Methicillinresistant Staphylococcus aureus: More patients, more treatments

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Methicillin-resistant Staphylococcus aureus
More patients, more treatments

• Marvin J. Bittner MD MSc
• Omaha, Nebraska

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MJB 11/75 Harvard statue
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Nosocomial bloodstream infections 1995-8
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Creighton 2002
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Nosocomial bloodstream species
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Preheim, ICHE 19878191
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MJB 11/75 Harvard statue
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MRSA 3 VAs 75 to 111 84
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MRSA 3 VAs 75 to 111 84
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VAs with MRSA Spread
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MJB about 1980
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VAs with MRSA Spread
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MJB JohnHarvard Statue2005
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MRSA in US ICUs 1989-2003
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Skin soft tissue infections 11 University ERs
8/04
Moran et al. N Engl J Med 2006355666
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Sternotomy infections ICU survival vs. days
after debridement
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MRSA A concern

• Gram-positive more common
• S. aureus major Gram-pos
• MRSA increasing to 50
• Impact of S. aureus

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ObjectivesBetter able to

• Recognize increasing impact MRSA
• Discuss key clinical issues MRSA, other S.
  aureus
• Describe most important clinical characteristics
  of MRSA drugs (some off-label use)

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MRSA in context

• Penicillinase-producing S. aureus
• MRSA features, infection control
• S. aureus eradication
• Community MRSA
• Coagulase-negative staphylococcus
• Vancomycin-resistant S. aureus

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Alexander Fleming penicillin
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Penicillinase-producing S. aureus
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MJB 4/16/50
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Penicillinase-producing S. aureus
Hospital
Community
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MJB 4/3/57
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Penicillinase-producing S. aureus
Hospital
Community
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MJB 6/10/72
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Penicillinase-producing S. aureus
Hospital
Community
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Coping with penicillinase

• Vancomycin Different class
• Nafcillin Stable to enzyme
• Clindamycin Other action
• Amoxicillin-clavulanate Enzyme inhibitor

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Mezlocillin rash
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Pen allergy overview
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Penicillin allergy

• Anaphylaxis? Avoid
• Consider skin testingbut time reagent
  preparation
• Cephalosporin cautiously
• Zosyn (piperacillin-tazobactam), Primaxin
  (imipenem) cross!

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Penicillinase-producing, non-MRSA S. aureus

• Parenteral nafcillin
• Spectrum
• No renal adjustment
• Uncommon neutropenia
• Oral dicloxacillin

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Methicillin-resistant S. aureus

• Penicillin-bind protein change
• Vancomycin reliable
• Caution S to tetracycline etc
• Newer drugs Synercid (quinupristin-dalfopristin)
  , Zyvox (linezolid), Cubicin (daptomycin),
  Tygacil (tigecycline)

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MRSA precautions

• Contact if entering room Gloves, gown
• More? Screening?
• Less? Standard?
• Out of isolation criteria vary

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Roccaforte, Decolonization
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47 eradication attempts
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Pre-op mupirocin (Bactroban)?

• Perl T. N Engl J Med 20023461871
• Twice daily 5 days to nares of 3864 patients
• General, GYN, cardiothoracic, neurologic surgery

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S. aureus surgical site infection
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891 (23) S. aureus colonized Surgical site
infection
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Medical patients mupirocin (Bactroban)?

• Heiman FL. Ann Intern Med 2004140419
• Twice daily 5 days to nares of 1602 S. aureus
  carriers
• Begun 1-3 days after admit

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S. aureus nosocomial infection
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Killer in the locker room
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Community MRSA

• Contrast with debilitated hospitalized patients
  Often ICU, surgery, antibiotics, exposed to MRSA
  patient
• Athletes, native Americans, gay men Los Angeles,
  prisoners, day care

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Pennsylvania college football

• Skin irritation
• Turf burn
• Body shaving
• Budget cuts, towel sharing

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MRSA after 10 days linezolid
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Community MRSA easier Rx

• Hospital Multi-resistant
• Community
• Resistant to beta-lactams
• Consider inducible resistance to clindamycin

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Penicillinase-producing S. aureus
Hospital
Community
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Key messages S. aureus

• Nearly all penicillinase-producing
• MRSA contact precautions
• Eradication limited success
• Community emerging Hygiene, non-beta-lactams

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Staphylococci Coagulase-negative vs. coagulase
pos.

