient, choice to use is individualized
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• MRSA Pneumonia
– For HA-MRSA or CA-MRSA
• IV vancomycin
• IV/PO linezolid
• IV/PO clindamycin
– 7 – 21 days therapy
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• MRSA Pneumonia (children)
– IV vancomycin
– IV clindamycin
• if resistance rate is low
– IV/PO linezolid 600 mg q12h for ≥ 12 years
– IV/PO linezolid 10 mg/kg/dose q8h
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• MRSA Bone and Joint Infections (adults)
–
–
–
–
–
–
IV vancomycin
Daptomycin
Healthtap.com
TMP/SMX 4 mg/kg/dose q12h + rifampin 600 mg daily
Linezolid
Clindamycin
Some experts recommend rifampin to all of the
above, started after bacteremia has cleared
• 8 weeks of therapy for osteomyelitis, 3-4 weeks is
usually sufficient for septic arthritis
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• MRSA Bone and Joint Infections (children)
– IV vancomycin
– IV clindamycin
• If stable and clindamycin resistance is low
– IV Daptomycin
– IV Linezolid
• 4 - 6 weeks of therapy for osteomyelitis, 3-4
weeks is usually sufficient for septic arthritis
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Treatment
• MRSA infections in the CNS
– Vancomycin + rifampin
– Linezolid
– TMP/SMX 5 mg/kg/dose q8-12h
– Clindamycin does not penetrate the CNS
• Meningitis – 2 weeks
• Abscess, etc – 4 to 6 weeks
• Vancomycin for pediatrics
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Adjunctive Therapies
• Clindamycin and linezolid are NOT routinely
recommended as adjunctive therapy for the
management of invasive MRSA disease
• The use of adjunctive IVIG is not
recommended
• Some experts may consider these agents in
selected situations
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Vancomycin Dosing
• Adults
– 15 – 20 mg/kg/dose (actual body weight) q8-12h,
NTE 2 grams/dose is recommended with normal
renal function
– A loading dose of 25-30 mg/kg may be considered
in seriously ill patients
– Loading doses and larger doses should be infused
over 2 hours to minimize “red-man” reaction
• diphenhydramine
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Vancomycin Dosing
• Adults
– For most patients with SSTI who have normal
renal function and are not obese, traditional doses
of 1 gram q12h are adequate and serum levels are
not required
– For serious infections (bacteremia, endocarditis,
osteo, meningitis, PNA, and severe SSTI,
vancomycin trough levels of 15 – 20 mcg/ml are
recommended
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
Vancomycin Dosing
Vancomycin Dosing
• Why do we need these levels?
– AUC/MIC best relates to antibacterial effect of
vancomycin
– (AUC24)/MIC of ≥ 400 is the target
– This number can be achieved with trough levels of
≥ 15 mcg/ml
• When is this really important?
– MIC of vancomycin is > 1 mcg/ml
– More severe infections
Vancomycin Dosing
• What is the risk?
– There is an increased risk of nephrotoxicity seen
with vancomycin where troughs are > 15 mcg/ml¥
• Nephrotoxicity was defined as a rise in serum
creatinine of 0.5 mg/dl or a >50% increase from
baseline level for two consecutive labs
• An incidence of 29.6% was observed when trough
levels exceeded 15 mcg/ml
• What does this mean to us?
¥ Bosso
JA, Nappi J, et al. Antimicrobial Agents and Chemotherapy 2011;55(12):5475-9
Treatment Alternatives
(when MRSA won’t clear or vanco fails)
• High dose daptomycin (10 mg/kg/day) in
combination with gentamicin 1 mg/kg IV q8h,
rifampin, linezolid, or TMP/SMX
• If reduced susceptibility to vancomycin or
daptomycin are present,
quinupristin/dalfopristin, TMP/SMX, linezolid
or telavancin should be considered either
alone or in combination
David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):616-687
What else do we have?
• Tigecycline
– Protein synthesis inhibitor “souped-up doxy”
– Low serum levels and probably not effective for
pneumonia limit it’s use
• Quinupristin/dalfopristin
– Protein synthesis inhibitor
– Frequent side effects, drug interactions, limited
data in severe disease
What else do we have?
• New Lipoglycopeptides
– Developed by altering the structure of vancomycin
– Added a lipophilic “tail”, increasing the
antimicrobial activity, and a hydrophilic moiety,
improving the pharmacokinetics
• Telavancin (VIBATIV®)
• Dalbavancin
• Oritavancin
Zhanel GG, Calic D, et al. Drugs 2010;70(7):859-886
What else do we have?
• Telavancin (VIBATIV®)
– Two mechanisms of action
– FDA approved for SSTIs, HAP
– Non-inferiority trials with vs vancomycin
– Some concerns with nephrotoxicity
• Not as effective in patients with CrCl < 50
– Pregnancy test (problems in animal models)
– Active against VISA, not VRSA
Zhanel GG, Calic D, et al. Drugs 2010;70(7):859-886
What else do we have?
• Dalbavancin (investigational)
– Effective for SSTIs
– Once weekly dosing due to long half-life
• Oritavancin (investigational)
– May be dosed once for the course
– May also be effective vs VRSA
Zhanel GG, Calic D, et al. Drugs 2010;70(7):859-886
What else do we have?
• Fusidic acid
– A protein synthesis inhibitor
– Has been used effectively across the globe
– “Resurrected” for use in the U.S.
– Less active vs β-hemolytic strep
– Oral availability
Moellering, R, Corey G. Clinical Infectious Diseases 2011;52(S7):S467-S468
What else do we have?
• Ceftaroline (Teflaro®)
– FDA approved for CABP (Strep pneumo) and SSTIs
(MRSA)
– Not as effective vs resistant gram-negatives
• Ceftibiprole (investigational)
– MRSA activity, gram-negative activity similar to
cefepime
• Tedizolid (investigational)
– Shorter course and fewer side effects
Learning Outcomes
• Describe the clinical presentation and
diagnosis of MRSA
• Classify the therapeutic options available for
the treatment of MRSA
• Formulate a therapeutic plan for the
treatment of MRSA in various situations