• Coagulase usual test for
• S. epidermidis (negative)
• S. aureus (positive)
• Contrasting patterns of disease

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Coagulase-negative staph

• Infections of Bionic Man
• Line sepsis common
• Other devices, role of slime
• Immunocompromise
• Skin contaminant
• Many methicillin-resistant
• Vancomycin drug of choice

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Fear Vancomycin-resistant Staphylococcus aureus

• Intermediate report 1999 US
• More virulent, more common than enterococci
• Very limited drugs for serious infections
• Use vancomycin sparingly

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Vancomycin-resistant Staphylococcus aureus, 2002

• VRSA MIC gt 32 mcg/ml
• MI diabetic dialysis patient given vancomycin for
  MRSA
• VRSA catheter site infection, had VRE VRSA in
  foot ulcer
• vanA gene in VRSA from VRE

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MRSA Drugs Highlights

• Vancomycin (Vancocin)
• Quinupristin-dalfopristin (Synercid)
• Linezolid (Zyvox)
• Daptomycin (Cubicin)
• Tigecycline (Tygacil)

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Vancomycin

• Large molecule, only iv (po is nonabsorbable for
  C. difficile)
• Cell wall
• Red man syndrome
• Levels controversy
• Use sparingly

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Red man syndrome

• Erythema, hypotension
• Prevent Infuse 60 min or longer
• Not allergy

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Advice on vancomycin dosing

• Usually 1 g iv q 12 hr
• Levels for infrequent dosing in renal
  insufficiency
• Target uncertain
• Trough lt 10?
• Peak gt 15?

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(No Transcript)
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Key messages Vancomycin

• Infuse 60 min or longer to prevent red man
  syndrome
• Routinely, no levels
• Use sparingly to reduce risk of
  vancomycin-resistant S. aureus

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Quinupristin-dalfopristin mechanism Protein
synthesis

• Contrast
• Quinolones DNA synthesis
• Penicillins Cell wall
• Varied protein synthesis inhibitors
  Erythromycin, clindamycin, gentamicin

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Quinupristin-dalfopristin uses (not all are FDA
indications)

• Enterococcus faecium, not E. faecalis (but most
  VRE is E. faecium)
• Methicillin-resistant Staphylococcus aureus
• MRSE, S. pyogenes

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Quinupristin-dalfopristin administration

• IV only
• Generally given through central line to reduce
  risk of phlebitis

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Quinupristin-dalfopristin inhibits CYP 3A4.
Expect increases in some drug levels. A few
examples

• Midazolam (Versed), short-acting benzodiazepine
• Also, lovastatin, cyclosporine, carbamazepine

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Quinupristin-dalfopristin toxicity, cost

• Phlebitis common
• Abnormal liver tests seen in high doses in
  investigational trials, joint pain
• About 180/day

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Key messages Quinupristin-dalfopristin

• Inhibits protein synthesis
• E. faecium only (most VRE)
• Generally central line
• Phlebitis risk

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Linezolid mechanism Protein synthesis
initiation

• Contrast
• Quinolones DNA synthesis
• Penicillins Cell wall
• Varied protein synthesis inhibitors
  Erythromycin, clindamycin, gentamicin

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Linezolid uses (not all are FDA indications)

• Enterococcus faecium, E. faecalis
• Methicillin-resistant Staphylococcus aureus
• Also, S. pyogenes S. agalactiae

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Linezolid administration

• IV or PO 600 mg bid
• About 100 bioavailable

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MRSA nosocomial pneumonia clinical cure
plt0.01
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MRSA ventilator-associated pneumonia clinical cure
plt0.001
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MRSA nosocomial pneumoniasurvival
P0.025
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MRSA ventilator-associated pneumonia survival
P0.02
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Bittner Funeral Chapel,Mitchell, SD 7/05
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Linezolid controversy

• Flawed statistics
• Superior only in MRSA
• Reserve for vancomycin intolerance resistant
  enterococcus . . . or widespread drug resistance

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MRSA nosocomial pneumonia Linezolid gt vancomycin?

• Anti-S. aureus drugs vary
• Not due to chance
• Biological explanation
• Consistent with other studies
• Vancomycin dose correct

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Do anti-Staphylococcus aureus drugs vary in
efficacy?

• 2003 Red Book on empiric Rx life-threatening S.
  aureus Start both vancomycin nafcillin
• ID expert preferences
• MSSA nafcillin over vanco
• MRSA vancomycin over trimethoprim-sulfamethoxazo
  le

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Success in MITT MRSA bacteremia, including
endocarditis
P0.22
20 of 45
14 of 44
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Not due to chance?

• Subset analysis, but logistic regression corrects
  for known confounders
• Post hoc analysis, but heuristic value

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Linezolid concentration vs. MIC90 Staphylococcus
aureus
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MRSA infections Lower extremity complicated
skin/soft tissue

• Vanc Line
• Clin cure/improve 43 97
• Amputations 7/30 0/30
• Median stay 6 d 3 d
• Median outpt qd 200 103
• Sharpe, Am J Surg 2005189425

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MRSA complicated skin soft tissue infections
micro cure
plt0.05
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Weigelt subset Surgical site infections

• Vanc Line
• Clin cure 87 98
• p 0.06
• MRSA micro cure 48 87
• p 0.0022
• Weigelt, Am J Surg 2004188760

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Diabetic foot infections Infected ulcers
clinical cure
plt0.018
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Vancomycin dose correct?

• Linezolid superior to 1 g q 12 Controlled
  trials
• Concept Higher vanco levels More efficacy, no
  toxicity
• Controlled trials vs. concept

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Linezolid controversy

• Flawed statistics, but trend seen
• Superior only in MRSAsicker
• Reserve for vancomycin intolerance resistant
  enterococcus . . . or widespread drug
  resistancejudicious use
• Not promoted as superior

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Linezolid concerns

• Resistance, especially with retained objects,
  abscesses
• Theoretical serotonin syndrome with SSRIs,
  absent in trials
• Need weekly CBCs (thrombocytopenia)
• Neuropathy in prolonged use

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Key messages Linezolid

• Inhibits protein synthesis
• E. faecium, E. faecalis, MRSA
• 100 bioavailable
• Superiority MRSA nosocomial pneumonia
• Monitor CBC, especially platelets

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Daptomycin (Cubicin)

• Large molecule C72H101N17O26 (only iv)
• Unique mechanism (membrane depolarization, rapid
  death)

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Killing of MRSAlog10 colony-forming units/ml as
a function of time in hours
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Killing of MRSAlog10 colony-forming units/ml as
a function of time in hours
Growth control
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Killing of MRSAlog10 colony-forming units/ml as
a function of time in hours
Growth control
Linezolid
Quinupristin-Dalfo
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Killing of MRSAlog10 colony-forming units/ml as
a function of time in hours
Growth control
Linezolid
Quinupristin-Dalfo
Vancomycin
Daptomy
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Daptomycin (Cubicin)

• Large molecule C72H101N17O26 (only iv)
• Unique mechanism (membrane depolarization, rapid
  death)
• Myositis if too frequent dose, check CPK weekly

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Daptomycin indications

• Complicated skin skin structure (not pneumonia)
• MSSA, MRSA
• Streptococcus pyogenes, S. agalactiae, other
  strep
• Vancomycin-susceptible Enterococcus faecalis

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Daptomycin indications

• Staphylococcus aureus bacteremia
• Including right-sided endocarditis
• MSSA, MRSA

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Daptomycin in vitro other Gram positives

• Corynebacterium jeikeium
• Enterococcus faecalis (VRE)
• E. faecium (including VRE)
• Staphylococcus epidermidis (including
  methicillin-resistant strains)
• Staphylococcus haemolyticus

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Daptomycin pharmacology

• Half-life 8-9 hr, given 4 mg/kg q 24 hr
• No CYP 450 interactions
• 78 in urine, reduce dose if creatinine clearance
  lt 30 cc/min

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Daptomycin in S. aureus endocarditis bacteremia

• 235 pts modified intent to treat
• 38 MRSA
• 23 endocarditis, 51 complicated bacteremia
• 139 patients per protocol

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Daptomycin in S. aureus endocarditis bacteremia

• 6 mg/kg qd daptomycin
• Semi-syn penicillin or vanco that arm also got
  gent 1st 4 d

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MITT Modified Intent to Treat

• Randomized
• Got at least 1 dose study drug
• Excludes those with high likelihood of left-sided
  endocarditis who were enrolled before a protocol
  amendment allowed their inclusion

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Success in MITT MRSA bacteremia, including
endocarditis
P0.22
20 of 45
14 of 44
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Daptomycin adverse events

• Generally similar to comparators
• General issues
• C. difficile colitis
• Alert for myositis

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Key messages Daptomycin

• Previous myositis
• Give once daily
• Rapid killing in vitro
• Trend toward superiority in S. aureus bacteremia,
  endocarditis

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Tigecycline mechanism Protein synthesis

• Contrast
• Quinolones DNA synthesis
• Penicillins Cell wall
• Varied protein synthesis inhibitors
  Erythromycin, clindamycin, gentamicin

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Tigecycline activity (not all are FDA
indications)

• Vancomycin-resistant enterococci
• Methicillin-resistant Staphylococcus aureus
• Resistant Gram-negatives, eg Acinetobacter
  baumanii
• Anerobes

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Tigecycline administration

• IV only
• 100 mg loading, then 50 mg q 12 hr
• t½ 42 hr

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Adverse events
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Key messages Tigecycline

• Inhibits protein synthesis
• Active vs. many resistant organisms
• Limited clinical data
• 29 nausea, 19 vomiting

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Key points MRSA impact

• 50 many hospitals
• Need to treat empirically when suspect severe
  infection
• Decolonization questionable because of limited
  efficacy
• Contact precautions

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Key points Community MRSA, MSSA, VISA, VRSA

• Community MRSA more susceptible
• MSSA often nafcillin, others
• Fear of VISA, VRSA Use vancomycin sparingly

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Key points Coagulase-negative staphylococcus,
VRSA

• Coagulase-negative staph Contaminant, bionic
  man, immunosuppressed often methicillin-resistant
  
• Limited reports vancomycin-resistant S. aureus

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Key points Vancomycin, quinupristin-dalfopristin

• Vancomycin
• Infuse 60 min or more
• Levels controversial
• Quinupristin-dalfopristin
• Central line
• Cost

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Key points Linezolid, daptomycin

• Linezolid
• IV and oral
• Superior MRSA pneumonia
• Daptomycin
• Daily IV
• Rapid killing in vitro
• Skin, S. aureus bacteremia

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Key points Tigecycline

• Tigecycline
• Active vs. MRSA, many resistant organisms
• IV only
• Nausea, vomiting

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MRSA in US ICUs 1989-2003
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FDA-approved MRSA drugs